This document is the Accepted Manuscript version of a
Published Work that appeared in final form in ACS Nano,
copyright © American Chemical Society after peer review and
technical editing by the publisher. To access the final edited
and published work see:
https://dx.doi.org/10.1021/acsnano.9b08133.
Nanomaterials for Nanotheranostics: Tuning Their

Properties According to Disease Needs

Xin Yi Wong†,‡, Amadeo Sena-Torralba†, Ruslan Álvarez Diduk†, Kasturi Muthoosamy§,*,

Arben Merkoçi†,ǁ,*
†
    Nanobioelectronics & Biosensors Group, Catalan Institute of Nanoscience and

Nanotechnology (ICN2), CSIC and BIST, Campus UAB, Bellaterra, 08193 Barcelona, Spain
‡
    Department of Chemical & Environmental Engineering, Faculty of Engineering, University

of Nottingham Malaysia, 43500 Semenyih, Selangor, Malaysia
§
    Nanotechnology Research Group, Centre of Nanotechnology and Advanced Materials,

University of Nottingham Malaysia, 43500 Semenyih, Selangor, Malaysia
ǁ
    ICREA, Institució Catalana de Recerca i Estudis Avançats, Pg. Lluis Companys 23, 08010

Barcelona, Spain




*Address correspondence to: kasturi.muthoosamy@nottingham.edu.my,

arben.merkoci@icn2.cat
TABLE OF CONTENTS GRAPHIC




ABSTRACT

Nanotheranostics is one of the biggest scientific breakthroughs in nanomedicine. Most of the

currently available diagnosis and therapies are invasive, time-consuming and associated with

severe toxic side effects. Nanotheranostics, on the other hand, has the potential to bridge this

gap by harnessing the capabilities of nanotechnology and nanomaterials for combined

therapeutics and diagnostics with markedly enhanced efficacy. However, nanomaterial

applications in nanotheranostics are still in its infancy. This is due to the fact that each

disease has a particular microenvironment with well-defined characteristics, which promotes

deeper selection criteria of nanomaterials to meet the disease needs. In this review, we have

outlined how nanomaterials are designed and tailored for nanotheranostics of cancer, and

other diseases such as neurodegenerative, autoimmune (particularly on rheumatoid arthritis)

and cardiovascular diseases. The penetrability and retention of a nanomaterial in the

biological system, the therapeutic strategy used and the imaging mode selected are some of

the aspects discussed for each disease. The specific properties of the nanomaterials in terms

of feasibility, physicochemical challenges, progress in clinical trials, its toxicity and their

future application on translational medicine are addressed. Our review meticulously and
critically examines the applications of nanotheranostics with various nanomaterials, including

graphene, across several diseases; offering a broader perspective of this emerging field.



KEYWORDS

nanotheranostics, nanomaterials, cancer, solid tumor, liquid tumor, neurodegenerative

diseases, autoimmune diseases, cardiovascular diseases, clinical trials, graphene



John Funkhouser, the PharmaNetics president and CEO, was credited by scientists in year

2002 for introducing the term theranostics (a portmanteau of Therapeutics and Diagnostics),

which epitomes the development of nanoparticle system for personalized medicine.1,2

Theranostics (or theragnostics) refers to comprehensive effort that integrates diagnostic and

therapy in a single system/platform.3,4

With the emergence of nanotechnologies and nanomaterials, the concept of nanotheranostics

was then introduced (Figure 1). Nanotheranostics was able to provide non-invasive imaging,

targeting and therapy at the disease sites, without affecting surrounding healthy cells.3,5

Hence, the use of empirical treatment can be avoided (therapy given based on experience,

usually without a prior definitive medical diagnosis and likely to cause infectious disease),

greatly improve the prognoses and subsequently expedite clinician’s therapeutic decisions.

Therefore, early diagnosis will increase the patient’s survival rate, and the optimized

treatment will contribute to high therapeutic efficiency along with best safety profile.3,6

Furthermore, over-dosing of drugs and cost of treatment can be effectively reduced.

Nanotheranostics will also enable real-time monitoring of the drug release and its

biodistribution in patients.7

Nanomaterials can be broadly categorized according to their composition, such as metal,

carbon, inorganic and organic nanoparticles (NPs).8,9 Generally, theranostic nanomaterials
can be made up of different chemical constructs: targeting moiety (for specific cellular

binding), therapeutic agents (for drug delivery), diagnostic agents (for non-invasive imaging),

and polymer coating or matrix that imparts colloidal stability and provide functional groups

for bio-conjugation.3,6 Some of the important advantages of nanomaterials are undoubtedly

their small size and large functional surface area to volume ratio, in addition to interesting

optical and electrical properties. These properties allow the diagnostic and therapeutic agent

to be adsorbed, dissolved or covalently attached to the surface, to form nanoparticle-

drug/imaging/targeting complexes.10 The complex can subsequently signal (diagnostics) and

deliver the agents to the cancer cells or other targeted sites to perform the therapy.11,12

Ideally, after the controlled release of encapsulated drug molecules, the residual nanoparticle

will be safely degraded and excreted from the body.10

Recently, the application of nanomaterials with multiple physical imaging modalities and

therapeutic capabilities has received increasing attention. There are several excellent review

papers with similar topics made, 8,13–17 however, these papers are either focused on specific

disease/cancer/illness, or emphasized on the theranostic properties of a specific nanomaterial.

In this review, we stratify the information on the basis of cancer- or disease-specific, enabling

comprehensive comparison of the nanomaterials for theranostics of up to three different

diseases. Specifically, we focus on the nanotheranostics of cancer (including solid and liquid

tumor) and several diseases: neurodegenerative, autoimmune and cardiovascular diseases (see

Table 1). The physiochemical properties of various nanomaterials, including graphene, a

rising star in the 21st century, have been critically reviewed. We also discuss the physical and

biological barriers that impede application of nanotheranostics in vivo, and provide an

overview of different nanomaterials that are currently in clinical trials. A future outlook of

this rapidly growing field will be given as a conclusion. By putting this information together,

this review may shed light on understanding nanomaterials for nanotheranostics while we are
expecting continuous breakthrough in this field.




Figure 1 Nanotheranostics: The use of nanomaterials with integrated diagnostic and

therapeutic properties across several diseases.


Physical and biological barriers that impede the application of nanotheranostics in vivo

The human body has multi-tiered physical, physiological, chemical and biological barriers to

protect it against foreign species/substances. Examples of the barriers that nanomaterials may

encounter in biological systems are the skin, air-blood barrier in the lungs, reproductive

system, circulation and blood-brain barrier.18,19 Nanomaterials must be precisely engineered

to overcome these biological barriers and perform nanotherapeutics at the disease site.20

While it is important to find a balance between therapeutic potential and toxicity of

nanomaterials, their biological effects on human body are not fully understood due to the

complexity of nanomaterial/biological barrier interaction.

In this section, we will discuss the interactions of nanomaterials with serum proteins and

mononuclear phagocyte system (MPS) in the tumor microenvironment, and provide an

overview of the barriers to the intratumoral delivery of therapeutic nanomaterials.

(i) Interaction of nanomaterials with serum proteins

When nanomaterials circulate throughout the body they are exposed to a complex fluid

containing blood, lymph, biomolecules, cytoplasm, etc.21,22 Protein and other biomolecules
such as albumin, transferrin, gamma globulin and fibrinogen, will compete for binding on the

surface of nanomaterials. This will slightly change the secondary structure of the proteins and

lead to the formation of both soft and hard protein corona.22–24 Formation of protein corona

on nanomaterials will affect the surface of nanomaterials and their subsequent interaction

with biological molecules (biodistribution and penetrance) and cellular compartments.18,25

The composition, properties and formation of protein corona are influenced by

physiochemical properties (size, shape, surface area, charge, chemical composition,

functionalization, colloidal stability, porosity, etc.) of nanomaterials. Nanomaterials could

exert both positive (act as carriers to immobilize enzyme, improve activity and stability of

proteins) and negative impacts (induce potential toxicity to cells and organs) on proteins.26

Supramolecularly built protein corona can also be exploited to shield nanomaterials’

interaction with serum proteins and macrophages while retaining its targeting specificity in

vitro and in vivo.24

Positively charged nanomaterials facilitate cellular uptake and improve lysosomal escape

without induction of toxicity, showing more specific interaction with negatively charged

biological membranes.18 Single-layer and multi-layered graphene oxide have been proven to

exhibit different behaviors in cell culture medium.27 The various types of carbon

nanomaterials (fullerene, carbon nanotubes, graphene and their derivatives) have particular

effects on the structure or activity of the proteins. For instance, the graphene sheet has a

stronger adsorption capacity for serum proteins than carbon nanotubes. Yet, the enzymatic

degradation of graphene and fullerenes derivatives is much complicated than carbon

nanotubes.26

The individual and in combination properties of nanomaterials play an important role in

determining their path, biological effect and immunological fate in biological systems.

(ii) Interaction of nanomaterials with MPS
One of the factors for low drug-delivery efficacy to the tumor and low therapeutic outcomes

is due to the MPS. The MPS mainly involves liver, spleen and lymph nodes. MPS serves as a

delivery barrier for invading pathogens, particulates and dead or damaged host cells.28

Among the MPS, Kupffer cells are the major phagocytic cells (e.g. macrophages) residing

inside the liver sinusoid.23 In principle, cationic nanomaterials have higher affinity for

macrophages than neutral and anionic nanomaterials.23 Attachment of surface protein, such as

opsonins on the nanomaterials may increase the chance of nanomaterials being recognized by

the scavenger receptors on the Kupffer cells. This will result in opsonisation and subsequent

phagocytosis.18,19,23 The nanomaterials will be ultimately taken up and cleared by

macrophages. Generally, MPS cuts off more than 95 % of the administered nanomaterials.23

Mammalian cells engulf intracellular contents using autophagosome, a double-membrane

vesicle, fuse with lysosomes, and later degrade or recycle the autophagic contents. This

process is known as autophagy.25 Autophagy is vital in maintaining the homeostasis of cells.

Dysregulation of autophagy in degrading overexpressed prions proteins may lead to

neurodegenerative disorders; while active autophagy aids in chemotherapeutic treatments of

cancer cells.25 Fe3O4 NPs were found to have the ability to induce autophagy in human

cervical carcinoma cells. Positive correlations between size/molecular weight of protein and

adsorption of protein on a 20 nm Fe3O4 NPs were confirmed.25 However, the higher the

adsorption of protein on Fe3O4 NPs, the lower the cell uptake of NPs and consequently lower

cell autophagy responses.25

An increase in the dosage of nanomaterials, on the other hand, raises toxicity concerns

induced by the accumulation of nanomaterials in organs such as liver and spleen.23 Solvents

and chemicals involved during the synthesis of nanomaterials are one of the causes of toxicity

in vivo.17 Their long-term cytotoxicity and related immune response should be taken into

consideration.
Four strategies (surface modification, tuning of physiochemical properties of nanomaterials,

biomimetic design inspired by nature and modulation of the MPS) have been identified to

oppose uptake by the MPS, lower off-target rate and enhance cancer therapeutic efficacy.23

For instance, modifying the surface of nanomaterials with zwitterions, polyethylene glycol,

carbohydrate moieties and dysopsonic proteins allow bypass of phagocyte-mediated cellular

barriers, which in turn increases nanomaterials blood circulation time and theranostics

efficacy.24 Another interesting strategy to protect the nanomaterials from phagocytosis is by

using the extracts of cell membranes from blood or tumor cells. The extracts can be used to

coat the nanomaterials, camouflaging the nanomaterials from uptake by the MPS.

(iii) Barriers of intratumoral delivery

Tumor microenvironment is generally composed of tumor cells, the extracellular matrix,

stromal cells, cells from the immune systems (macrophages, lymphocytes, natural killer

cells), etc.12,19 Macrophages act as immune cells to maintain immunohomeostasis. The failure

of existing therapies is mainly attributed to the tumor microenvironment limiting drug access

to the tumor cells.12,29 This is because upon entering through the blood vessel leakage,

nanomaterials would interact with the microenvironment factors.

The intratumoral microenvironment serves as a physical and biological barrier for the

delivery of therapeutic nanomaterial to the solid tumor (e.g. pancreatic cancer).18 In normal

tissues, the extracellular matrix is loose and elastic, with sufficient oxygen supply, and the

overall redox environment is homeostasis.30 In contrast, the basement membrane in the tumor

is thicker, with higher cross-linked extracellular matrix, hypoxic, acidic and has harsh redox

environment.31,32 Differentiated macrophages, named as M2-type tumor-associated

macrophages, will trap and degrade the functional nanomaterials delivered into the tumor.30

High tumor interstitial fluid pressure will also force the nanomaterials back to blood
circulation, further preventing them from reaching the tumor sites.30 These

pathophysiological properties greatly impede intratumoral delivery of nanomaterials.

Dissolution (or generation of metal ions in target organs and cellular barriers), is another

common phenomenon in metal and metal oxide nanomaterials in biological systems due to

their high surface area and reactivity.18 Different strategies, such as the use of stromal

depletion molecules, targeting of transforming growth factor-beta (TGF-β) and interleukin-6

(IL-6) pathways, etc. have been studied to overcome the stromal barrier.18,33,34 Pei et al.

(2019)29 also demonstrated that simultaneous targeting of both TGF-β signaling and KRAS

mutation attenuates the dense stroma barrier, enhances tumor blood perfusion and improves

therapeutic efficiency in pancreatic cancer.

In short, it is important to understand the interaction between nanomaterials and tumor

microenvironmental factors before constructing functional nanomaterials that are expected to

be able to overcome the above-mentioned challenges.



CANCER

Cancer is a broad name given to the diseases featured with uncontrolled rapid cell division

that may form growths called tumors. Nobel Laureate Otto Warburg discovered that low

oxygen was a hallmark of cancer cells. Cancer cells “reprogram” themselves under stressful

conditions (lack of oxygen, limited nutrient resources or energy, etc.), with a faster growth

rate than the rate of new blood vessel formation.35,36

Cancer can be further classified into solid and liquid tumors, each with differences in terms of

their tumor vascularity and heterogeneity, thus requiring different diagnostic and targeting

strategies.37 For centuries, surgery, chemotherapy and radiation therapy remain as the most

common cancer therapies. However, these few alternatives often come with the possibility of

recurrence after the treatment (since not all cancer cells can be completely removed by
surgery), severe toxic side effects (chemotherapy and radiotherapy) and limited specificities

to cancer cells.38,39 Due to their low molecular weight, conventional chemotherapeutic drugs

generally have low half-lives in the blood and are rapidly distributed in healthy tissues and

organs, limiting their therapeutic efficacy.40 Furthermore, the use of centralized diagnostic

platform in most of the cancer management can be complex, time-consuming and not tailored

to patients and malignancies.37

Theranostic nanomedicine possess the ability for specific cancer biomarker detection and

concurrent cancer cells ablation, in a simple and non-invasive way, making them suitable

candidates for nanotheranostics.37 For instance, the nanomedicine can be delivered and

accumulated at the tumor sites to perform therapeutic action. Yet, the drug delivery is still

limited in poorly vascularized regions, some cancer cells are able to continue

proliferating.10,39 In contrast, liquid tumors (such as leukemia and lymphoma) are spread

throughout the bloodstream, its diagnostics and therapies are often challenged by poor

selectivity, low therapeutic efficacy, multi-drug resistance and long-term side effects.37

Tumor microenvironment varies between cancer types of different or the same anatomical

region.12 The discovery of the right diagnostics and therapeutics intervention is highly

important in cancer treatments.

Continuous research efforts in nanotheranostics from drug delivery vesicles to imaging of

contrast agents and targeting modalities have rapidly driven nano-oncology towards an all-in-

one, localized early detection and treatment. This section will comprehensively review the

recent advances regarding the development of different therapies (besides chemotherapy) and

imaging modalities (such as optical, photoacoustic imaging, magnetic resonance imaging

(MRI)) for solid and liquid tumors diagnosis and treatment, using functional nanomaterials.
Solid tumor

Solid tumor is an abnormal mass of tissues, may be benign (non-cancerous) or malignant

(cancerous). Examples of solid tumors are carcinomas (tumors formed in epithelial cells) and

sarcomas (tumors in blood vessels, bones, fat tissues, muscles, etc.).

Hypoxia, a condition in which the body tissues are deprived of oxygen, mainly due to the

disorganized vasculature and poor blood circulation, is an important characteristic of solid

tumors.41,42 The hypoxia microenvironment may confer the resistance of tumors to cancer

treatment,31 especially photodynamic therapy (PDT), an externally activable and oxygen-

dependent therapeutic modality.38 PDT works by using cytotoxic oxygen species (such as

singlet oxygen or reactive oxygen species (ROS)) generated from photosensitizer molecules

upon light exposure, which destruct tissue structure and subsequently kill cancer cells.41

Besides, solid tumors are 2-3 times more radio-resistant than normoxic tumors.43 Hence, the

hypoxic and radio-resistance nature of solid tumors cause the cancer treatment even more

challenging.44

Intracellular environment of tumor cells is also rich in hydrogen ions (H+) and hydrogen

peroxide (H2O2) due to rapid glycolytic metabolism and superoxide dismutase over-

expression.45 This contributes to the weakly acidic extracellular pH (pH 6.0-6.8) in tumors, in

contrast to weakly basic normal tissues (pH 7.2-7.4).5,41 Hence, an ideal solid tumor

theranostic nanomaterial should be sensitive enough to respond to the minute difference in

extracellular pH between blood and tumors.46 Other common cancer phenotypes are high

abundance of antioxidants and elevated glutathione (GSH) level (about 4-fold higher than

normal cells).5,39,42

In addition, the original size of the nanocarrier should be maintained below 160 nm for

optimum deposition on the tumor tissues and exploit the enhanced permeability and retention

(EPR) effect.47 EPR is a phenomenon where nanomedicine leaks preferentially into tumor
tissue, through the permeable tumor vasculature. The nanomedicine will be retained in the

tumor bed owing to the reduced lymphatic drainage.36,48 EPR effect aids in the delivery (with

a relatively modest effect of less than a 2-fold increase) and accumulation of nanomedicine at

the solid tumors, and subsequently improves the therapeutic efficacy.23,32,49 The potential side

effects are greatly reduced, since there is very low accumulation of nanomedicine within the

normal tissue.36 The ability of the NPs to cluster into large size aggregates after successful

cellular internalization could prevent the lysosomal exocytosis, which may minimize the loss

of their therapeutic activity.47 Nevertheless, the drug delivery remains limited in poorly

vascularized regions of the tumors, some cancer cells are still able to survive.10,18,32 Also, the

efficiency of EPR effect is highly dependent on cancer type.18

Researchers have been putting efforts to design and tailor different stimuli-responsive

nanomaterials to overcome multiple biological and physiological barriers in drug delivery,

and simultaneously serve as a nanotheranostic platform for cancer. The following section

provides comprehensive review on the nanotheranostic features of each nanomaterial,

together with their advantages and limitations.


Gold nanostructures

Gold (Au) nanostructure is a collective term given to different shape of gold nanoparticles

(AuNPs). It has received increasing attention for being able to provide a versatile and

multifaceted platform for biomedical applications.38,49–51 Apart from having excellent

biocompatibility and facile surface chemical features, Au nanostructures are able to act as

photothermal transducers. They are capable of absorbing visible or NIR radiation and then

convert them into heat with high efficiency to destroy nearby biological structures (coined as

photothermal therapy, PTT).31,41,42,45,47 The potential side effects of using Au nanostructures

for cancer treatment can be reduced to minimum by controlling the intensity of light and
amount of injected nanomaterials, making it a highly selective material in cancer

treatment.17,52–55

Hepatocellular carcinoma (HCC), a type of solid tumor, is the most common primary liver

cancer.56 Being the third leading cause of cancer death worldwide, HCC has often been

chosen as the focus of many clinical research.57,58 HCC tumors, like other solid tumors, have

scant stroma and necrosis in the central area due to poor vascularization. HCC is nodular and

can either appear as a single solitary tumor with a large mass or multiple small tumors.56 A

tumor microenvironment responsive and triple-synergistic therapeutic nanoplatform based on

AuNPs with Cu (II)-aptamer complexes has been developed for HCC treatment [Figure 2a

(ii)].41 Aptamer is a small and easy to synthesize secondary structure ligand made up of single

DNA or RNA sequence. Aptamers confer lower immunogenicity and have high targeting

affinity to cell surface receptors,59 whereas chlorin e6 (Ce6) is a widely used

photosensitiser.38,60 Possessing high singlet oxygen generation capability, Ce6 labelled

aptamer has been chosen to specifically target the HCC cells and activate PDT. The binding

of Ce6 labelled aptamer onto AuNPs not only avoids rapid clearance of AuNPs from the

body, but also serves as a cargo for the Cu (II) coordinated chemotherapeutic prodrug AQ4N

(or banoxantrone, a hypoxia activated prodrug to enhance anti-tumor effects). The high level

of intracellular GSH and acidic extracellular pH in cancerous cells induce the release of the

AQ4N. The electrostatic aggregation of AuNPs induced by the free Cu (II) also switches on

the PTT effects to ablate solid tumors. This system successfully permits the synergistic

PDT/PTT/chemotherapy of HCC by single laser irradiation at 670 nm.41 However, this

approach has some limitations especially when selecting AQ4N as the prodrug. Since AQ4N

has ultra-high aqueous solubility (260 mg/mL), large dose and multiple dosing (≥ 100 mg/kg)

are required during combination therapy.61 Although the potential side effects of AQ4N

loaded nanomedicines have not been reported thus far, low AQ4N loading content and
encapsulation efficiency, non-specific release and short-term in vivo retention time (half-life

in vivo ≤ 6 h) are some of the concerns.

On the other hand, it is technically difficult to keep photoirradiation localized only on cancer

cells due to uncontrollable distribution of the photothermal agents in the intracellular micro-

environment.62 Alternatively, laser beam allows precise focusing to a tiny region of tumor

cells. It has therefore been used as a stimulus to cross-link photothermal AuNPs covalently

with the surface diazirine groups of polyethylene glycol (PEG) ligands [see Figure 2a (i)].63

Upon 405 nm laser irradiation, diazirine groups generate a highly active carbene intermediate

that can form covalent bonds with ligands within close proximity of AuNPs. The interparticle

cross-linking of AuNPs has significantly improved photothermal ablation effects, with an

optical-thermal conversion efficiency of about 78.8 % as compared to 21.6 % for the non-

cross-linked AuNPs. This innovative approach has effectively shifted the surface plasmon

resonance of 20.5 nm AuNPs to NIR region. It was also noted that the as-synthesized

photocross-linked AuNPs have longer blood circulation time and shorter biological half-life

than particle aggregates.63 Nevertheless, the penetration depth of 405 nm laser remains

limited. In fact, for in vivo imaging application, the chosen NPs need to have the ability to be

imaged at greater tissue penetration depth (including thick bone penetration for imaging of

brain tumors, air-filled cavities for imaging of lung tumors, etc.), without compromising the

spatial resolution.17,39,64 NIR shows better penetration depth in the tissue than visible light,

yet, its clinical utility is still hindered due to auto-fluorescence, potential blink, scattering and

photobleaching effects in various tissues.54,59 In fact, it is difficult to compare and evaluate

the efficacy of different Au nanostructures in nanotheranostics, as their behavior is highly

dependent on various parameters, such as size, shape and surface functional group.65 Au

nanocages, with cubic shape, are particularly attractive as photothermal transducers for

nanotherapeutics, owing to their interesting features such as flexible tuning of the localized
surface plasmon resonance (LSPR) peaks to any wavelength of interest (in the range of 600-

1200 nm) and a large NIR absorption cross section (five orders of magnitude greater than the

conventional organic dyes). With a compact size of about 40 nm, the hollow and porous

structures of Au nanocages permit drug encapsulation with controlled release upon irradiation

with NIR light.52 In another study, it was reported that cationic NPs exhibit superior cellular

internalization, but inferior systemic circulation compared to their anionic and neutral

counterparts 46. In view of this, the idea of integration of photothermal Au nanocages with

zwitterionic stealth ligand has been proposed. As aforementioned, zwitterionic medication

endows NPs with surface properties resistant to aggregation, binding plasma proteins and

macrophage uptake, prolonging blood circulation time.59 Zwitterionic polymers coated on Au

nanocages has successfully extended the NPs’ systemic circulation lifetime by 4-fold, without

compromising its cellular internalization, breast tumor targeting ability and PTT efficacy.

Sensitive to the changes in cell’s extracellular pH, the zwitterionic ligands on Au nanocages

switch from “zwitterionic” at physiological pH (7.0-7.4) to “cationic” at acidic pH ( 6.5).

Triggering of this charge reversal makes the NPs attach to the surface of cancer cells, leading

to targeted accumulation within tumors.46

Cervical cancer is the fourth most common cancer in women and has the fourth highest

mortality rate (among cancers in women).66 Additionally, it is a solid tumor associated with

human papillomavirus infection.66 An example of synergistic PTT and drug delivery for

cervical cancer is the use of multi-layered single-walled carbon nanotubes, termed

SWNT@BSA@Au-S-PEG-FA@DOX, which was prepared using a facile layer-by-layer

assembly process.67 Carbon nanotubes display hemodynamic properties as its shape greatly

affects its circulation time and biodistribution. 68 For example, the needle-like morphology of

nanotubes contributes to increased specific area for interaction with plasma proteins and

cells; permits cell penetration via both endocytosis and diffusion across the plasma
membrane; and allows longer circulation time (up to 10 times longer) in blood, as compared

to spherical nanomaterials.69 Coating of bovine serum albumin (BSA) on oxidized and cut-

single-walled carbon nanotubes (SWNTs) provides abundant active sites for the nucleation of

Au seeds, subsequently converting Au into AuNPs by in situ reduction. Possessing ideal

photothermal properties, the SWNT@BSA@Au was further modified with folic acid

terminated-polyglycol (FA-PEG-SH), which endows the material with high water-

dispersibility, biocompatibility and selectivity towards human cervical cancer cells.

Doxorubicin (DOX) was subsequently loaded onto the system, with a high loading ratio of up

to 590 %. The resulting complex exhibited high efficacy, especially when combined with

PPT (irradiation of the tumor with a 808 nm laser, 1 W/cm2 or 5 min, 24 h after systemic

injection of the nanomedicine). Besides, release of DOX is induced by the pH value and

temperature in the tumor microenvironment, adding selectivity to the system. The system

completely eradicated tumors in vivo without systemic toxicity, as substantiated by several

hematological and biochemical parameters and histopathological analysis.67 However, it is of

utmost importance to note that the usage of high laser irradiance (1-48 W/cm2) is practically

not applicable for clinical treatment of tumors, as they exceed the skin tolerance threshold

values (maximum permissible exposure of skin at 808 nm is 350 mW/cm2, with an exposure

time of 10-1000 s).70 Future studies can be focused on the interactions between SWNTs and

actual biological environment such as blood, since the presence of protein corona in the

biological fluids might affect the BSA coatings on SWNTs and subsequently modulate their

biological fate.69

Gold nanorod (AuNR) is an excellent photothermal agent owing to their adjustable

longitudinal surface plasmon resonance and high light-to-heat conversion efficiency.71,72

These rod-shaped NPs allow prolonged blood circulation time and facilitate deeper mammary

tumors penetration than nanospheres with the same diameter.40,71 Dendrimers are inherent
polymeric scaffolds for encapsulation of small inorganic NPs (2-20 nm) used to further

increase blood circulation time, solubility and dimensional stability of nanohybrids.73 A smart

nanohybrid, termed Au nanorod/dendrimer-assembly nanohybrids (AuNR@Da NHs), with

size of about 130 nm, has been constructed by supramolecular encapsulation of 83.0 w/w%

AuNR into dendrimer assemblies.73 The amphiphilic dendrimer assemblies are composed of

PEGylated and antitumor adriamycin (ADR)-decorated dendrons, containing tumor

microenvironmental matrix metalloproteinase (MMP)-cleavable linkages, intracellular GSH-

degradable disulfide bonds and pH-breakable hydrazone bonds that are highly responsive

towards tumor microenvironment. Li et al. (2018)73 investigated the biological adapting

ability of the nanohybrids under different biomimetic stimulations. The group proved that

AuNR@Da NHs could adapt sequential biological barriers through triple-responsive features:

enzyme/redox/pH, to facilitate deep tissue penetration and high internalization in tumors,

particularly in human ovarian tumors that are deep within the abdominal cavity and most of

the time difficult to palpate.74 The permeability of nanohybrids in ovarian tumors are further

improved, credit to the efficient photothermal properties of AuNRs in AuNR@Da NHs

(about 70 %, as compared to single AuNRs about 60 %). The amount of internalized AuNR

and ADR mediated by nanohybrids, were about 27-fold and 6.6 times higher, respectively,

than individual AuNR-treated. Furthermore, the nanohybrids were capable of generating

hyperthermia (up to 67 C), with tumor accumulation of more than 2.3 times higher. NIR-

induced hyperthermia subsequently induces the rupture of the lysosome, accelerates the

endosomal release of ADR/AuNRs and thus inhibits the human ovarian tumor cells in vivo.

In brief, AuNR@DA NHs with laser irradiation offered strong curative effects, with an

inhibition rate of 80.7 %, on synergistic chemo-photothermal treatment for combating

multidrug resistance.73
Overall, targeting and therapeutic efficacy of Au nanostructures can be enhanced by tuning

its physiochemical properties such as size, surface chemistry and shape. On the other hand,

tumor pathological characteristics also play an important role in penetration of

nanomedicines in tumor, as tumor microenvironment is highly heterogeneous between

different types of tumors. Hence, characterization of both Au nanostructures and pathological

properties of tumors are equally important in the design of nanomedicine with

nanotheranostic properties.


Other nanomaterials

Inorganic nanomaterials are multifunctional NPs platform synthesized from metals, metal

oxides and metal sulfides. Inorganic nanomaterials are relatively stable over large ranges of

pH and temperature,10 resistant to enzymatic or photochemical degradation,70 thus suitable

for nanotheranostics in tumor microenvironment.70,75

Copper sulfide (CuS) NPs are featured with several properties compared to other commonly

used NPs, such as prominent absorbance, effective heat conversion, small particle size, easy

modification and facile synthesis.76 A tumor-targeting nanocomposite (CuS@BSA-MBA-

cRGD) with photothermal effect for targeting of liver-intestinal metabolism pathway was

synthesized recently.77 The biocompatibility and stability of CuS NPs were improved via

capping effect of BSA. Then, NIR fluorescence probe (MBA) and tumor-targeting ligand

cyclic arginine-glycine-aspartic acid (cRGD) peptide were further conjugated on the surface

of CuS@BSA. Peptides are another commonly used ligand targeting moiety, with advantages

in terms of chemical stability, ease of synthesis and reduced immunogenicity.59 cRGD can

target the cell-adhesion molecule, αvβ3 integrin, that is over-expressed on tumor new-blood

vessels and some tumor cells.78 The as-synthesized CuS@BSA-MBA-cRGD served as an

infrared thermal imaging contrast agent for infrared thermal imaging and as a photothermal

agent for tumor ablation via PTT. However, the obtained nanocomposite has a mean diameter
of about 51.2 nm,77 raising concerns regarding its uptake by reticuloendothelial system (RES)

organs that may cause slower elimination from the body and potential toxicity after effective

treatment.79

Generally, most of the nanomaterial-based PDT requires an additional photosensitizer or

high-power laser sources for effective therapy. However, the high concentration of NPs and

laser irradiation with long irradiation time may lead to a heat generation during NIR therapy.

The rise in temperature will subsequently lead to cell death rather than ROS generation for

PDT. Srivani et al. (2018)70 proposed copper bismuth sulfide (Cu3BiS3) nanocrystals as an

innovative human breast tumor treatment alternative, after showing the potential of Cu3BiS3

inducing PDT without any photosensitizer, at safe laser zone (808 nm, 10 mW/cm2, 10 min),

and in the deep tissue penetrative NIR region. Bi, with high x-ray attenuation, could serve as

an efficient x-ray contrast probe; while Cu ions, with broad NIR absorption, could serve as

NIR-responsive PDT and PTT agents. Upregulation of Cu ion leaching upon irradiation

coupled with Bi efficiently capturing more photons is believed to contribute to the realization

of Cu3BiS3 in exceptional PDT effects at low laser power.70 Although the group has shown

that the as-synthesized Cu3BiS3 nanocrystals are highly biocompatible without any genotoxic

effects, yet, the uptake of this 12 nm nanocrystals by RES organs, their in vivo degradation

behavior and clearance after PDT still require further investigation. Besides, the influence of

Cu3BiS3 nanocrystals on the biogenesis and activity of cellular organelles require further

understanding as organelle dysfunctions will lead to dramatic consequences on human health.

A photosensitiser-Pd@Pt nanosystem has been designed for highly efficient PDT in human

breast tumors [see Figure 2b (ii)].44 Palladium (Pd)-based nanomaterials have good catalase-

like activity, which can decompose H2O2 to produce oxygen and water. This subsequently

improves the hypoxic environment of solid tumor.44 However, like other inorganic

nanomaterials, Pd has chemically/biologically inert framework, which raises concerns over
the low biodegradation and biosafety issues.10 Functional inorganic 2D biomaterials, MnO2

nanosheets, have been introduced recently for improved theranostic performance [see Figure

2b (iv)].80 Preliminary studies demonstrate its biocompatibility as Manganese (Mn) is one of

the necessary trace elements in the human body. The ultra-thin MnO2 nanosheets structure,

with an average thickness of 2 nm, is highly sensitive towards the endogenous (acidic and

reducing) tumor microenvironment.80 It was found that the MnO2 nanosheets started to

disintegrate and release Mn2+ only within 3 min in acidic (pH 5.0) and reducing ([GSH] = 5.0

mM) solutions, with longitudinal relaxitivity (r1) of 5.45 mM-1s-1 and 4.81 mM-1s-1,

respectively. The r1 of MnO2 nanosheets in neutral solution was only 0.87 mM-1s-1. High

values of r1 coupled with various direct photographic images demonstrated the potential of

MnO2 nanosheets structure as the contrast agents for MRI, since the higher accessibility of

the released Mn2+ to water molecules could enhance brightening effect of MRI signal. MnO2

nanosheets also possess high intrinsic photothermal-conversion capability for PTT.

Furthermore, surface modification of the MnO2 nanosheets with soybean phospholipid

improved the stability of the nanosheets in physiological condition.80 Mesoporous NiO

(mNiO) NPs also appear as a photothermal conversion agent for cancer PTT [see Figure 2b

(iii)].81 Artemisinin (ART) is a traditional Chinese medicine that is believed to inhibit tumor

growth. Attachment of mNiO NPs and terbium complexes bestow mNiO with luminescence

imaging features. The mNiO-Tb serves as a MRI contrast agent, a luminescence imaging

probe and a vehicle for ART. Synergistic PTT and radical-induced therapy of cervical tumors

was achieved using this ART-loaded mNiO nanoplatform.81 Nonetheless, the selective

damage mechanism of ART to cancer cells remains elusive, and the toxicity of ART

derivatives to normal cells needs to be explored.

Perfluorocarbon (PFC) is a chemically inert molecule with high oxygen-carrying capacity

and good biocompatibility for in vivo application.47 Owing to the intrinsic hydrophobic nature
of the PFC compounds, their clinical application usually involves encapsulation by a carrier

matrix. Porous hollow magnetic Fe3O4 NPs (PHMNPs) have a large central cavity for the

loading of small molecules and/or the therapeutic cargo, while retaining favorable biological

properties of conventional iron oxide NPs (intrinsically super-paramagnetic, as a contrast

agent for MRI). In view of this, PFC and etoposide (EP) were loaded onto PHMNPs. Oxygen

was released at a moderate rate from the PHMNPs over an extended period of time,

effectively reducing the hypoxia-induced EP resistance of liver tumor cells and facilitating

concurrent chemotherapy. Modification of the surface of PHMNPs with lactobionic acid

(LA)-containing amphiphilic polymers (LA-PEG-S-S-C18PMH), through hydrophobic

interaction, facilitates selective targeting of LA against the asialoglycoprotein receptor

present on the plasma membrane of hepatocytes.47 Besides, the intracellular agglomeration of

the nanocarriers after GSH-triggered removal of the hydrophilic LA-PEG segment could

significantly enhance intracellular accumulation and improve therapeutic efficacy.47

In addition, the upconversion NPs (UCNP)-based theranostic micelles have been proposed

for dual-modality imaging and PDT in HCC [see Figure 2b (i)].82 Loading of mitoxantrone

(MX) and anti-epithelial cell adhesion molecule (anti-EpCAM) onto PEGylated UCNP

micelles has improved the biocompatibility and synergistic antitumor efficiency of the

system, without any noticeable systemic toxicity.82 Like other commonly used UCNP-based

therapeutic approach, the as-synthesized 23.4 nm UCNPs are difficult to fabricate in ultra-

small (< 15 nm diameter) sizes. The quantum yield of these UCNPs was not reported.

Besides, since water has an absorption peak around 980 nm, laser excitation at 980 nm will

result in unnecessary tissue heating during PDT. It is of interest to develop UCNPs which can

be excited by other NIR wavelengths and allow deeper tissue penetration. Lastly, overall

understanding of nanotoxicology of UCNPs (NPs distribution, excretion, metabolism,

pharmacokinetics etc.) in animal models is of utmost importance.83
Quantum dots (QDs) is a luminescent inorganic nanomaterial with rich surface chemistry and

optical properties. The application of QDs in biomedical field has been challenged by its non-

specific internalization and toxicity.84 Shi et al. (2018)84 covalently coupled folic acid (FA)

and 5-fluorouracil acetic acid (FUA) on the surface of QDs, to produce a HCC targeted

therapy system, named FA-QDs-FUA. FA is responsible for the specific targeting of the

system to the hepatocarcinoma cells; while QDs acts as the delivery vehicles and imaging

agent. FUA which interferes with nucleic acid synthesis, has been chosen as the therapeutic

agent. PEG has been selected as the linker chain to facilitate attachment of FUA to the QDs’

surface and dramatically suppress the non-specific interaction of QDs. The optimal

proportion of FA: PEG-QDs: FUA = 10: 1: 100 was used. Noteworthy, the content of FA in

the system is controlled within 10 %, since excess FA may promote undesired tumor cell

growth. The system was observed to exert reduced toxic side effects and better anti-tumor

efficacy.84 Nevertheless, the particle size of FA-QDs-FUA was about 220.28 nm, which is

bigger than 160 nm, raising concerns about the cellular uptake and accumulation of the FA-

QDs-FUA at tumor sites. Another similar work has been reported by Ma et al. (2018).85 The

group coupled second near-infrared window fluorescent (NIR-II) Ag2Se QDs with

gadopentetate dimeglumine injection (Gd-DTPA) for dual-modality: T1-weighted MRI and

fluorescence imaging. The excellent temporal resolution and high tissue penetration depth

were achieved by fluorescence imaging, further supporting the potential of QDs as

multifunctional contrast agents for multimodal imaging in clinical diagnosis.85

Magnetic metal oxide nanomaterials (MMONPs) are negative contrast agents for T2-weighted

MRI. In response to intratumoral oxidability and acidity, MMONPs degrade and release

corresponding metal ions that can serve as highly efficient positive T1-weighted contrast

agent. The ratio of increase of T1 signals against decrease of T2 signals (T1/ T2) from

MMONPs, is known as ratiometric MRI, which is highly selective for solid tumor imaging.45
Cobalt oxide nanoprism (Co3O4), a type of MMONPs, has been selected and tuned for

selective ratiometric MRI tumor imaging and synergistic cancer theranostics (PTT,

chemodynamic and chemotherapy). The as-prepared Co3O4 nanoprism is cuboidal, with a

thickness of 3.26 nm and a length of 33.29 nm, instead of triangular structure. This could be

due to the presence of high concentration of surfactant used during the synthesis which

subsequently inhibited nanomaterial growth in specific spatial directions.45 It is interesting to

note that although the sharp vertices of the triangular nanoprism may lead to stronger near-

field enhancements for plasmonic applications, unfortunately, its high surface energy vertices

most likely will make the nanoprism highly unstable and readily degradable.86 Nevertheless,

the Co3O4 nanoprism possess significant photothermal conversion efficiency (= 60.07 %),

outstanding MRI contrast (r2= 5.42 mM-1s-1) and good DOX delivery (29.36 mg/g), with a

low detection limit (50 nM) and broad linear range (0-50 M).45 In turn, the cuboidal

structure and fast degradation property of the as-prepared Co3O4 nanoprism could contribute

to enhanced drug delivery and controllable drug release.

Radiotherapy is another major modality of cancer therapy. However, radio-resistance, one of

the intrinsic features of solid tumors, often gives rise to unsatisfactory therapeutic outcome

and subsequent tumor relapse.13,43 Du et al. (2017)87 constructed a multifunctional theranostic

agent, with a mean diameter of 15 nm, integrating radiation therapy with high-depth PTT.

Functionalization of amphiphilic D-α-tocopherol PEG 1000 succinate (TPGS-Cu3BiS3) with

bimetallic chalcogenide nanocrystals (NCs) increased the deposition of X-ray irradiation

energy within cancer cells and triggered radiation damage in vivo. Moreover, conversion of

NIR light (1064 nm) into heat greatly improved tumor oxygenation via increasing the blood

flow, overcoming the hypoxia-associated radio-resistance of the tumor. The presence of

copper ions is capable of catalyzing the conversion of endogenic H2O2 into highly reactive

hydroxyl radicals and increase the level of oxygen radicals, hence further destroy the cancer
cells. The as-synthesized NCs also have strong absorption in the second NIR window (1000-

1400 nm), allowing a deeper tissue penetration ability, with low scattering and energy

absorption by tissues, than in the first NIR window (650-950 nm).87 High atomic number NPs

such as platinum, gold and bismuth are high electron emitters. These elements can act as

radiosensitizers and amplify the effects of radiation.88 Bismuth heteropolytungstate (BiP5W30)

nanoclusters have also been explored as radiosensitizers for radiotherapy enhancement.43

Owing to the electron structure and multi-electron property, BiP5W30 nanoclusters deplete

GSH via redox reaction, catalyze the decomposition of H2O2 to HO (about 1.3-fold) to

enhance ROS generation upon x-ray radiation. The coupling of BiP5W30 nanoclusters with

reduced graphene oxide (rGO) formed a heterostructure that not only promotes electron-hole

separation to improve radio-catalytic activity (about 4-fold) but also improves the oxygen

level within tumors since rGO can promote mild photothermal effect.43

Overall, inorganic nanomaterials serve as a platform for biomedicine, yet the often-neglected

characterization and fairly weak fundamental understanding of its structure-function

correlations often limits its predictive capabilities in nanotheranostics.
Figure 2 Brief overview of nanomaterials used for solid tumor theranostics, with their

respective TEM images. (a) Gold nanoclusters (i) The photocross-linkable Au

nanoparticles for photothermal therapy and photoacoustic imaging of tumors in vivo.

Adapted with permission from ref 42. Copyright 2019 Ivyspring International Publisher.

(ii) Preparation of the smart Cu (II)-aptamer complexes based gold nanoplatform for

synergistic PDT/PTT/chemotherapy of hepatocellular carcinoma. Adapted with

permission from ref 41. Copyright 2017 Ivyspring International Publisher. (b) Inorganic

nanomaterials (i) The structure of PEGylated upconversion-based micelles which

permits dual-modality magnetic resonance/upconversion luminescence-guided

synergistic chemotherapy and photodynamic therapy in hepatocellular carcinoma.

Adapted with permission from ref 82. Copyright 2018 Royal Society of Chemistry. (ii) A

photosensitizer-Pd@Pt nanosystem (Pd@Pt-PEG-Ce6) in enhancement of tumor-

specific photodynamic therapy. Adapted with permission from ref 44. Copyright 2018

John Wiley and Sons. (iii) The artemisinin-loaded mesoporous nanoplatform for
synergistic photothermal and radical-induced tumor theranostics. Adapted with

permission from ref 81. Copyright 2018 American Chemical Society. (iv) Overview of 2D

ultrathin MnO2 nanosheets in magnetic resonance imaging and ultrasensitive stimuli-

responsive photothermal therapy. Adapted with permission from ref 80. Copyright 2018

Elsevier.


Polymeric nanoparticles

Polymeric NPs is a collective term given for any type of polymer NPs, but specifically for

nanospheres and nanocapsules built from synthetic polymers (e.g. poly(organophosphazene)

(POP), poly(ethylene glycol) (PEG), etc.) or natural polymers (e.g. chitosan, gelatin, etc.).10

The highly electron-delocalized structures, excellent light-harvesting and light amplifying

properties, versatile surface modification, excellent photostability and biocompatibility of

polymeric NPs contribute to their rapid advancements in solid tumor theranostics. Besides,

with the size range between 10-1000 nm, polymeric NPs have proven to be viable carriers of

therapeutic agents.

Encapsulation of methotrexate (MTX), a chemotherapeutic agent, in polymeric NPs is crucial

in controlling its toxicity and side effects.89 Two different block copolymers (poly(ethylene

glycol)-b-poly(glutamic acid)-b-poly(ethylene glycol) (GEG) and poly(ethylene glycol)-b-

poly(glutamic acid) (EG) conjugated with FA have been designed and used to encapsulate

MTX. Both NPs, named M-GEG and M-EGFA NPs, are employed for passive and active

targeting of cervical carcinoma, respectively [see Figure 3a (ii)].89 FA has been used as a

homing device to actively target and direct M-EGFA NPs towards the tumor, facilitating

targeted drug release at the tumor site. On the other hand, M-GEG NPs passively target and

accumulate at the cancer cells, by exploiting the EPR effect. Subsequently, M-GEG NPs

release MTX inside the cytoplasm at a controlled rate to induce cell apoptosis. This

mechanism of M-GEG NPs allowed long-term cytotoxicity action on the tumor cells while
minimizing side effect to healthy tissues.89 The entrapment efficiency for both polymeric NPs

was found to be about 93-96 %, with drug-loading content of about 38-47 %. Both polymeric

NPs have improved the systemic circulation and intracellular delivery of MTX. The potential

of these polymeric NPs as alternative to conventional chemotherapy for human cervical

carcinoma are supported by their complete biological evaluation in terms of cytotoxicity,

intracellular drug uptake and release, as well as induction of apoptosis.89 Future research can

be expected on fabrication of stimuli-responsive block copolymers, for specific targeting and

precise control of the drug-release and versatility in clinical applications.

On the other hand, poly(ethylene glycol)-b-poly(ɛ-caprolactone) (PEG-PCL) is a

biodegradable and biocompatible block polymer.90 PEGylation delays renal filtration,

prolongs plasma circulation and reduces non-specific uptake of nanomaterials by

macrophages.18,19,91 Encapsulation of silicon naphthalocyanine (SiNc), a photostable

fluorescence molecule, within the hydrophobic core of the PEG-PCL NPs serves as a real-

time activatable theranostic nanoplatform [see Figure 3a (i)].90 The as-synthesized nanoprobe

is predominantly fluorescent at tumor/cancer site (quantum yield at about 11.8 %). This is

mainly because the poor water soluble SiNc (<1 ng/mL) in the PEG-PCL NPs tend to

aggregate in aqueous environment and lead to fluorescence self-quenching. However, once

SiNc infiltrated into the core of the solid tumor, the complex acidic intracellular environment

(pH 6.5-6.8) and the interior of the endosome/lysosome (pH 4.5-6.5) will disrupt the

structural integrity, trigger the leaching of SiNc from the nanoprobe, leading to NIR

fluorescence recovery.90 The nanoprobe reveals high cancer-to-normal tissue contrast ratio

(about 1.6-1.9-fold) specifically at the tumor sites, and with none or minimal fluorescence

signal in healthy organs.90 This highly sensitive fluorescence switching nanoplatform

successfully broaden the imaging and treatment window, making it highly promising for

further clinical studies. The group also validated that heat can be efficiently generated by the
nanoprobe up to 12 mm deep within tumors from the point of NIR light (1.3 W/cm2) for PTT,

which is beneficial for nanotheranostics of ovarian cancer which usually started in one or

both ovaries or fallopian tubes located in the female pelvis. Moreover, the chemistry involved

in the SiNc-mediated combinatorial phototherapy can be easily tailored via photo irradiation

dosage.90 On the other hand, self-assembly of PEG-PCL with folate-PEG-cholesterol micelles

forms a spherical and self-luminescing nanosystem (called POCL nanoreactor) with a

diameter of about 50 nm.92 POCL encapsulates bis[3,4,6-trichloro-2-(pentyloxycarbonyl)

phenyl]oxalate (CPPO, a chemical power source with high reactivity to H2O2), poly[(9,9’-

dioctyl-2,7-divinylene-fluorenylene)-alt-2-methoxy-5-(2-ethyl-hexyloxy)-1,4-phenylene]

(PFPV, a chemiluminescence converter), and tetraphenylporphyrin (TPP, a photosensitizer

with NIR emission and singlet oxygen. The folate ligand on the POCL surface allows specific

targeting at the tumor site. Upon trigger by the high level of H2O2 at the tumor site (10-6 M,

normal condition = 10-7 M), POCL can be used for chemiluminescence imaging and PDT via

a series of intraparticle relayed resonance energy transfer. The tumor cells are converted to a

“light on” state and subsequently destroyed by the generated singlet oxygen. With such an

excellent NIR light emission and singlet oxygen generation abilities, POCL showed a high

image contrast in fluorescence imaging with a high antitumor effect and low systemic

toxicity.92

Ursolic acid (UA), a pentacyclic triterpenoid extracted from Hedyotis diffusa Willd, has

shown great potential in cancer therapy but their efficacy is extremely hindered by limited

water solubility and poor pharmacokinetics in vivo. Yan et al. (2018)93 has employed cationic

nanomicelles derived from pluronic F127 as a delivery vehicle of UA for colorectal cancer

treatment. Pluronic F127 is a widely-used biocompatible polymeric drug delivery vehicle,

comprising of polyethylene oxide–poly-propylene oxide–polyethylene oxide (PEO–PPO–

PEO) chains. The PPO segment of pluronic F127 allows incorporation of lipophilic drugs
while hydrophilic segment of F127 prevents adsorption and aggregation with other bio-

macromolecules. Since the positively charged NPs have stronger affinity with negatively

charged cell membranes, therefore, cationic polymer of stearoyl chloride grafted

polyethylenimine copolymer (C18-PEI) was functionalized to increase UA uptake by

colorectal cancer cells.93 This UA loaded cationic nanomicelles, termed as FUP, was

fabricated through simple self-assembly of UA, F127 and C18-PEI in ethyl alcohol. FUP can

effectively block colorectal cancer cell proliferation by interfering cell cycle arrest at the G1

checkpoint and induce cell apoptosis mechanism.93 Nonetheless, further studies on the

degradation behavior and clearance of NPs after performing therapy are necessary.

Photoacoustic imaging (PAI) is a biomedical imaging modality combining the high contrast

of optical imaging with the high spatial resolution of ultrasound imaging.5,42,45,72 PAI can also

be defined as the non-radiative conversion of light energy into sound energy.17 Based on the

use of non-ionizing laser pulses, PAI non-invasively visualizes anatomical structures with

greater penetration depth (several cms) and specificity than conventional optical imaging,

suitable for imaging superficial tumors at breast and skin.94 On the other hand, high intensity

focused ultrasound (HIFU) is a minimally invasive therapeutic modality. HIFU concentrates

multiple intersecting beams of ultrasound into the targeted tumor region. Subsequently, it

generates hyperthermia and mechanical effects to destroy the affected areas.95 A

multifunctional poly(lactic-co-glycolic acid) (PLGA) nanocapsule, termed Cu2-

xS/PFBO@PLGA       or in short CPPNs, encapsulating PAI contrast copper sulfide nanodots

(Cu2-xS NDs) and a typical HIFU synergistic liquid, perfluorooctyl bromide (PFOB) has been

constructed using emulsion solvent evaporation strategy.95 The high performance of Cu2-xS

NDs in the absorption and conversion of NIR confers high PAI contrast capability to the

CPPNs, by which the location of the CPPNs within a tumor can be monitored successfully

under PAI. Shifting absorption from the first to the second NIR-window could enhance PAI
contrast in imaging of deep lying living structures in vivo.17 Due to the encapsulated PFOB,

the cavitation effect in CPPNs is improved, thus enhances the ablation efficacy under HIFU

exposure. With a particle size of 123.7 nm, CPPNs show its potential as a theranostic agent

for future photoacoustic image-guided HIFU synergistic therapy of breast cancer.95 However,

high level of ultrasound energy (usually more than 100 W/cm2) may cause damages to

healthy tissues, especially along the path of ultrasound propagation, hence leading to severe

side effects.96

Aggregation-induced emission (AIE) is a concept originated from the phenomena that a class

of fluorogens are non-emissive as free molecules but luminescent as aggregates.57,97 AIE-

based bioprobes are suitable to use in real-time imaging probes, credit to their low

background, high sensitivity and resistance to photobleaching. A smart nano delivery system,

named STD nano-micelle (STD-NM), with ST and TD peptide functionalization and AIE

“switch on” characteristics has been presented for precise theranostics and apoptosis

monitoring of colon cancer.97 Comprising of pH-triggered targeting peptide STP (sequence:

SKDEEWHKNNFPLSPG), a caspase-3 responsive peptide linker (sequence: DEVD) and an

AIE molecule tetraphenylethylene (TPE), ST could recover the fluorescence of the

nanocarrier during apoptosis. Meanwhile, TD, a tumor acidity-activated peptide made up of

the cell-penetrating peptides TAT and 2,3-dimethylmaleic anhydride, maintained the

“stealth” stability of the nanocarrier in the physiological environment.97 Upon exposure to

tumor microenvironment, STP and TAT were switchably stimulated and activate the peptides

to penetrate through the colon cancer cells and subsequently release the anticancer drugs (cis-

platinum and DOX) into the tumors. The AIE signal will then be “switched on”. Gene

analysis by RNA-seq has also been performed, supporting the superior therapeutic effect of

anticancer drugs-loaded STD-NM treatment. 97
Generally, poor spatial resolution, shallow tissue penetration and relatively low quantum

yield of NIR-emissive polymeric NPs than other common fluorescent imaging probes are

some of the concerns for polymeric NPs in theranostics. The interaction between light-

induced charge transfer of polymeric NPs with other biological activities requires further

detailed study.


Lipid nanoparticles

Solid lipid NPs are made up of rigid core of hydrophobic lipids surrounded by a monolayer of

phospholipids. This structure improves their biocompatibility and stability in biological

environment, making them suitable as a carrier system.98

A multifunctional hypoxia-responsive theranostic liposome co-encapsulating a

photosensitizer Ce6, hypoxia-activated prodrug tirapazamine (TPZ) and gene probe miRNA-

155 was designed for synergistic PDT-chemotherapy of breast cancer.99 The liposome was

fabricated using an innovative hypoxia-responsive 2-nitroimidazole derivative conjugated

PEG amphoteric polymer. The gene probe is a molecular beacon probe with the loop

sequence complementary to the target miRNA-155. In absence of target, the fluorescence of

the gene probe is switched off; upon hybridization with the target, the fluorescence is

switched on, and effectively used for detection and diagnosis of intracellular oncogenic

miRNA biomarker in breast cancer.99 Subsequent laser irradiation (670 nm, 0.48 W/cm2, 10

min) induced Ce6-mediated PDT by consuming oxygen to generate intracellular ROS, such

as singlet oxygen, which causes severe hypoxia. The PDT-induced hypoxia led to the

disassembly of the liposome, intracellular TPZ leakage to cell nucleus and induce DNA

damage and cell apoptosis.99 A detailed nanotoxicology study of the as-produced liposome

system is imperative for possible clinical application as TPZ is currently under Phase III

clinical trial.
An ultrasound molecular probe based on lipid NPs has been introduced for precision

theranostics at an early stage of HCC [see Figure 3b (i)].100 As common lipid NPs lack of

specific targeting ability, hyaluronic acid (HA) has been chosen as a ligand to actively target

the overexpressed CD44 cell adhesion factor on HCC. Cysteine-flanked cell-penetrating

peptide (CPP), CG-TAT-GC, has been selected to improve the delivery of macromolecular

substances into the nucleus without causing cytotoxicity.100 The as-synthesized lipid NPs is

known as HA-mediated cell penetrating peptide-modified with 10-hydroxycamptothecin-

loaded on a phase-transformation lipid NPs (HA/CPPs-10-HCPT-NPs). Upon trigger by low-

intensity focused ultrasound (LIFU) sonication, the NPs in tumor tissue and cells undergo

acoustic droplet vaporization (ADV) and are transformed into microbubbles.100 The resultant

microbubbles not only able to provide significant contrast enhancement in tumor-site

imaging, but also increase permeability of NPs into tumor blood vessels and cell membrane.96

Since the acoustic intensity of LIFU sonication is usually low, no more than 3.2 W/cm2, it is

less likely to cause tissue necrosis as compared to HIFU.96 This fascinating mechanism

successfully induces local release of antitumor drug in the cytoplasm and nucleus.100

However, there are some concerns with this approach. Although the ligand-mediated active

targeting has been used to improve the targeting efficiency, it is important to fully understand

and avoid the adverse side-effects due to off-target distribution of the CPP and its cargo

which might induce mutations, cytotoxicity or initiate immune responses in the host.

Secondly, the pharmacokinetics, stability and circulation time of the system in bloodstream

should also be further investigated. In addition, since the effect of ultrasound is highly

localized, their applicability in tumor metastasis is highly compromised.

On the other hand, abnormal levels of H2O2 (about 50-100 µM) often correlate with

physiological and pathological conditions like inflammation and cancers. Generally, the

concentration of H2O2 in physiological environments should be below 50 µM.101 Liposomal
nanoprobe loaded with horseradish peroxidase (HRP) and its substrate, 2,2-azino-bis(3-

ethylbenzothiazoline-6-sulfonic acid) (ABTS), has been presented for in vivo detection of

inflammation, photoacoustic detection and imaging of H2O2 (down to sub/micro molar

concentrations) [see Figure 3b (ii)].101 In the presence of endogenous H2O2, HRP loaded in

liposomes would catalyze ABTS (colorless) into its oxidized form (greenish) and show strong

NIR absorbance (700-900 nm), allowing sensitive PAI of early stage tumors (as small as 2

mm in size). Meanwhile, based on the difference in H2O2 contents, the nanoprobe also allows

diagnosis and imaging of LPS- (a lipoglycan that triggers inflammation) and bacteria-induced

inflammation, orthotopic brain tumors, breast tumors and metastatic tumors. Besides, this

spherical shape liposomal NPs with an average diameter of about 100 nm concurrently

achieve selective PTT of tumors with high efficacy and minimal non-specific heating damage

to surrounding normal tissues.101 However, the loading capacity of ABTS and HRP were

found to be limited at about 23.17 and 5 %, respectively. This could be due to premature

release of the drug from the lipid matrix as changes in temperature during administration may

cause polymorphic transitions of the lipid matrix.10 The depth-dependent light attenuation and

interference of unwanted background signals remain challenges for the clinical application of

PAI.

Superparamagnetic iron oxide nanoparticles-loaded solid lipid (SPIONs) is made from iron,

one of the most abundant metals present in metabolism. SPIONs have big potential as

theranostic agent as they display interesting cellular and in vivo interactions with no dramatic

toxicity.69,102,103 A smart nanovehicle with DOX and SPIONs delivery system, in short

DOX/SPIONs-loaded DFSLNs, has been constructed for oral chemo/magnetothermal

combination therapy of colon cancer.98 Despite the system combined both DOX

chemotherapy and hyperthermia therapy (generated from SPIONs) with high frequency

magnetic field (HFMF), its therapeutic efficacy is still limited by the systemic drug
absorption into blood circulation. Thereby, the group innovatively coated folate (FA) and

dextran on the surface of the NPs in a sequential layer-by-layer manner.98 Although the

fabrication of SPIONs can be relatively easy and reproducible, biocompatible polymer layer,

such as PEG and polyvinyl alcohol (PVA), is normally coated on the SPIONs surface to

improve their biocompatibility and stealthiness for specific targeting. This is because naked

SPIONs tend to sediment and aggregate at physiological conditions, resulting in an increased

risk of toxicity.69 Coating of the polysaccharide dextran shell layer on the NPs surface not

only evaded the cellular transport and systemic absorption by at least 2 folds, but also

enhanced the particle accumulation at the tumor sites by specific association with dextranase

present only in colon. The subsequent enzymatic degradation and removal of dextran coating

led to the exposure of the FA residues that further facilitate cellular level targeting and uptake

of the system by receptor-mediated endocytosis. The preliminary results demonstrated

prominent therapeutic efficacy (a 15-fold decrease in tumor mass of mice than the PBS

control) of DOX/SPIONs-loaded DFSLNs for the oral administration, with no apparent

systemic side effects or toxicity.98 The particle size of DOX/SPIONs-loaded DFSLNs is

approximately 132 nm. In fact, the optimal size of the nanomaterials designed for colorectal

cancer should be between 10-100 nm in order to avoid triggering of immune response and

clearance by glomerular filtration in the kidneys.104 The spherical shape of the nanomaterials

would encourage longer circulation time in blood and faster uptake by colorectal cancer

cells.105

In short, the potential side effects arising from the off-target distribution of the molecular or

drug-loaded lipid NPs require more studies for validation on the effectiveness of the delivery

system. The pharmacokinetics, stability and circulation time of the nanomedicine in the

bloodstream should also be further investigated.
Figure 3 Brief overview of nanomaterials used for solid tumor theranostics, with their

respective TEM images. (a) Polymeric nanoparticles (i) Illustration of a tumor-

activatable silicon naphthalocyanine (SiNc) encapsulated in a copolymer, PEG-PCL

nanoparticles, that permits NIR fluorescence-guided surgery and combinatorial

phototherapy of ovarian cancer tumors. Adapted with permission from ref 90.

Copyright 2018 Ivyspring International Publisher. (ii) Overview of block copolymer

(PEG and PGA) based nanoparticles in passive and active theranostic intervention of

cervical cancer. Adapted with permission from ref 89. Copyright 2017 American

Chemical Society. (b) Lipid nanoparticles (i) A multifunctional ultrasound molecular

probe (cell-penetrating peptide-modified targeted drug-loaded phase-transformation

lipid nanoparticles) with low-intensity focused ultrasound in hepatocellular carcinoma.

Adapted with permission from ref 100. Copyright 2018 Ivyspring International

Publisher. (ii) A H2O2-responsive liposomal nanoprobe capable for photoacoustic
inflammation imaging and photothermal therapy of early-stage of small tumors and

metastatic lymph nodes. Adapted with permission from ref 101. Copyright 2017 PNAS.


Graphene

Graphene and its derivatives have become the spotlight of nanotheranostics since the last

decade, owing to their electrically tunable surface chemistry and mechanical

robustness.102,106–108 The sp2-hybridised carbon atoms in a honeycomb network provide

graphene with a large surface area, enabling the compounds to adsorb/functionalize on both

sides of its planar surface. Moreover, the large molecular weight of graphene oxide (GO)

enhances the imaging contrast,109 while its electrical properties allow long-range fluorescence

resonance energy transfer (FRET).110 GO presented low uptake in the RES and long blood

circulation time at 1 mg/kg body weight within days.111

Melanoma is a form of skin cancer caused by excessive exposure to the sun’s ultraviolet

radiation.112,113 A work using only GO (without the co-presence of any photosensitizers) to

sensitize the formation of singlet oxygen for dual nanomaterial-mediated PDT and PTT of

solid melanoma tumors was reported in 2016.114 The group proved that the nano-sized

graphene is suitable for in vivo fluorescence imaging operated using inexpensive laser setups.

GO is able to absorb NIR light that subsequently induces the generation of singlet oxygen

and offers deeper tissue penetration depths.114

However, the relatively hydrophobic nature of graphene makes it difficult to be taken up by

cells, which in turn minimize their therapeutic efficacy. Hwang et al. (2016)110 has therefore

suggested to graft a biopolymer of HA and a CD44 receptor-specific polysaccharide, onto the

GO surface (see Figure 4a).110 The as-synthesized 170 nm HA-GO conjugate improved

stability and solubility of GO in ionic solutions, without any aggregation. With such an idea,

the group has also successfully developed an interesting fluorescence-switchable theranostic

platform that is able to sense oncogenic miR-21 using anti-sense miR-21 peptide nucleic acid
probes and show therapeutic effect on breast cancer simultaneously.110 On the other hand,

GO/gold nanorods (GO/GNR) theranostic nanohybrids have been synthesized in situ at room

temperature for precise tumor computed tomography (CT) imaging and PTT of pancreatic

cancer.115 GO is chosen as the template for the synthesis of GNR due to the presence of many

oxygen-containing functional groups which can improve solubility and biocompatibility of

the system.115 Meanwhile, the synthesis method is straightforward, environmental-friendly,

highly adaptable for different types of synthesis of GO/NPs and most importantly does not

form any aggregates. The GO/GNRs showed photothermal effect in vitro, with good optical

morphological stability up to six cycles of 808 nm laser irradiation.115

Graphene quantum dot (GQD) is a zero-dimensional carbon material with excellent chemical

stability, optical and electronic properties, biocompatible and allow easy surface

modifications.116,117 Besides, GQD can produce ROS with significantly high quantum yield

(greater than 1.0) for PDT, due to their excellent electron donating and accepting

capability.118 GQD has the property of extremely high intrinsic mobility of charge carriers.119

The work of loading IR780 iodide (IR780) onto FA-functionalized GQD via π-π stacking

interactions has been reported recently.119 The GQDs-FA contains a large and intact sp2

domain with carboxyl groups around the edge which exhibits excellent water solubility and

suitable for further conjugation (see Figure 4b).119 IR780 is an effective theranostic agent for

simultaneous NIR fluorescence imaging and PTT. Yet, its application is often hampered by

its insolubility in different solvents due to the presence of the rigid chlorocyclohexenyl ring

in the structure. Interestingly, the water solubility of IR780 (33.19 %) is increased by over

2400-fold when loaded onto the GQDs-FA system, with a high photothermal conversion

efficiency (87.9 %). The photostability and tumor-targeting ability were greatly improved

too. Most importantly, IR780/GQDs-FA, with a particle size of about 9 nm, is capable of

producing sufficient hyperthermia to effectively kill cervical cancer cells and completely
eradicate tumors upon 808 nm laser irradiation.119 For future studies, it would be

advantageous if pH-responsive features could be incorporated into this system, so that the

therapeutic mechanism will be initiated once exposed to acidic tumor microenvironment.

Generally, the clinical translation of PDT is often challenged due to the low yield of ROS,

poor tissue penetration depth of the photosensitizer and short lifetime of ROS.57,120 A

mitochondrial specific PDT, named UCNP-GQD/TRITC, has been presented with the use of

rare-earth doped UCNPs mediated NIR-GQD.120 UCNPs are a kind of inorganic

nanomaterials capable of emitting efficient and sharp visible or UV light when excited at

NIR. These features of UCNPs permit high penetration depth in biological tissues with high

detection sensitivity.121 Generation of singlet oxygen by the GQD becomes more prominent

after UV light emission from UCNPs (see Figure 4c).120 The high concentration of singlet

oxygen observed in mitochondria is due to intrinsic advantages of GQD as well as the highly

efficient energy transfer from UCNPs to GQD. Furthermore, surface modification of UCNP-

GQD with mitochondrial-targeting fluorescent probe, tetramethylrhodamine-5-isothiocyanate

(TRITC), allows the system to target mitochondria precisely and triggers breast cancer cells

apoptosis irreversibly (with an inhibition ratio of more than 75 %).120 However, toxicity from

long-term exposure and high quantum yield of singlet oxygen, surface-dependent therapeutic

responses, and biological corrosion resistance (a phenomenon in which metallic ions and

particles are released in a complex aqueous environment through electrochemical

processes)122 of the GQD are some of the concerns raised regarding this strategy. Also, since

GQD (with a 6 nm diameter) is attached on the surface of UCNPs via amide linkages, it is

possible that the resultant UCNP-GQD/TRITC composites would cleave off easily when the

system is dispersed in a solvent. Glycyrrhetinic acid (GA), a natural product from

Glycyrrhiza glabra, is another mitochondrion targeting ligand.123 A biocompatible GA-

functionalized GO has been fabricated and used as a carrier for targeted delivery of DOX into
mitochondria. Both in vitro and in vivo studies revealed the activation of the mitochondria-

mediated apoptosis pathway, suggesting GA-GO@DOX’s potential for liver cancer

treatment.123

Zhao et al. (2018)111 has presented a chitosan/dimethymaleic-modified chitosan (CS/CS-

DMMA)-functionalized GO NPs, also known as GON/CS/CS-DMMA. Chitosan (CS), a

natural polysaccharide that commonly exists in the hard shells of marine crustaceans, has

been actively explored to construct various CS-based nanomaterials because of its

biocompatibility, biodegradability and structural variability.124 This hybrid nanocarrier is pH-

sensitive and has surface charge-reversible ability, which is due to self-assembly of

deprotonated carboxyl of GO NPs and the protonated amine of CS via electrostatic

interactions. A chemotherapeutic drug, DOX, was adsorbed onto the GO via π-π stacking

interaction between the large π conjugated structures of GO and the aromatic structure of

DOX. The outer CS-DMMA polyelectrolyte shell of the nanocarrier is negatively charged

which prevented premature release of the co-loaded DOX, when circulating in the blood

system. Upon reaching the slightly acidic microenvironment (pH 6.5) of liver cancer, the

nanocarrier switches to positive charge, due to detachment of chitosan coating, which re-

expose the amino groups of the positively charged CS. Consequently, GON/CS/CS-DMMA

was capable of delivering DOX effectively at a controlled release rate.111 In another study,

reduction and functionalization of GO using dopamine formed reduced graphene

oxide/polydopamine (RGO-PDA).109 The formed PDA stabilizes the RGO against

agglomeration and fouling effects. It also attenuates the in vivo toxicity of RGO and allows

covalent surface modification with desired molecules. Conjugation of BSA (as a drug carrier,

capturing agent for 4T1 breast cancer cells) onto the RGO-PDA system further permits a

higher loading of MRI contrast agent diethylenetriaminepentaacetic acid (DTPA)-Mn(II)

complex and anticancer drug (MTX). This multifunctional and biocompatible theranostic
hybrid system is electrochemically proved to allow higher sensitivity (by a factor of four)

towards breast tumor.109




Figure 4 Brief overview of graphene for nanotheranostics. (a) Illustration of hyaluronic

acid-coated graphene oxide synthesis and its theranostic effect by targeting oncogenic

miR-21. Reprinted with permission from ref 110. Copyright 2017 Elsevier. (b) Schematic

illustration of the IR780 iodide on folic acid-functionalized graphene quantum dots for

targeted PTT. Reprinted with permission from ref 119. Copyright 2017 American

Chemical Society. (c) Overview of mitochondrial specific PTT by rare-earth

nanoparticles mediated near-infrared graphene quantum dots. Reprinted with

permission from ref 120. Copyright 2018 Elsevier.


Liquid tumor

Although the nanotheranostic strategies are focused more on the diagnosis and therapy of

solid tumors, a considerable increase in their application to liquid tumors has been noted in

recent years. However, while it is true that liquid tumors are classified as leukemia,
lymphoma and myeloma, only the former two have generated interest in the scientific

community.37 The strategy to carry out nanotheranostics in tumors are selected according to

several variables, the most important being the disposition and accessibility of the tumor by

the nanomaterials. Liquid tumors are more accessible than solid tumors, since they are

present throughout the bloodstream, whereas in solid tumors, the nanostructures must cross

tissue barriers to detect and treat.125 In this section, we will evaluate how and why the specific

nanomaterials are selected to carry out nanotheranostic strategies in liquid tumors.


Metal nanoparticles

Metal NPs are presented as an interesting strategy for the detection and therapy of lymphoma

and leukemia. Their ability to generate heat from the optical energy allows them to be

nanoagents for PTT. However, its application for liquid tumor theranostics have not been

fully studied and this is due to the fact that these types of circulating tumors are not located at

a certain point and therefore may cause ablation of adjacent tissue.126 In this context, 100 nm-

sized iron oxide NPs (IONPs) functionalized with FA have been evaluated as promising

platform for imaging followed by therapy of tumors related to the lymphatic system. Coating

with FA does not require the use of linkers and therefore prevents the NPs from being

oversized and enhances its accessibility to the lymph vessels. Moreover, FA provides stability

to the NPs as it provides a negative surface charge, and this increases its retention in vessels.

Finally, FA on the IONPs could specifically recognize the folate receptor that is

overexpressed on the surface of cancer cells.127 However, IONPs tend to aggregate when

placed in biological suspensions and therefore its heating ability is reduced. In order to

exceed this limitation, IONPs have been functionalized with a protective mesoporous silica

shell, which gives high heating and relaxivity properties when applied in vivo, while keeping

its size below 100 nm.128 Moreover, it should be noted that unlike other metal NPs, these

modified IONPs allow positive MRI contrast by displaying bright region and therefore allows
effective visualization of the tumor. However, although this nanoparticle has interesting

properties, its effectiveness for magnetic hyperthermia therapy of circulating cancer has yet

to be demonstrated. The nanomaterial that has proved to be an excellent nanotheranostic

agent for in vivo leukemia treatment is Cu-Au alloy nanostructures, where the higher thermal

conductivity of the copper allows excellent heating under laser irradiation once the tumor is

visualized by NIR imaging. This nanoplatform was proven to target and destroy cancer cells

in mice within five minutes (see Figure 5a).129 Despite this, issues concerning renal clearance

and lymphatic fenestration are hindering the current nanotheranostic strategies for liquid

tumor treatment. In this context, it is essential to select nanomaterials with a size range from

20-50 nm, as they have proven to enhance in vivo tumor penetration and inhibition.130


Lanthanide-doped nanoparticles

The lanthanide oxyfluoride NPs appear as an alternative to lipid and polymeric based

delivery systems, which have low retention and non-specific cellular uptake, respectively.131

The excellent photoluminescence property of the lanthanide and the conjugation of the

nanoparticle with anti CD33 antibody enable it to be an interesting nanotheranostic agent for

myeloid leukemia. These NPs are conjugated with anti CD33 that allows retention and

internalization in CD33+ AML cells, which otherwise could not accumulate in the blood

vessels and therefore making it effective for diagnosis and therapy. (see Figure 5b).131 They

have shown to be successful antitumor agents both in vivo and ex vivo by acting as a specific

delivery vehicle of PMI peptide, which antagonizes the inhibitors of the tumor suppressor

protein p53.


Polymeric nanoparticles

Polymeric NPs have been applied mostly for image-guided anticancer drug delivery. In this

context, several types of polymeric NPs have been used depending on the diagnostic strategy

to be followed. For the treatment of non-Hodgkin lymphoma, amphiphilic polymers
composed of hydrophobic fluorescent curcumin and hydrophilic PEG were designed as self-

assembled anti-cancer drug nanovesicles [see Figure 5c (i)].132 Limitations associated with

the drug, such as low solubility and low bioavailability, was curtailed with PEG. The most

attractive aspect of this nanomaterial is the ability of curcumin to act as both a strong

fluorescent probe and an anti-cancer drug, avoiding the need of a fluorophore.133

Furthermore, a multifunctional imaging theranostic approach based on core-shell chitosan-

HA NPs has been applied in murine model of B-cell lymphoma.134 Since they are initially

conjugated with fluorophores and then loaded with paramagnetic tracers, the most suitable

imaging agent can be chosen depending on the tumor type; fluorescent reflectance imaging

for scanning of superficial structures such as sentinel lymph node and MRI for deep tissue

visualization. Another advantage is that the HA has numerous active groups that are useful

for specific targeting. In this context, these polymeric NPs were decorated with a specific

mimotope (pA20-36) that exclusively recognize A20 lymphoma cells and induce cell

apoptosis. Moreover, amphiphilic perylene diimide (PDI) derivatives were developed and

further self-assembled into a series of PDI NPs with different sizes of 30, 60, 100, and 200

nm. They have been proven to perform activable PAI and effective PTT [see Figure 5c

(ii)].135


Lipid nanoparticles

Lipid NPs have also been applied as carriers for lymphoma theranostics, but as an alternative

to improve cell internalization and simultaneous drug delivery. Liposomes that contain

SPIONs and functionalized with rituximab antibody has been developed as theranostic agent

for central nervous system lymphoma (see Figure 5d).136 Blood-brain barrier regulates the

movement of molecules, ions and cells between the continuous non-fenestrated

microvasculature and the central nervous system.137 The restrictive nature of the blood-brain

barrier pose challenges for targeted drug delivery to the central nervous system, and it is
usually associated with neurological diseases including neurodegenerative diseases.138 In this

case, free rituximab is not able to cross the blood-brain barrier, hence it requires a drug

delivery system to perform effective therapy. The liposome is used as a rituximab vehicle,

with sizes of less than 200 nm. Surface modification of liposome with a non-ionic surfactant

allows penetration into the blood-brain barrier and therefore can develop its antitumor

function. The liposome which also contains SPIONs allows in vivo MRI with both T1 and T2

modes. Nevertheless, the anti-lymphoma activities of the liposome have only been tested in

vitro and therefore this strategy only remains as a promising tool for clinical translation.136
Figure 5 Nanomaterials applied as theranostic agents for liquid tumor. (a) Metal

nanoparticles. Cu–Au alloy nanostructures coated with aptamers for NIR imaging and

photothermal therapy in in vivo leukemia cancer theranostics. Adapted with permission

from ref 129. Copyright 2016 Royal Society of Chemistry. (b) Lanthanide-doped

nanoparticles. Lanthanide-doped nanoparticles conjugated with an anti-CD33 antibody

and a p53-activating peptide for acute myeloid leukemia therapy. Adapted with

permission from ref 131. Copyright 2018 Elsevier. (c) Polymeric nanoparticles. (i)

Curcumisome loading on nanovesicles for fluorescence imaging and drug delivery
strategy in leukemia theranostics. Adapted with permission from ref 132. Copyright 2015

Royal Society of Chemistry. (ii) Application of perylene diimide nanoparticle on lymph

node mapping and cancer photoacoustic imaging and photothermal therapy. Adapted

with permission from ref 135. Copyright 2017 American Chemical Society. (d) Lipid

nanoparticles. Application of liposome-containing SPIONs conjugated with anti-CD20

antibody as a theranostic agent for central nervous system lymphoma. Adapted with

permission from ref 136. Copyright 2018 Elsevier.



NEURODEGENERATIVE DISEASES

Neurodegenerative diseases are a set of heterogeneous disorders that result in a progressive

loss of certain neuronal systems and finally loss of cognitive abilities. Alzheimer's disease

(AD), Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease are the

prototypes of degenerative diseases.139 Among them, AD is the most common

neurodegenerative disorder, and this is the reason that most of the nanotheranostic strategies

applied on brain diseases are focused on this specific disorder. While it is true that the

causative mechanism of the disease is unknown, there are several hypotheses that consider

the deregulation of metal levels in the brain is associated with multiple pathological factors of

the disease, such as amyloid aggregation and oxidative stress. In this context, the

nanotheranostic platforms are classified according to the therapeutic strategy to be performed,

which is usually the amyloid-β aggregation inhibition and metal chelation.140


Nanomaterials for amyloid-β aggregation inhibition

The application of nanotheranostics to AD is a clear example of how nanoplatform is

designed according to the type of therapy to be performed. Unlike nanotheranostics for

cancer disease, in which the therapy is usually tumor thermal ablation or specific drug

delivery, for AD the therapy is usually based on the inhibition of the Aβ aggregation, since
these have a direct relationship with the disease’s poor prognosis. In this context, three NIR

dyes (DMA-SLOH, DBA-SLOH, and DPA-SLM) for in vivo imaging of Aβ species and

inhibition of Aβ aggregation have been developed (see Figure 6a).141 The advantage of using

fluorescence imaging is that the use of high cost and low sensitivity MRI and positron

emission tomography (PET) imaging (in which radioactive compounds and use of

sophisticated instruments) are completely avoided. Moreover, the use of NIR fluorescence

reduces the interference caused by native fluorescence biological compounds, which have

wavelength emission peak below 550 nm. Furthermore, the NIR dyes are proven to have

excellent blood-brain barrier permeability, good biostability and renal clearance ability.141

However, since the strategies of nanotheranostics reported for inhibiting the aggregation of β-

amyloids have shown to fail in clinical trials, a multifunctional nanocomposite has been

developed for the specific targeting of Tau and its aggregation inhibition. Tau aggregation is

an independent amyloid-β AD pathology that leads to mitochondrial dysfunction and

consequently oxidative stress generation and cognitive deficit. The nanocomposite consists of

a mesoporous silica nanoparticle that acts as a carrier of ceria and iron oxide nanocrystals, for

antioxidant function and MRI probe, respectively (see Figure 6b).142 The Tau aggregation

inhibition is due to the loading of the carrier with methylene blue. This nanomaterial proved

to be an effective in vivo theranostic agent due to its retention capability in the axon and its

synergic therapeutic effect on AD. Despite this, in order to promote clinical translation of this

nanoplatform, the nanocomposite must fulfill the Lipinski’s rules, which determine its

capability to cross the blood-brain barrier.143


Nanomaterials for Cu2+ chelation

The process of Aβ aggregation is promoted by the increase in the concentration of trace metal

ions, such as Cu2+; therefore, determining its concentration in the brain is an essential tool for

diagnosis of AD. In this context, fluorescence chelators, BTTA composed of a cyclen group
and a benzothiazole aniline group (BTA) has been developed, in which BTA allows specific

fluorescence imaging of Aβ species and the cyclen group acts as an attenuator of the metal

induced Aβ aggregation (see Figure 6c).144 This nanotheranostic agent satisfies the restrictive

terms of Lipinski’s rules and has demonstrated its functionality in vitro and its ability to

penetrate the blood-brain barrier in vivo. However, it should be noted that it requires

structural modifications for longer fluorescence emissions or even NIR emission with

acceptable penetration depth.144 For this reason, UCNPs modified with complex 8-

hydroxyquinoline-2-carboxylic acid (HQC) have been developed. The fluorescence emission

of the UCNPs is quenched when Cu2+ is detected, due to luminescence resonance energy

transfer. As the Cu2+ is captured by HQC, it inhibits the aggregation of Aβ and subsequently

eliminates the toxic Aβ intermediates (see Figure 6d).145 Although this nanomaterial was

reported as a promising nanotheranostic agent in human brain, it is noteworthy that the in

vivo experiment was performed on zebrafish, which has a transparent brain compared to a

complex human brain. In order to determine the efficacy of this nanotheranostic agent for AD

patients, further in vivo assays should be conducted.
Figure 6 Nanomaterials applied as theranostic agents for neurodegenerative diseases.

(a) NIR dyes for in vivo imaging of Aβ species and Aβ aggregation inhibition. Adapted

with permission from ref 141. Copyright 2016 Elsevier. (b) ceria and iron oxide

nanocrystals functionalized nanocomposite as a nanotheranostic agent for MRI and

Tau aggregation inhibitor. Adapted with permission from ref 142. Copyright 2018

American Chemical Society. (c) BTTA for fluorescence imaging and Cu2+ chelators

applied in Alzheimer’s disease. Adapted with permission from ref 144. Copyright 2016

Royal Society of Chemistry. (d) Upconversion nanoparticles for NIR Alzheimer’s
disease detection and therapy based on Cu2+ chelation. Adapted with permission from

ref 145. Copyright 2016 Elsevier.



AUTOIMMUNE DISEASES

The immune system in our body protects us from disease and infection. However, if a person

has an autoimmune disease, the body’s defense mechanism will launch an attack against

specific cells, body tissues and organs of the host. Autoimmune diseases can affect many

parts of the body and significantly affect the patient’s well-being. Environmental, infectious

and genetic factors are some possible factors initiating or exacerbating autoimmune diseases.

There are more than 80 types of autoimmune diseases; with the classic symptom of

inflammation. Current clinical treatment modalities are generally non-specific and focus on

reduction of inflammation. Moreover, the use of anti-inflammatory drugs lack of desired

specificity, has severe toxic effects and limited therapeutic benefits.146

NPs can be used as a drug delivery system to specifically target cells and tissues. Co-delivery

of targeting and therapeutic agents using NPs can greatly improve pharmacokinetics and

enhance bioavailability of therapeutics. NPs used for the treatment of autoimmune diseases

can be classified as colloidal NPs (consist of a metal core stabilized by an organic/polymeric

coating) and organic-based NPs (either polymeric or lipid-based).147 The biodegradability,

biocompatibility, biodistribution and clearance of NPs are very important issues to take into

consideration when constructing an efficient NPs-based nanomedicine for autoimmune

disease theranostics.


Rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease, characterized by

severe cartilage, bone destruction and massive synovial joint inflammation. Currently, there

is no cure for RA.148 The integration of targeting and therapeutic agents in RA into a single
nanomaterial-based theranostic platform is increasingly advancing in rheumatology. This

section will present few nanomaterials that have been discovered lately, with the potential for

synergistic RA theranostics.

Activated macrophages are the main “culprit” of inflammation in RA. The macrophages

actively release cytokines which trigger onset and persistence of RA. Dextran sulfate (DS) is

a hydrophilic polysaccharide that can specifically target the scavenger receptor (SR, one of

the receptors overexpressed on the macrophages). MTX is achemotherapy drug that is

commonly used for the treatment of RA. However, the utility of MTX is limited by its severe

drug resistance, random distribution in the body which may cause serious side effects.

Combining both the benefits of nanoscale prodrugs and modified conjugates, a biocompatible

polymer-drug conjugate, namely dextran sulfate-graft-methotrexate conjugate (DS-g-MTX),

has been designed for treatment of RA (see Figure 7a).149 The conjugate (about 100 nm in

diameter) exhibited excellent SR targeting properties, with improved anti-inflammatory

efficiency in the affected joints of collagen-induced arthritis (CIA) mice.149 Similar work has

also been presented by Heo et al. (2017)150 using MTX-loaded DS NPs (220 nm in diameter),

with the loading efficiency of 73 % (see Figure 7b).150 NPs permit prolonged circulation in

the bloodstream, passive accumulation of drugs into inflamed synovial tissues (12-fold higher

than control), with controlled drug release at desired action sites. The results further

confirmed that polymeric NPs are potentially useful theranostic nanomedicine for RA.150

Solid lipid NPs (SLNs) are formed by a mixture of solid lipids dispersed in inner cores. SLNs

are widely used as matrix for drug encapsulation, mainly because SLNs possess attractive

features such as good physical stability, enhanced biocompatibility and biodegradability,

protection against labile drug degeneration, controlled release and facile synthesis.98,151 HA is

another commonly used drug carriers and targeting ligands in RA treatment.148 HA targets the

over-expressed hyaluronic receptor CD44 on the surface of activated macrophages.
Encapsulation of glucocorticoid prednisolone (PD) can be carried out within the SLNs

conjugated with HA and the resultant product is known as HA-SLNs/PD, with approximately

147.8 nm in diameter. Encapsulation of PD in HA-SLNs improved colloidal stability, slowed

down PD release (37.6 % compared to 56.22% from free drug solution during the first 30

hours), enhanced biodistribution and therapeutic efficacy in CIA model (with a

histopathology score of 2.0).152

Metallic NPs have been successfully translated to RA treatment due to their size and

magnetic properties which can serve as a multifunctional drug delivery and theranostic

platform.148 In a study, researchers designed drug-loaded gold/iron/gold plasmonic NPs for

simultaneous magnetic targeted chemo-photothermal treatment and dual (NIR absorbance

and magnetic resonance) imaging of RA.153 The NPs combine the properties of both iron

(magnetic) and gold (surface plasmon resonance), and the gold exterior shell provides an

anchorage site for further functionalization. Arginine-glycine-aspartic acid (RGD) peptide

was conjugated onto the Au surface to target αvβ3 integrins expressed at the inflammation

sites. Meanwhile, MTX was loaded inside the poly(lactic-co-glycolic acid, PLGA) NPs.

PLGA is selected due to its excellent biodegradability, biocompatibility and stability.154 This

RGD-conjugated MTX-loaded PLGA Au/Fe/Au half-shell NPs has an average diameter of

135 nm. Upon NIR irradiation, NIR resonance of the Au half-shells generates heat at the

inflammation sites to accelerate the release of MTX from PLGA NPs. Besides, the Fe half-

shell layer embedded between the Au half-shell layers allows in vivo T2- MRI and NIR

absorbance imaging [(see Figure 7d).153 The externally generated magnetic field not only

speeds up the delivery of the NPs to the inflammation sites, but also enhances the retention of

the NPs. The combination of NIR absorbance imaging and MRI allow higher spatial

resolution of inflammation regions with outstanding contrast features, higher sensitivity and

specificity. Interestingly, the MTX dosages required in this case is only 0.05% as compared
to free MTX therapy for the treatment of RA.153 The in vivo behavior (such as biodistribution

and vascular penetration) of the as-synthesized NPs requires in-depth studies before wide

clinical application.

A combined strategy PSDT (PDT followed by sonodynamic therapy), using PLGA phase-

transition NPs co-loaded with oxygen and indocyanine green (ICG), termed OI-NPs, has been

proposed for theranostic of RA by Tang et al. (2017).154 PSDT may reduce the sensitizer

dosage and ultrasound/light energy that can alleviate side effects, while improving the

curative effect dramatically. ICG can strongly absorb NIR once activated by light and

ultrasound, suitable for therapy or imaging. The stability of the ICG is improved when co-

loaded with oxygen onto PLGA phase-transition NPs. The synergistic oxygen and ICG are

found to act as a sensitizer and oxygen carrier for PSDT. The prepared NPs have advantages

in terms of biosafety and stability, at the same time showing cytotoxic effects on

synoviocytes (a specialized cell type located inside the joints, responsible in producing

cytokines and proteases, which cause cartilage destruction).154 Nonetheless, the authors did

not report on the performance of the as-synthesized NPs in in vivo model and its therapeutic

effect in hypoxic environment.

Titanium dioxide (TiO2) has shown potential in PDT for some diseases, mainly because of its

excellent biocompatibility, easy availability and ROS generation properties upon excitation.

Tetra sulfonatophenyl porphyrin (TSPP) is a porphyrin derivative that can generate ROS for

PDT, but its application is often hampered by neurotoxicity, phototoxicity and non-specific

accumulation in body tissues. Interestingly, the photo-activated TSPP-TiO2 nanocomposites

were found to be able to ameliorate RA by PDT in CIA models, when coupled with allogenic

bone marrow stem cells (BMSC).155 Meanwhile, Cu is an essential element in the human

body, useful in promoting osteogenesis and chondrogenesis. Cu-based nanomaterials were

reported as excellent PTT agents and photosensitizers for PDT. An approach using Cu-based
nanomaterials in RA treatment has been proposed with good biocompatibility and facile

synthesis (see Figure 7c).156 Upon NIR irradiation at 808 nm, the as-synthesized L-cysteine

(Cys) assisted CuS NPs (named Cu7.2S4 NPs) not only showed better bone preservation, but

also displayed outstanding antibacterial ability during intra-articular injection. Hence, the

Cu7.2S4 NPs could serve as a synergistic PDT and PTT modality for RA.156

Drug delivery systems can be manipulated in a way that the nanomaterials only release the

drug from the conjugate in response to certain conditions. This is important in avoiding

systemic distribution of drugs in the body that necessitates the use of sustained high-dose

therapy and may give rise to adverse effects. As such, Li et al. (2017) presented pH-sensitive

polymeric micelles for targeted drug delivery to inflamed joints.157 The polymeric micelles

(with particle size of 45.76 nm) are stable in the bloodstream, until it reaches the

inflammation sites. An imbalance between increased metabolism and insufficient oxygen

supply contributes to low pH in the inflamed synovial fluid (as low as pH 6.0, in some cases

even lower than 5.0).158 Recognition of acidosis of synovial fluid triggers hydrolysis of

hydrazone bonds, subsequently releasing the drug, PD in affected joint areas. Same process

has also been reported for targeted drug delivery to the acidic microenvironment of solid

tumors. The results demonstrated improved therapeutics efficacy, with the therapeutic

benefits from each injection lasting for 48-72 hours in preclinical models,159 fulfilling the

needs of sustained prodrug activation kinetics for RA treatment. The as-prepared polymeric

micelles inevitably display minimal toxicity, which could be due to micelle uptake by

phagocytic cells in liver and spleen that initiates inflammatory responses.157 Key mechanistic

details that induce potential toxicity and inflammatory effects, long-term nanomaterial fates

in clearance organs as well as macrophage-nanomaterial interactions are generally

unexplored.160 Future research can be anticipated on fabrication of micelles with bone

regeneration capabilities in eroded joints.
Generally, the RA severity often fluctuates over time. Usually, the treatment offered, doses of

drug applied and its release rates are irrespective of disease stage, resulting in non-optimal

therapeutic efficacy with potential side effects. Herein, a drug-loaded hydrogel that responds

to RA flare-ups in real time has been innovatively introduced.159 A hydrogel is a three-

dimensional polymer network of hydrophilic monomers that can absorb and retain a large

amount of water, without affecting its shape. Since it can mimic a native tissue’s architecture

and functions, hydrogel often has been used as drug-delivery carriers.161 In this case, a

hydrogel is formed from the self-assembly of triglycerol monostearate (TG-18), encapsulated

with drug triamcinolone acetonide (TA).159 Synovial fluid from RA joints has higher

expression of matrix metalloproteinases (MMPs) and other tissue-degrading enzymes than

synovial fluid from healthy joints.159 Therefore, upon exposure to synovial fluids from

patients with RA, MMPs cleave the ester bond in TG-18, disassemble the hydrogel and

release the encapsulated TA on-demand, which exclusively corresponds to the concentration

of MMPs expressed in the synovial fluids. The severity of the RA is reflected by the co-

loaded fluorescent dye 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide

(DiR).159 Metalloproteinases-3 (MMPs-3) gene is one of the biomarkers of RA and often

correlated with systemic inflammation. Although the precise role of MMPs-3 in RA

progression requires further elucidation, TA is believed to be able to alter genes expression of

MMPs-3.162 However, the system still requires extensive in vivo biocompatibility evaluation,

sustained TA drug release and encapsulation studies especially in large animal models. It is

challenging to maintain a consistent release profile in the setting of constant physiochemical

changes.
Figure 7 Brief overview of the structure of the nanomaterials used for rheumatoid

arthritis theranostics. (a) MTX prodrug, TEM microimages of DS-g-MTX and its ex

vivo FITC image of affected joints. Adapted with permission from ref 149. Copyright

2017 Ivyspring International Publisher. (b) DS-NPs as a nanocarrier for targeted RA

theranostic. Adapted with permission from ref 150. Copyright 2017 Elsevier. (c)

Application of Cu7.2S4 NPs in RA theranostic when combined with PTT and PDT. The

respective TEM image, SAED and interplanar crystal spacing of Cu7.2S4 NPs. Adapted

with permission from ref 156. Copyright 2018 John Wiley and Sons. (d) MTX-Au/Fe/Au

plasmonic NPs for magnetic targeted chemo-photothermal treatment of RA. Adapted

with permission from ref 153. Copyright 2015 Elsevier.



CARDIOVASCULAR DISEASES

Cardiovascular diseases (CVDs) are the leading cause of non-communicable illness

worldwide. Current surgical intervention and therapy for CVDs are not completely effective
and face many medical challenges. For instance, current recommended therapeutic regimes

barely lead to full recovery and often involve poor efficacy, drug instability and resistance, as

well as adverse effects and high costs.163 Advances in nanomedicine offers theranostic

approaches for CVDs.161 It is observed that most of the scientific researches are focused on

the study of non-invasive biological imaging applications (particularly MRI and near-infrared

fluorescence (NIRF)) for early detection of atherosclerotic plaque. Additional therapeutic

strategies for CVDs are highly imperative in actualizing CVDs theranostic applications.


Atherosclerosis

Atherosclerosis, a systemic disease affecting arteries, is the major pathological cause of

CVDs. Atherosclerosis is characterized by the formation of atherosclerotic plaques, which are

developed through the accumulation of cholesterol and formation of foam cells in the arterial

wall.164 Atherosclerotic plaques tend to induce hardening of the artery and thus obstruct blood

circulation.165

Report for non-invasive fluorescence imaging of atherosclerosis in live atherosclerotic mice

has been published in 2016, with the use of Simian virus 40 virus-like particles (SV40 VLPs)

as a platform to load imaging probes, targeting elements and therapeutic compounds (see

Figure 8a).166 Controllable in vitro self-assembly and the capacity as the cargo for foreign

peptides or proteins, makes SV40 VLPs stand out as a nanomaterial in various

nanotheranostic applications.167 Encapsulation of NIR QDs (QD 800) inside SV40 VLPs

improved QDs photostability, brightness and detection sensitivity during fluorescence

imaging of atherosclerotic plaques in mice.166 In fact, different atherosclerosis biomarkers or

targeting peptides are present at various developmental stages of atherosclerosis.168 Vascular

cell adhesion molecule-1 (VCAM-1), macrophages and fibrin have been identified and used

to target atherosclerosis at early, development and late stage, respectively. The

multifunctional QDs, with a diameter of 26 nm, permits its accumulation inside the
atherosclerotic plaque tissues mediated by EPR effect, in response to the inflammatory

process in the vascular. Enhanced targeted delivery of anticoagulant drug Hirulog (about 6.5-

fold increase) and higher anti-thrombin activity (1.8 µg/mg of tissue) at atherosclerotic

plaques has been reported when QDs are functionalized with VCAM-1 targeting peptide.166

However, the group did not provide strong justification on the atherosclerosis efficacy of

these NPs, such as reduced areas of plaques, counts of infiltrated immune cells or the

expression of inflammatory markers.169 Future studies should be focused on more detailed

biocompatibility evaluation of the SV40 VLPs, including blood-half life, immunogenicity

and comparisons with other protein cages to justify its potential as theranostic tools for

atherosclerosis.

H2O2 is a highly promising theranostic biomarker in various pathological disorders, however,

its fluorescence imaging modalities are hindered by its short tissue penetration depth. ICG is a

widely used photoacoustic contrast agent with a high signal to noise ratio and maximum

emission at around 800 nm. Yet, its application is often challenged by instability, rapid blood

clearance and non-targeting ability.170 Jung et al. (2018) loaded ICG onto boronated

maltodextrin (BM) NPs to form spherical ICG-BM NPs with a diameter of 500 nm.170

Maltodextrin, one of the polysaccharides obtained from partial hydrolysis of starch, is water

soluble, biocompatible, biodegradable, versatile and easy to modify. Hence, maltodextrin is

suitable to be used as a diluent, coating material and carrier of diagnostic or therapeutic

agents in drug delivery system. Substitution of hydroxyl groups of maltodextrin with boronic

ester forms BM, rendering maltodextrin with H2O2-responsive properties. ICG-BM NPs react

with H2O2 to generate echogenic carbon dioxide (CO2) bubbles which significantly enhanced

fluorescence (almost 2-fold higher); ultrasound (signal detectable even with low-frequency

ultrasound transducer); and photoacoustic signals in H2O2-triggered manner. Moreover, ICG-

BM NPs could exert therapeutic effects by scavenging the overexpressed H2O2 and
simultaneously release therapeutic 4-hydroxybenzyl alcohol (HBA). HBA displays anti-

inflammatory, antioxidant and antiplatelet functions by suppressing the expression of pro-

inflammatory tumor necrosis factor-alpha (TNF-α) and soluble CD 40 ligand in activated

platelets,171 thus relieving inflammation and accelerating angiogenesis.170 Future work can be

anticipated on reducing the size of ICG-BM, since NPs with sizes over 100 nm are easily

recognized by macrophages and accumulate in lymph nodes, liver, spleen as well as lungs.59

High density lipoproteins (HDL) are responsible for reverse cholesterol transport (RCT), a

process to efflux excess cholesterol in the periphery back to the liver. RCT is important in

protecting against CVDs. A magnetic nanostructure (MNs) functionalized with phospholipids

and apolipoprotein A1 (apoA1), named HDL-MNs, has been developed to mimic the natural

HDL particles present in the body (see Figure 8b).172 The MNs are biocompatible and

composed of Fe3O4 NPs, suitable to be used as contrast agents for MRI. The use of HDL-

MNs for CVDs is a non-invasive imaging and therapeutic approach. Apart from being

capable of precise targeting of macrophages, HDL-MNs are able to perform RCT by inducing

cholesterol efflux (about 4.8 %, in natural HDL is about 4.7 %) from cholesterol-rich

macrophages. The HDL-MNs have also shown 5 times higher MR contrast enhancement than

commercial FDA approved T2 MRI contrast agent (Ferumoxytol). The HDL-MNs are found

not inducing cytotoxicity in in vitro setting, in macrophages of up to 350 µM HDL-MNs.172

The hydrodynamic diameter of the nanostructure, however, is approximately 80-100 nm,

which is too big for EPR-based extravasation and may impact its circulation time in blood

and accumulation at atherosclerotic plaques. It is of interest to further investigate the

targeting ability of this nanostructure in in vivo setting. In addition, the use of iron-based NPs

could potentially generate harmful radicals (Fenton reaction). This may limit their use in

humans for diagnosis and treatment, especially under oxidative stress-related conditions.
Recently, researchers have turned their attention to activation of transient receptor potential

vanilloid subfamily 1 (TRPV1) signaling pathway as one of the alternatives for attenuating

atherosclerosis (see Figure 8c).164 Activation of TRPV1 cation channels may reduce lipid

storage and formation of atherosclerotic lesions. Yet, clinical use for the normally used

TRPV1 cation channels activator, capsaicin, is limited by its chronic toxicity and infusibility.

Unlike the optical absorption in gold nanostructures, which is due to the surface plasmon

resonance, NIR absorption of CuS NPs derives from the d-d transition of Cu2+ ions. In other

words, CuS NPs absorption would less likely be influenced by the solvent or the surrounding

factors, which is perfect for in vivo setting. CuS NPs also possess almost analogous high heat

conversion efficiencies (as high as 80 %) compared to gold nanostructures, making them

remain stable under prolonged optical excitation.173 Coupling of CuS NPs to antibodies

targeting TRPV1 acts as a photothermal switch for TRPV1 signaling in vascular smooth

muscles. Upon irradiation of CuS NPs by continuous wave laser at 980 nm, 5 W/cm2 for 350

s, the NPs (with particle size of 13 nm) generate local heat and strong photoacoustic signal

which subsequently opens TRPV1 channels and causes calcium ions (Ca2+) influx. The

increase in intracellular Ca2+ induces autophagy, reduces lipid accumulation and foam cell

formation. The cholesterol efflux was enhanced with no obvious long-term toxicity in vivo.

With photoacoustic imaging, high resolution visualization with high temporal and spatial

precision of blood vessels in the deeper cardiac regions (such as aortic arch, carotid artery

and femoral artery) were achieved.164
Figure 8 Brief overview of the structure of the nanomaterials used for atherosclerosis

theranostics. (a) Multifunctional virus-like particles of Simian Virus 40 NPs (SV40

VLPs) with the TEM image. Adapted with permission from ref 166. Copyright 2016

American Chemical Society. (b) High-density lipoprotein-like magnetic nanostructures

(HDL-MNs) with their TEM images when synthesized using different approaches.

Adapted with permission from ref 172. Copyright 2017 American Chemical Society. (c)

Copper sulfide (CuS) NPs as a photothermal switch for TRPV1 signaling to attenuate

atherosclerosis, with the TEM image. Adapted with permission from ref 164. Copyright

2018 Springer Nature.
Thrombosis

The vulnerable plaques located in the arterial wall are prone to rupture due to soft and weak

fibrous cap. The rupture exposes collagen and various components to the blood, leading to

the formation of blood clots (thrombi (plural); thrombus (singular)) in the lumen. This

condition is known as arterial thrombosis.164 Thrombosis rarely show any symptoms until late

stage and sudden death.174 Generally, a thrombus is made up of blood factors, mainly

activated platelets and water-insoluble fibrin. P-selectin is an adhesion molecule mainly

involved in the pathophysiology of thrombosis and other CVDs.174 Li et al. (2018)

innovatively functionalized fucoidan, a marine polysaccharide that specifically targets P-

selectin in thrombus, on polysaccharide-coated microbubbles (MBs).174 Ultrasound imaging

is one of the commonly used medical diagnostic imaging modalities owing to their

portability, non-invasiveness with excellent safety profile, high spatial resolution, lack of

ionizing radiation, reasonable cost and real-time imaging properties.59 The as-synthesized

fucoidan functionalized microbubbles (fucoidan-MBs) exhibit high echogenicity and stability

in suspension at 4°C (up to 2 months),174 hence suitable to be used as a sensitive molecular

ultrasound contrast agent by creating strong acoustic reflections that may identify thrombus.

However, possible treatments for thrombosis after imaging are not discussed by the authors

of this study. Future studies could, therefore, focus on theranostic capabilities, safety and

efficacy of fucoidan-MBs, as well as the possibility of incorporation of antithrombotic drugs

into the system.

A thrombus is also usually associated with an elevated level of H2O2. H2O2 is an important

signaling messenger regulating the activity of signaling proteins, enzymes and ion channels.

Upregulation of H2O2 may bring harmful oxidative damage, leading to apoptosis and tissue

damage.161 Inspired by these phenomena, fibrin-targeted imaging and anti-thrombotic

nanomedicine (FTIAN) has been constructed for thrombosis theranostic (see Figure 9a).165
With a diameter of 160 nm, FTIAN has been prepared from self-assembly of IR820 NIR

fluorescent dye-conjugated boronate antioxidant polymers (fBAP) and lipopeptides (lipid-

PEG-CREKA) composed of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), PEG,

and a pentapeptide, CREKA (Cys-Arg-Glu-Lys-Ala). High level of H2O2 in thrombus

oxidizes boronate in FTIAN and stimulates subsequent release of HBA from fBAP,165

initiating antioxidant and anti-inflammation activities.171 On the other hand, high affinity of

CREKA in the lipopeptide towards fibrin facilitates the specific targeting of fibrin on the

obstructive thrombus using FTIAN. With the use of IR820 as an NIR fluorophore and

photoabsorber, the fluorescence/photoacoustic imaging of thrombi has also significantly

enhanced by 5-fold. Most importantly, the intrinsic anti-thrombotic activity of FTIAN has

suppressed thrombus formation (required a dose of 24 µg/kg of tirofiban only as compared to

a clinically used dose of 80 µg/kg).165

Another thrombus-specific theranostic (T-FBM) NPs have been developed with a mean

diameter of 260 nm (see Figure 9b).171 T-FBM NPs is composed of lipopeptide,

GPRPPC−PEG−DSPE (distearoylphosphatidylethanolamine). The pentapeptide, GPRPPC, is

used to target the thrombus since it has high affinity to fibrin as well. PEG (3.4 k) serves as a

surface corona which may prevent non-specific interaction of T-FBM NPs with plasma

proteins. The ultrasound/photoacoustic contrast of T-FBM NPs has been significantly

enhanced (by 5-fold) when triggered with H2O2. This is because H2O2 generate CO2 bubbles

to amplify the photoacoustic signal. These NPs are also suitable to be used as an anti-

thrombotic nanomedicine, since the NPs can release anti-oxidant and anti-inflammatory HBA

under oxidative stress-related conditions. Based on the findings, there is an obvious

suppression of the thrombus formation in the studied mouse models. However, for most of

the works described in this section, the researchers did not report the dose, pharmacokinetics,

side effects and toxicology of the NPs used. In fact, the biocompatibility and biodegradability
of the NPs are equally important in future clinical applications. Also, unlike non-motile solid

tumor, thrombi ultrasound imaging analysis is often challenged by poor contrast resulting

from the interference of motion artifact caused by respiratory and cardiac activities.174




Figure 9 Brief overview of the nanomaterials used for thrombosis theranostics, with

their TEM images. (a) Fibrin-targeted and H2O2-responsive NPs as a theranostics for

thrombosed vessels. Adapted with permission from ref 165. Copyright 2017 American

Chemical Society. (b) T-FBM NPs as a H2O2-activatable photoacoustic signal amplifier

and a thrombus-specific nanotheranostic agent. Adapted with permission from ref 171.

Copyright 2018 American Chemical Society.



BACTERIAL INFECTION

Bacterial infection is one of the world’s leading causes of premature deaths and mortalities.

Current methodologies for diagnosis and therapy of bacterial infection are often hindered by

a difficult bacteria isolation and early detection, low numbers of bacteria in the clinical
specimen, false negatives and contamination of the specimen.1 Poor sensitivity and late

diagnosis often delay the therapy and thus increase the cost and discomfort to the patients.

The development of drug resistance in the bacterial pathogen and the overuse of antibiotic are

also concerns in bacterial infection management. This section will discuss different

nanomaterials with their potential in bacteria nanotheranostics and provides a critical review

on their advantages and limitations.

The work on both in vitro and in vivo multi-modal mapping and targeted PTT against

bacterial infection of gastrointestinal tract was introduced in 2015, with the use of tungsten-

based theranostic agents.175 Since then, different nanoprobes capable of selectively imaging

bacteria with high anti-microbial properties have been proposed. Selenium (Se) is a semi-

metallic element with low electronegativity and large atomic radius compared with sulfur,

endowing Se-containing compounds with high reactivity and sensitivity.176 Moreover, the

stimulus-responsive property of Se gives the materials a big potential in construction of smart

and sensitive theranostic systems responding to biomolecules.176 Ruthenium (Ru) is a rare

metal in the earth’s crust with diverse biomedical and antimicrobial applications, especially

in its complex form.177 For instance, Ru complexes have been found to display synergistic

antimicrobial activity with antibacterial peptide UBI29-41 (PEP)-modified Se particles (see

Figure 10d).178 This multifunctional theranostic nanoplatform, or known as Se@PEP-Ru

NPs, displayed good biocompatibility, excellent selectivity and potent antimicrobial activity.

The NPs strongly interact with both gram-positive and gram-negative bacteria cell

membranes, followed by severely damaging the structures of the bacterial cell and

cytoplasmic membranes. The wound sizes of the mice treated with Se@PEP-Ru NPs were

found to decrease by about 40% at the fourth day after surgery, showing a significant

therapeutic effect. Besides, since Se@PEP-Ru NPs are sensitive to sites of bacterial infection,

it was found to be able to identify and distinguish bacterial infection from inflammation and
tumor-induced tissue infection with high specificity.178 Evident fluorescence can be observed

(after 4-48 hours of injection) at the site of the bacterial infection but the fluorescence was

almost negligible (2-3 times weaker) at the site of inflammation. Future studies can be

focused on engineering the as-synthesized Se@PEP-Ru NPs (with a size of about 78 nm) into

a smaller size as the size and surface area of NPs could affect the antibacterial activity.179

Smaller NPs (less than 10 nm) are generally more effective since it allows favorable surface

area of NPs for interaction with the bacterial cell membrane and disruption of bacterial

permeability and respiration.180

Metabolic biomolecular labelling is an emerging technology to modify the surface of cells

and pathogen with chemical functional groups, which in turn allows conjugation of

fluorescent dyes (for imaging purpose) or drugs (for therapeutic effect) onto cell

membrane.181 Metal-organic frameworks (MOFs) can be engineered as drug nanocarriers,

thanks to their versatile chemical properties, good biocompatibility, sensitive to low pH

tumor environment and fast body clearance after drug delivery. A bacteria theranostic

strategy through coupling of MOFs with metabolic labelling technique has been reported

recently (see Figure 10a).181 Mao et al. (2018)181 innovatively used MIL-100 (Fe)

nanoparticles (with an average diameter of 120 nm) as the nanocarriers for metabolic

labelling molecule and 3-azido-D-alanine (D-AzAla), to target bacterial cells. The NPs are

stabilized by polymer pluronic F-127. The high H2O2 inflammatory environment stimulates

degradation and rapid release of D-AzAla from MIL-100 (Fe) at the inflammation sites. Upon

internalization of D-AzAla by the bacteria, unnatural azide groups will be expressed on the

bacterial cell walls. Ultrasmall photosensitizer NPs with around 10 nm, named

dibenzocyclooctyne (DBCO)-modified 2-(1-(5-(4-(1,2,2-tris(4-

methoxyphenyl)vinyl)phenyl)thiophen-2-yl)ethylidene)malononitrile NPs (US-TPETM NPs),

with aggregation-induced emission characteristics are subsequently administered. DBCO
groups on the surface of NPs will bind and react with the bacteria through in vivo click

chemistry. The bacterial cell walls will be lightened up to produce fluorescence signals for

imaging, facilitating subsequent image-guided antibacterial therapy and PDT.181 This

breakthrough in in vivo incorporation of unnatural functional group into bacteria for

metabolic labelling and antibacterial therapy could soon enable the discovery of more

effective bacterial theranostic approaches.

Luminescent porous silicon (LuPSi) has tunable porosity and surface chemistry, good

biocompatibility and degradability, making them suitable as optical biosensors for

bioimaging and drug delivery. LuPSi can be loaded with antibiotics ciprofloxacin (CIP) to

form CIP-LuPSi for theranostic application.182 For wound care application, a smart bandage

composed of polyurethane (PU) membrane and chitosan film, has been presented by Chen et

al. (2017) for monitoring and inhibition of wound infection.182 High level of ROS and

elevated pH (above 7.4, normal skin pH= 5.5- 6) are two main biomarkers in chronic or

infected wounds.182 The luminescent property of LuPSi is correlated with its surface

chemistry. The blue luminescence of CIP was quenched by red LuPSi due to the fluorescence

resonance energy transfer (FRET) effect. When the smart bandage is applied onto the

infected wound that usually associated with an elevated level of ROS and alkaline ions (such

as PO43- or OH-), the surface of LuPSi was oxidized into an insulating oxide layer that

blocked the energy transfer between LuPSi and CIP. As a result, the fluorescence of CIP

recovered (from red to blue) and can be observed by naked eyes and a cell phone camera.

Therefore, by detecting the ratiometric fluorescence intensity, the kinetic process of surface

oxidation of CIP-LuPSi can be precisely measured. The oxidation of LuPSi also

simultaneously trigger the release of CIP to inhibit bacterial activity. In the same year, Zhao

et al. (2017) developed silica NPs coated with vancomycin-modified polyelectrolyte-cypate

complexes (SiO2-Cy-Van), with a size of about 72.7 nm, as a bacteria-activable theranostic
nanoprobe (see Figure 10c).183 The polyelectrolyte acts as an adsorbate or dissociation energy

barrier on silica NPs, conferring the NPs with bacteria-responsive feature, as well as

enhanced biocompatibility and relatively prolonged blood circulation. The cell wall of

methicillin-resistant Staphylococcus aureus (MRSA) bacteria is capable of forming hydrogen

bonding with vancomycin (Van) on the nanoprobes. The interaction between Van and MRSA

detaches the layer-by-layer assembled polyelectrolytes from silica NPs, changing the state of

cypate (Cy), a dye with NIR fluorescence emission at around 825 nm, from OFF

(aggregation) to ON (disaggregation). This leads to rapid MRSA-activated NIR imaging (4

hours post-injection, high sensitivity up to 105 colony-forming units) and effective PTT upon

808 nm laser irradiation.183 However, the possibility of autofluorescence and influences of

bacterial environment on the sensitivity and selectivity of the nanoprobes are not clearly

demonstrated. On the other hand, the idea of bacteria-responsive intelligent wound dressing

proposed by Zhou et al. (2018)184 has also offered a different perspective in the fabrication of

nanomaterials to combat bacterial infection. The group constructed a biocompatible UV-

photocrosslinkable methacrylated gelatin (GelMA) encapsulating both antimicrobials and

self-quenching dye carboxyfluorescein vesicles. The working principle is that upon bacterial

infection, toxins or enzymatic factors secreted from bacteria could break down the lipid

vesicles and release the payloads. This eventually leads to bacterial inhibition in addition to a

visual color change (due to the fluorescence recovery of carboxyfluorescein). Supported by

both in vitro and in vivo studies, the release of antimicrobials occurs only when pathogenic

bacteria (specifically MRSA and Pseudomonas aeruginosa) exist.184

Gold nanomaterials are antibiotic agents owing to their tunable size, facile functionalization

and minimal toxicity. It is interesting that recently, gold nanoclusters (AuNCs) have been

demonstrated to exhibit anti-bacterial activity,185 especially by manipulating their surface

ligand chemistry.186 Quaternary ammonium (QA) capped AuNCs (QA-AuNCs), with the size
about 2 nm, can selectively target MRSA and Van-resistant Enterococci (VRE), in vivo.185

Since QA-AuNCs can disrupt the bacterial cell membrane (in terms of integrity, permeability

and inner potential), catalyze the generation of ROS and disturb the intracellular metabolic

pathway of the bacteria, QA-AuNCs displayed excellent therapeutic effects. The intensely

fluorescent QA-AuNCs interact with live/dead bacteria differently, suggesting their potential

for image-guided bacteria discrimination and counting. Besides, QA-AuNCs are stable for

long-term storage, even at room temperature.185 On the other hand, it should be noted that it

is difficult to compare the anti-bacterial performances of different nanomaterials, since the

composite design and concentration of each multifunctional nanomaterial used can be very

different, unless more comparable studies are conducted under standard experiment

conditions.

Gold nanorods (AuNRs) are an excellent contrast agent for PA imaging and have

characteristic strong NIR absorption. Kim et al. (2018) have developed a gold/silver hybrid

NPs, named as Au/AgNRs, as theranostic antibacterial/photoacoustic agent (see Figure

10b).187 Au/AgNRs (with a diameter of 104.9 nm) are formed by coating AuNRs with silver

(Ag) to decrease the photoacoustic signal.187 Oxidative etching of the Ag shell induced by the

addition of ferricyanide solution (1 mM) could recover the photoacoustic contrast as the Ag is

released. The release of Ag also effectively triggers and monitors the release of Ag+ ions (a

well-known antibacterial agent) from its reservoir AgNPs. Ag+ ions exhibit strong

bactericidal efficacy towards both MRSA (32 µM Ag+) and Escherichia coli (8 µM Ag+).

The photoacoustic signal increased by 730 % pre- and post-etching, and the bacterial counts

in infected tissues were reduced by 1000-fold (log CFU/g= 4.15 vs 7.75) in the treated

group.187 This is the only report that quantitates Ag release in vivo and correlates the released

dose to antibacterial outcomes.
Hydrogels are the three-dimensional water-swollen polymer networks composed of

hydrophilic polymers. It can be used as a scaffold for local bacterial drug delivery since it can

achieve long retention at the focal area with low unwanted diffusion.188 A NIR light-

triggerable and thermo-sensitive hydrogel that can combat bacterial infection and promote

wound healing have been introduced recently.188 This injectable hydrogel is composed of

ciprofloxacin (Cip)-loaded polydopamine NPs (PDA NPs) and glycol chitosan (GC). The

aromatic rings on the surface of PDA NPs enable the adsorption of drugs via - stacking

and hydrogen bonding; while the quinone groups on the surface of PDA NPs allow facile

conjugation with the chemicals containing thiol or amine groups. GC is rich in amine,

therefore, has been used to crosslink with PDA NPs. With a uniform size of about 30 nm,

PDA NPs also possess excellent photothermal effect (the ability to convert NIR light into

heat), biocompatible and biodegradable. The positive charge of GC and the adsorbability of

PDA NPs are able to trap bacteria on the surface of the hydrogel with minimal leakage under

physiological conditions. Once irradiated with NIR light, Cip antibiotic will be released.

Meanwhile, PDA NPs in the hydrogel will be activated and subsequently generate local heat

to kill the bacteria, with a bactericidal efficacy up to 98.9 %.188

Despite its efficacy, inorganic NPs as antibacterial agents are constrained by their non-

specific biological toxicity or potential long-term in vivo retention. Applications of metal-free

antibacterial agents such as polymers are still facing limitations, including poor

biocompatibility, complicated synthetic steps, limited structural tunability and/or the need for

suitable carriers to ensure the spatial stabilization at the injection site. Generally, it is difficult

to compare different nanomaterials from the aspects of their photothermal conversion

efficiency or bactericidal performances.
Figure 10 Brief overview of the nanomaterials used for bacterial infections theranostics,

with their TEM images. (a) H2O2-responsive MOFs assisted in vivo metabolic labelling

of bacteria and precise antibacterial therapy. Adapted with permission from ref 181.

Copyright 2018 John Wiley and Sons. (b) Formation of Au/AgNRs hybrid NPs by Ag

coating on AuNRs. The addition of ferricyanide solution results in oxidative etching of

the Ag shell. Adapted with permission from ref 187. Copyright 2018 American Chemical

Society. (c) SiO2-Cy-Van as a theranostic nanoprobe against MRSA infections. Adapted

with permission from ref 183. Copyright 2017 American Chemical Society. (d)

Fabrication of Se@PEP-Ru NPs for identification of bacterial infection with

simultaneous targeted antibacterial activity. Adapted with permission from ref 178.

Copyright 2017 Elsevier.
TABLE OF SUMMARY

Table 1 A Summary of Functional Nanomaterials Developed for Different Cancer/Diseases/Illness

 Cancer/Disease   Type of          Formulation     Mean size    Therapeutics    Imaging   Animal     Brief description/    Ref.

 /Illness         nanomaterial                     (nm)         modality        modality model       Remarks
                                                                                                                           63
 Cancer (Solid    Gold             Diazirine-      20.5 ± 1.9   PTT             PAI       Female     Light-addressable

 tumor)           nanostructures   decorated                                              BALB/c     cross-linking at

                                   Au@PEG-NH2                                             mice       405 nm laser

                                                                                                     irradiation
                                                                                                                           41
                                   AQ4N-Cu(II)-    137.07 ±     PDT, PTT,       Optical   Male       Tumor

                                   AptCe6-GNPs     4.26         chemotherapy              BALB/c-    microenvironment

                                                                                          nude mice -triggered,

                                                                                                     programmed

                                                                                                     synergistic therapy

                                                                                                     at 670 nm laser

                                                                                                     irradiation
                                                                                       67
SWNT@BSA@      20–30        PTT,           Optical    Female     High drug loading

Au-S-PEG-      (estimated   chemotherapy              nude mice ratio (150–590 %);

FA@DOX         thickness)                                        808 nm laser

                                                                 irradiation
                                                                                       46
Stealth-AuNC   80-100       PTT            Optical    BALB/c     850 nm laser

NPs                                                   mice       irradiation; longer

                                                                 circulation half-

                                                                 life (> 4-fold)
                                                                                       73
AuNR@Da        130          PTT,           Fluoresc   Nude       Photothermal

NHs                         chemotherapy   ence,      mice       conversion

                                           PAI                   (80 %); 27-fold

                                                                 higher internalized

                                                                 AuNR mediated

                                                                 by NHs; 6.6 times

                                                                 higher internalized

                                                                 ADR; 2.3 times
                                                                 higher tumor

                                                                 accumulation due

                                                                 to NIR-induced

                                                                 hyperthermia
                                                                                        80
Other           MnO2-SPs     295           PTT   MRI   BALB/c-   Ultra-sensitivity to

inorganic       nanosheets   (average                  nude mice endogenous tumor

nanomaterials                thickness =                         microenvironment

                             2.0 nm)                             and exogenous

                                                                 NIR irradiation;

                                                                 808 nm laser

                                                                 irradiation; high

                                                                 photothermal-

                                                                 conversion

                                                                 efficiency

                                                                 (21.4 %)
                                                                                    82
Anti-EpCAM-   93.5   Chemotherapy, MRI,          Female      MX loading level

UPGs-MX              PDT             upconver    BALB/c      (12.5 wt %);

                                     sion        mice        980 nm laser

                                     luminesc                irradiation

                                     ence
                                                                                    81
mNiO-TB-ART   310    PTT, radical-   Optical     HeLa        T2-weighted MRI,

                     induced         luminesc    tumor       r2 = 6.30 (mg

                     therapy         ence, T2-   mice        mL−1)−1 s−1;

                                     weight      models      NIR laser

                                     MRI                     irradiation at 785

                                                             nm
                                                                                    44
Pd@Pt-PEG-    80     PDT, PTT        Optical     4T1         Laser irradiation at

Ce6                                              subcutane   660 and 808 nm;

                                                 ous tumor   hypoxia

                                                 mice        modulation

                                                 model
                                                                  function with mild

                                                                  PTT effect

                                                                                         43
BiP5W30 NCs   1.5           Radiotherapy,   Optical     HeLa      Laser irradiation at

              (thickness    PTT                         tumor-    808 nm; increased

              of rGO)                                   bearing   radiation dose

                                                        mice      deposition within

                                                                  tumors; tumor

                                                                  microenvironment

                                                                  -manipulated
                                                                                         77
CuS@BSA-      51.2 ± 2.46   PTT             Optical     EAC       Laser irradiation at

MBA-cRGD                                    (infrared   tumor-    808 nm;

                                            thermal)    bearing   synergistic tumor-

                                                        mice      targeting delivery

                                                                  and PTT effects
                                                                                         87
TPGS-Cu3BiS3    15            Radiotherapy,   Optical    Female     Photothermal

NCs                           PTT                        BALB/c     conversion

                                                         nude mice efficiency at 1064

                                                                    nm = ∼67.29 %;

                                                                    808 nm =

                                                                    ∼18.27 %; 980 nm

                                                                    = ∼61.06 %
                                                                                         84
FA-QDs-FUA      220.28        Chemotherapy    Optical    Balb/c     Zeta potential= -

                                                         Nod/Scid   13.3 mV; drug-

                                                         mice       loading content =

                                                                    36.85 % ± 1.61 %

                                                                    (n= 3)
                                                                                         85
Gd-DTPA-        4.08 ± 0.58   -               Optical,   Female     Contrast agents in

coupled Ag2Se                                 MRI        Balb/c     in vivo dual-

quantum dots                                             mice       modality T1-

                                                                    weighted MR
                                                           imaging; NIR-IIb

                                                           fluorescence

                                                           imaging with high

                                                           spatial resolution
                                                                                47
PHMNPs-S-S-    16.07    Chemotherapy   Optical,   Nude     High

PEG-                                   MRI        mice     etoposide/oxygen

LA@PFC(O2)/E                                               loading capacity,

P                                                          tumor-targeting

                                                           capability and

                                                           programmable

                                                           intracellular

                                                           agglomeration

                                                           behavior
                                                                                70
Cu3BiS3        12 ± 4   PTT, PDT       Optical,   BALB/c   Ultra-low NIR

nanocrystals                           x-ray      nu/nu    laser irradiation

                                       contrast   mice
                                                                                45
Co3O4       3.26 x 33.29 PTT,               MRI,   Nude   Photothermal

nanoprism   (thickness x   chemodynamic optical    mice   conversion

            length)        , chemotherapy                 efficiency, =

                                                          60.07 %; MRI

                                                          contrast, r2= 5.42

                                                          mM-1s-1;

                                                          significant

                                                          hydroxyl radical

                                                          generation; low

                                                          toxicity; DOX

                                                          delivery = 29.36

                                                          mg/g; low

                                                          detection limit (50

                                                          nM), broad linear

                                                          range (0-50 M);

                                                          high sensitivity
                                                                                 and selectivity for

                                                                                 H2O2
                                                                                                       90
Polymeric       SiNc-PNP,         40         PTT, NPs-      Optical   Female     Real-time

nanoparticles   encapsulated in              mediated                 athymic    intraoperative

                PEG-PCL                      image-guided             nude mice image-guided

                                             surgery                             surgery; 785 nm

                                                                                 laser irradiation;

                                                                                 process can be

                                                                                 tailored via photo

                                                                                 irradiation dosage
                                                                                                       89
                M-GEG NPs,        105 (GEG   Chemotherapy   Optical   New        Sustained and

                M-EGFA NPs        NPs), 90                            Zealand    targeted drug

                                  (EGFA                               albino     release at the

                                  NPs)                                rabbits,   tumor site

                                                                      athymic
                                                 mice

                                                 models
                                                                              92
POCL           50       PDT            Chemilu   BALB/c   Self-luminescing;

nanoreactor                            minescen nude mice tumor

                                       ce                 microenvironment

                                                          activated; non-

                                                          invasive
                                                                              93
FUP cationic   30-150   Chemotherapy   Optical   -        Surface charge of

nanomicelles                                              zeta potential

                                                          +20.1 mV;

                                                          antitumor

                                                          apoptosis

                                                          mechanism might

                                                          be related to the

                                                          regulation of

                                                          Fas/FasL and
                                                          activation of

                                                          caspase-8 and

                                                          caspase- 3
                                                                                 95
Cu2-          123.7   HIFU           PAI        Balb/c    Core/satellite/shell

xS/PFBO@PLG                                     nude mice sandwich

A                                                         structure;

                                                          favorable

                                                          biosafety; high

                                                          PAI contrast

                                                          capability with

                                                          enhanced ablation

                                                          efficacy under

                                                          HIFU
                                                                                 97
STD-NMdrug    25      Chemotherapy   Optical,   BALB/c    Therapeutic effect

                                     AIE-       nude mice monitoring by AIE

                                     based                signal ‘switch on’;
                                                       two-                   therapeutic

                                                       photon                 property supported

                                                                              by gene analysis

                                                                              (RNA-seq)
                                                                                                   100
Lipid           HA/CPPs-10-   284.2 ±   Chemotherapy   Optical,    BALB/c     Can undergo ADV

nanoparticles   HCPT-NPs      13.3                     ultrasoun   nude mice and ultrasound-

                                                       d                      targeted

                                                                              microbubble

                                                                              destruction;

                                                                              triggered by LIFU;

                                                                              allow penetration

                                                                              into extracellular

                                                                              matrix, cellular

                                                                              membrane and

                                                                              nucleus
                                                                                     101
Lipo@HRP&A      100           PTT           PAI      Female   Under 808 nm

BTS                                                  BALB/c   NIR laser

                                                     mice     irradiation; in vivo

                                                              H2O2-responsive

                                                              chromogenic

                                                              assay; detection of

                                                              inflammation;

                                                              enable

                                                              differentiation of

                                                              metastatic lymph

                                                              nodes
                                                                                     98
DOX/SPIONs-     132.1 ± 8.7   Chemo/magnet Optical   BALB/c   Hierarchical and

loaded DFSLNs                 othermal               mice     dual targeting for

                              combination                     the oral delivery

                              therapy                         of dual-modality

                                                              local therapy
                                                                                                                    99
                                 Lip/Ce6/TPZ    162 ± 4   PDT,           Optical   MCF-7-    Light- triggered

                                 NPs                      chemotherapy             beared    and hypoxia-

                                                                                   mice      responsive; good

                                                                                             biocompatibility

                                                                                             with little toxicity

                                                                                             toward normal

                                                                                             cells without

                                                                                             irradiation
                                                                                                                    127
Cancer (Liquid   Metal           FA-IONPs       100       PTT            MRI       LnCaP     Specific targeting

tumor)           nanoparticles                                                     cells     due to FA

                                                                                             functionalization
                                                                                                                    128
                                 EMG-308 IONP   60        PTT            MRI       LnCaP     IONP aggregation

                                                                                   cells     prevention
                                                                                                                    129
                                 Cu-Au@F-Apt    30        PTT            Optical   Male      Cu high thermal

                                 NSs                                               athymic   conductivity
                                                              BALB/c

                                                              mice

                                                                                                 131
Lanthanide-     antiCD33-      5.6   Chemotherapy   Optical   Primary      Real time

doped           LONp-PMI                                      cells from   visualization of

nanoparticles                                                 patients     AML cells

                                                              with         apoptotic events

                                                              AML
                                                                                                 132
Polymeric       CCM-PEG        228   Chemotherapy   Optical   HL-60,       Natural

nanoparticles                                                 HepG2,       biocompatible

                                                              HEK293       material with

                                                              T, HDF       anticancer activity

                                                              cells
                                                                                                 134
                pA20-36        70    Chemotherapy   Optical   Balb/C       Multimodal

                Chitosan-HA-                                  nude mice imaging

                NPs                                                        depending on the

                                                                           site of tumor
                                                                                                                     135
                                   PDI NP          60     PTT            PA and    U87MG        Size dependent

                                                                         PET       tumor-       tumor

                                                                                   bearing      accumulation

                                                                                   nude mice effect
                                                                                                                     189
                  Lipid            Lip/PEG/Tween   7-10   Chemotherapy   MRI       Athymic      Blood-brain

                  nanoparticles    80/SPIONs-                                      nude mice barrier

                                   PVA/RTX                                                      internalization
                                                                                                                     141
Neurodegenerati   Dyes             DBA-SLOH        -      Chemotherapy   Optical   APP/PS1      NIR dye

ve diseases                                                                        transgenic

                                                                                   (Tg) mice
                                                                                                                     142
                  Multifunctiona   CeNC/IONC/M     131    Chemotherapy   MRI       Male         Synergistic

                  l                SN-T807-MB                                      Sprague−     therapeutic effect

                  nanocomposite                                                    Dawley       of CeNC and MB

                                                                                   rats
                                                                                                               144
              BTTA chelator    BTTA        -         Chemotherapy   Optical   C57BL/6J Fluorescent

                                                                              male mice chelator

                                                                                                               145
              Multifunctiona   UCHQs       114       Chemotherapy   Optical   C57BL6     Tissue

              l upconversion                                                  female     autoluminiscence

              nanoparticle                                                    mice       circumvented by

                                                                                         NIR excitation
                                                                                                               149
Autoimmune    Polymer          DS-g-MTX    104.4 ±   Chemotherapy   Optical   CIA mice   Targeting on SR-

diseases      conjugate                    14.4                                          expressed

(Rheumatoid   micelles                                                                   activated

arthritis)                                                                               macrophages
                                                                                                               150
              Polymeric NPs    MTX-DSNPs   220       Chemotherapy   Optical   CIA mice   MTX loading

              (amphiphilic)                                                              efficiency

                                                                                         (73.0 %); targeting

                                                                                         on macrophages
                                                                                scavenger receptor

                                                                                class A

                                                                                                     154
Phase-           OI-NPs          277.80 ±   PSDT           Optical   -          Exposed to LIFU,

transition NPs                   22.49                                          caused a

                                                                                sonodynamic

                                                                                reaction; laser

                                                                                irradiation at 808

                                                                                nm
                                                                                                     153
Plasmonic NPs    MTX-Au/Fe/Au    135        PTT,           MRI,      CIA mice   NIR light

                 plasmonic NPs              chemotherapy   optical              irradiation at 808

                                                                                nm; T2 weighted

                                                                                MRI; magnetic

                                                                                targeted chemo-

                                                                                photothermal

                                                                                treatment; higher
                                                                                           therapeutic

                                                                                           efficacy with

                                                                                           smaller MTX

                                                                                           dosage (0.05 %)
                                                                                                                156
                   Inorganic NPs   Cu7.2S4NPs   120        PTT, PDT   Optical   CIA mice   NIR irradiation at

                                                                                           808 m, can

                                                                                           prevent bacterial

                                                                                           infection using

                                                                                           intra-articular

                                                                                           injection
                                                                                                                164
Cardiovascular     Inorganic NPs   CuS-TRPV1    13 ± 1.2   PTT        PAI,      ApoE −/−   Targeting on

diseases                                                              optical   mice       TRPV1 signaling;

(Atherosclerosis                                                                           NIR laser

)                                                                                          irradiation at 980

                                                                                           nm; showed no
                                                                          obvious in vivo

                                                                          toxicity

                                                                                               166
QDs            SV40 VNPs   26 ± 1.2   Chemotherapy   Optical   ApoE −/−   Encapsulating

                                                               mice       NIR QDs, bearing

                                                                          atherosclerotic

                                                                          targeting peptides

                                                                          and anti-coagulant

                                                                          drug Hirulog;

                                                                          targeting on

                                                                          VACM-1,

                                                                          macrophages and

                                                                          fibrin
                                                                                               172
Magnetic NPs   HDL-MNS     80-100     Reverse        MRI       -          Serve as

                                      cholesterol                         cholesterol efflux

                                      transport                           agents (4.8 %);
                                                                         show a 5 times

                                                                         higher contrast (r2

                                                                         relaxivity up to

                                                                         383 mM-1s-1)
                                                                                               171
Polymeric NPs   ICG-BM NPs   500   Antioxidant,   Fluoresc    Balb/c     Photoacoustic

                                   anti-          ence,       male mice signal is detectable

                                   inflammatory   ultrasoun              with low

                                                  d,                     frequency

                                                  photoaco               ultrasound

                                                  ustic                  transducers;

                                                                         excellent

                                                                         antioxidant, anti-

                                                                         inflammatory,

                                                                         proangiogenic

                                                                         activities;

                                                                         pathological
                                                                                    stimulus-

                                                                                    activatable

                                                                                    multiple contrast

                                                                                    amplification
                                                                                                          165
Cardiovascular   Polymeric NPs   FTIAN   160   Chemotherapy   PAI,      FeCl3-      Targeting on fibrin

diseases                                                      optical   induced     and elevated level

(Thrombosis)                                                            carotid     of H2O2; intrinsic

                                                                        arterial    anti-oxidant, anti-

                                                                        thrombosi   inflammatory and

                                                                        s mice      anti-platelet

                                                                        model       activity; anti-

                                                                                    thrombotic when

                                                                                    loaded with

                                                                                    antiplatelet drug

                                                                                    tirofiban;

                                                                                    irradiation of
                                                                       pulsed laser at 808

                                                                       nm
                                                                                             171
Inorganic NPs   T-FBM NPs   320   Chemotherapy   PAI,      FeCl3-      CO2 bubble

                                                 optical   induced     generation and

                                                           carotid     photoacoustic

                                                           arterial    waves formation

                                                           thrombosi   when exposed to

                                                           s mice      ultrasonic

                                                           model       transducer; H2O2-

                                                                       activatable

                                                                       ultrasound/photoa

                                                                       coustic signal

                                                                       amplification;

                                                                       antithrombotic

                                                                       effect
                                                                                                      174
             Polymer       Fucoidan-MBs   2–6 μm   -     Ultrasou   Wistar      Stable in

             nanobubbles                                 nd         male rats   suspension at 4 °C

                                                                                up to 2 months;

                                                                                exhibit high

                                                                                echogenicity;

                                                                                could completely

                                                                                burst under high

                                                                                destructive pulse
                                                                                                      181
Bacterial    Composite     MIL-100 (Fe)   120      PDT   Optical    MRSA-       H2O2-responsive

infections   materials     NPs                                      bearing     MOFs assisted

                                                                    mice        bacteria metabolic

                                                                                labelling strategy;

                                                                                incorporation of

                                                                                unnatural

                                                                                functional group
                                                           into bacteria in

                                                           vivo

                                                                                 178
Se@PEP-    78 ± 13   Antibacterial   Optical   BALB/cA High stability,

RuNPs                                          -nude       excellent light

                                               mice        stability; no

                                                           obvious

                                                           cytotoxicity,

                                                           negligible

                                                           hemolytic effect;

                                                           could promote

                                                           wound healing
                                                                                 187
Au/AgNRs   104.9     Antibacterial   PAI       Wild-type   Strong bactericidal

                                               male        efficacy towards

                                               C57BL/6     both MRSA (32

                                               mice        µM Ag+) &
                                                                        Escherichia coli (8

                                                                        µM Ag+); PA

                                                                        signal increased

                                                                        by 730% pre- and

                                                                        post-etching;

                                                                        bacterial counts

                                                                        reduced by 1000-

                                                                        fold (log CFU/g=

                                                                        4.15 vs 7.75) after

                                                                        treatment
                                                                                              182
Inorganic NPs   CIP-LuPSi   17.3   Bacterial        Optical   SD male   High

                                   inhibition via             rats      biocompatibility

                                   drug release                         & drug-loading

                                                                        ability; silicon-

                                                                        based smart

                                                                        bandage in wound
                                                                care and

                                                                bioimaging
                                                                                      183
SiO2-Cy-Van   72.7 ± 3.2   Antimicrobial,   Optical   MRSA-     Activated by

                           PTT                        bearing   bacteria-

                                                      mice      responsive

                                                                dissociation of the

                                                                polyelectrolyte

                                                                from silica NPs;

                                                                rapid MRSA-

                                                                activated NIRF

                                                                imaging (4 hours

                                                                post-injection,

                                                                high sensitivity up

                                                                to 105 colony-

                                                                forming units);

                                                                effective PTT
                                                   upon 808 nm laser

                                                   irradiation

                                                                         185
QA-AuNCs   2    Antibacterial   Optical   MRSA     Imaging-guided

                                          T144     bacteria counting;

                                          mouse    discrimination of

                                                   live/dead bacteria;

                                                   non-toxic to mice

                                                   at doses of up to

                                                   100 mg/kg
                                                                         188
PDA NP-    30   PTT,            Optical   BALB/c   NIR laser

Cip/GC          antibacterial             female   irradiation at 808

hydrogel                                  mice     nm; bacterial

                                                   killing activity

                                                   with wound

                                                   healing ability
                                                                                           175
Organic NPs   PEG-W18O49   18 x 5 x 1   PTT   X-rays,     Kunming   NIR laser

                           (height x          CT,         mice      irradiation at 808

                           width x            MRI,                  nm; excellent

                           thickness)         ultrasoun             colloidal stability,

                                              d                     low cytotoxicity &

                                                                    neglectable

                                                                    hemolysis
CLINICAL TRANSLATION OF THERANOSTIC NANOMATERIALS

While we focus here on nanotheranostics of different diseases (see Table 2), theranostic

nanomaterials in human clinical trials are still in its infancy when compared to its NPs

predecessor, which focuses only on either imaging, diagnostics or therapy. There are

numerous review articles on NPs for single function that are in clinical trials.190–194 An all-in

treatment (comprising of imaging, diagnosis and therapy) is lucrative, however, years of

clinical trials are required in order to gain patients’ confidence.

Based on our extensive search, only one nanoparticle qualifies as a theranostic agent:

gadolinium nanoparticles (GdNPs), under the name of (AGuIX) where imaging, targeting and

therapy were incorporated into a single system.88 GdNPs in the AGuIX function as a

radiosensitizer. GdNPs improve tumor-targeting and diagnosis of HCC using external beam

radiotherapy.195 Conjugation of cisplatin and polysiloxane on the GdNPs allows therapy and

passive tumor-targeting, respectively. Besides, functionalization of AGuIX NPs with a

chelator of radiometal (64Cu or 68Ga), NIR heptamethine cyanine dye and a bioconjugatable

handle form a trifunctional (PET, MRI and optical) imaging probe with fast tumor

accumulation and renal clearance.196 AGuIX demonstrated an enhanced MRI contrast than

other FDA-approved Gd chelates, and is currently under Phase Ib clinical trials and estimated

to be completed in April 2021.197

Another close relative is the NBTXR3, a hafnium oxide radio-enhancer, which have been

used in various types of cancer patients and is currently in Phase II-III clinical trials. Besides

these, there are various NPs in clinical trials that have successfully incorporated dual-

functions: either as imaging and targeting or imaging and therapeutic agent. Magnetic NPs

have been used for anemic patients as therapy and recently developed as an MRI-contrast

agent. Some commercially known brands (such as Ferumoxtran and Ferumoxytol) are ultra-



                                                                                        101 | Page
small SPIONs NPs coated with either dextran or synthetic carbohydrate shell. SPIONs NPs

were initially tested clinically on various types of cancer (such as head, neck, prostate and

cervical cancer) by differentiating cancerous and non-cancerous lymph nodes with the aid of

an MRI. 104,198 Recently, SPIONs NPs have been used in diagnosis of multiple sclerosis,

myocardial infarction diseases (see Table 2). Some Phase I clinical trials have been

completed and a few studies have even advanced to Phase IV.199,200

Similarly, AuNPs have been translated into clinical trials since year 2008 and have been used

for thermal ablation of tumors.191,192 However, to the best of our knowledge, AuNPs has

advanced to only Phase I clinical trials due to the limitation in penetration depth of laser light

during PTT and their application in vivo.17,201,202 The use of a fibre optic NIR laser for deeper

laser penetration into tumors or a synergistic PTT and other therapies (or surgery) are some

of the possible alternatives to the use of nanomaterials for PTT.17

Another addition to clinical trials is the Cornell or C dots which are inorganic protein-coated-

fluorescent-silica NPs with potential in theranostics of melanoma.203 C dots allow real-time

pre-operative and intraoperative sentinel lymph node (SLN) tissue localization and retention

using a hand-held fluorescent camera.79 Although complete lymph node dissection for

patients who had SLN biopsy was deemed inappropriate as a form of treatment after 2017,113

the C dots are still believed to possess therapeutic effects by reduction in size of tumor and

are currently under further investigation.203 Phase III trials of both concurrent triplet

combination therapy (vemurafenib, cobimetinib, atezolizumab) and sequential combination

therapy (vemurafenib and cobimetinib alone) in advanced melanoma patients are ongoing.204

The results of the trials would allow better understanding of the safety and efficacy of

targeted therapy and immunotherapy combinations.

Most of the targeted theranostic probes for ovarian cancer are still in various phases of

clinical trials, have yet to be approved by the FDA.205 For the triple-negative breast cancer,


                                                                                        102 | Page
only paclitaxel and irinotecan loaded liposomes, also known as EndoTAG-1 and MM-398

have proceeded through clinical studies.206 Phase III trial of EndoTAG-1 in combination with

gemcitabine is currently ongoing in patients with pancreatic cancer. Recently, Phase I study

to understand the biodistribution of MM-398 and the feasibility of using ferumoxytol as a

solid tumor and brain cancer imaging agent has been completed.

Nanomaterials such as carbon nanotubes and graphene are not yet approved for clinical trials

as wearable sensors, implantable devices, aid in clinical interventions and treatments of

various diseases.108 Primary challenges including human health risks (biocompatibility,

biological toxicity), environmental impact, selectivity for biomarkers detection, long-term

stability, should be addressed before clinically approved graphene and its derivatives move

forward.

There are various clinical trials that have been terminated due to numerous reasons such as

inadequate enrolment, variations in the clinical findings and no improvements compared to

controls/placebos. For example, CALAA-01, a targeted nanocomplex that contains anti-

ribonucleotide reductase small interfering RNA (siRNA) has been terminated after Phase I.

Despite showing the potential in solid tumor, the nature and complexity of CALAA-01 raised

several concerns (possible immunostimulation, coagulopathic effects, kidney toxicity, off-

target deposition, hepatotoxicity), therefore hindering its clinical translation.207

One of the flaws in clinical trials is the disconnection between mice and human models.202

Nanomaterials showing positive theranostic results in in vitro and in vivo settings do not

grant their applicability in clinical trials, mainly due to a combination of multiple complex

bio-nano interactions in the body.68,208 Research on nanotheranostic nanomaterials is rapidly

advancing to incorporate biocompatibility, specific targeting, advanced imaging and

diagnosis, as well as localized drug delivery in the human body.12,17,23,56,138 An increase in

knowledge of physiochemical properties of nanomaterials coupled with the design of


                                                                                       103 | Page
multifunctional theranostic platform and microenvironment-priming approaches is likely to

radically expedite clinical approval of more nanotheranostic nanomaterials and bring them to

clinical applications.




                                                                                  104 | Page
TABLE OF SUMMARY

Table 2 A Summary of Functional Theranostic Nanomaterials Translated into Clinical Studies

 Cancer/Disease/      Type of               Physiochemical          Therapeutic/          Clinical trial      Ref.

 Illness              nanomaterial/         properties              Imaging modality      phase/Status

                      Composition
                                                                                                              209
 Solid tumors         Ruthenium NPs         Targeting of GRP78      Targeting & therapy   Phase I completed

                      (NKP-1339)            (key regulator of                             (2012)

                                            misfolded protein

                                            processing); mean

                                            half-life: 113 hours;

                                            mean total clearance

                                            (CLtotal):

                                            164 mL/hour




                                                                                                                     105 | Page
                                                                                               210,211
Gold nanospheres,        Size: 27 nm; liquid,     Targeting &           Phase I completed

bounded to PEG-          intravenous injection;   immunostimulant       (2012)

THIOL &                  net negative surface     therapy

recombinant human        charge

tumor necrosis factor

alpha (rhTNF)
                                                                                               207,212
Polymeric NPs,           Size: 70 nm; liquid,     Targeting & therapy   Phase I terminated

containing               intravenous injection;   (RNAi)                (2012), progressive

cyclodextrin-based       siRNA is not                                   disease was observed

polymer, small           chemically modified;

interfering RNA          1:1 charge ratio of

(siRNA), human           positive charged

transferrin protein      polymer to negatively

(hTf) targeting ligand   charge nucleic acid;

& hydrophilic PEG        endosomal disruption

(CALAA-01)               & siRNA release into


                                                                                                         106 | Page
                                         the cytoplasm of

                                         target cells due to

                                         imidazole residues
                                                                                                                210,213
Advanced solid   Colloidal gold NPs,     Size: 7-20 nm; intra-     Targeting,            Phase I completed

tumors           bounded with            tumour injection;         immunotherapy &       (2009)

                 recombinant human       well-tolerated doses      imaging

                 tumor necrosis factor   at 50-600 μg/m2;

                 alpha (rhTNF) &         85 % complete

                 thiolyated PEG          remission rates

                 (CYT-6091)
                                                                                                                214
Breast cancer    Liposome NPs            Size: 100 nm;             Targeting & therapy   Phase II/III

                 encapsulating DOX       enhanced antitumor                              terminated (2017)

                 & trastuzumab (for      activity, activation of                         (does not show

                 targeting of HER2       p53 protein levels                              benefit over control

                 receptor protein)       phosphorylation/activ                           & confirmed via

                 (MM-302)                ation; decreased                                futility analysis)


                                                                                                                          107 | Page
                                           intracellular signaling

                                           (p-Akt); increased

                                           DNA damage

                                           signaling
                                                                                                              215
                     CdS/ZnS core-shell    Size: 1-10 nm;            Imaging & therapy   Phase I recruiting

                     quantum dots,         conjugation with                              (estimated

                     carboxylic acid-      VELD at pH 7;                                 completion year

                     functionalized,       somatostatin                                  2022)

                     coated with           receptors (SSTR)

                     veldoreotide (VELD)   agonist with anti-

                                           cancer activity; in the

                                           form of topical cream
                                                                                                              216
Squamous cell cancer Manganese oxide       Intravenous injection; Targeting & therapy    Phase I completed

of the head & neck   (GC4419)              about 2 hours half-                           (2015)

                                           life with minimal




                                                                                                                    108 | Page
                                             accumulation upon

                                             repeated dosing

                                                                                                               79
Head and neck        Silica NPs (cRGDY-      Size: 6-7 nm;           Tracking & imaging    Phase II ongoing

melanoma, breast     PEG-Cy5.5-C dots)       superior brightness;                          (estimated

cancer, colorectal                           enhanced tumor                                completion year

cancer                                       tissue retention with                         2020)

                                             low background

                                             signal; portable &

                                             real-time optical

                                             detection of nodal

                                             metastases
                                                                                                               217
Head and neck        Ultrasuperparamagne     Size: 17-31 nm; 3D      Targeting & imaging   Phase I completed

cancer               tic nanoparticle iron   quantitative tumor      (MRI)                 (2019)

                     oxide (Ferumoxytol)     characterization




                                                                                                                     109 | Page
                                                                                                                218
Atherosclerosis      Gold NPs coated on      Size: 90–150 nm;         Targeting & therapy   Phase I completed

                     silica/iron oxide       stenting & micro-        (plasmonic            (2016)

                     shells                  infusion of stem cells   photothermal & stem

                                             bearing NPs into the     cell therapy)

                                             lesion
                                                                                                                219
Myocardial infarction Ultrasuperparamagne    Size: 17-31 nm; 4-6      Targeting & imaging   N/A Completed

                     tic nanoparticle iron   times enhanced                                 (2012)

                     oxide (Ferumoxytol)     phagocytosis; higher

                                             uptake by cells due to

                                             cardiac

                                             inflammation;

                                             possible visualization

                                             of heart muscle

                                             damage area




                                                                                                                      110 | Page
                                                                                                             220
Type 1 diabetes    Gold NPs coupled      Size: 5 nm;              Targeting & therapy   Phase I ongoing

                   with proinsulin       intradermal delivery                           (2016)

                   peptide (C19-A3       by microneedles;

                   GNP)                  negatively charged (-

                                         40 to -60 mV)
                                                                                                             221
                   Ultra                 Size: 30 nm;             Targeting & imaging   N/A completed

                   superparamagnetic     monocrystalline; with                          (2009)

                   nanoparticle iron     long-circulating

                   oxide (Ferumoxtran-   properties; real time

                   10), dextran-coated   visualization of

                                         inflammatory lesions

                                         in vivo
                                                                                                             222
Brain metastases   Gd NPs (AGuIX)        Size: 4.5 nm; can be     Targeting & imaging   Phase I recruiting

                                         used in combination      (MRI)                 (estimated

                                         with fractionated                              completion year

                                         stereotactic radiation                         2020)


                                                                                                                   111 | Page
                                          in oligo brain

                                          metastases
                                                                                                                223
Gliosarcoma        Spherical gold NPs     Size: 13 nm; can          Targeting & therapy   Phase I ongoing

                   carrying nucleic acids cross the blood-brain                           (2017)

                   & drugs (NU-0129)      barrier; targeting of

                                          Bcl2L12 gene to stop

                                          cancer cells from

                                          growing
                                                                                                                224
Transthyretin-     Lipid NPs Patisiran    Size: 60-100 nm;          Targeting & therapy   Phase III completed

mediated (hATTR)   (ALN-TTR02)            liquid, intravenous       (gene silencing)      (2017)

amyloidosis                               injection; prevented

                                          the deterioration of

                                          left ventricular global

                                          longitudinal strain

                                          over 18 months




                                                                                                                      112 | Page
                                                                                                              225,226
Thyroid cancer    Lymphotrophic          Size: 30 nm;            Imaging (MRI) &       N/A completed

                  superparamagnetic      intravenous injection   therapy               (2015)

                  NPs loaded with drug   (lyophilized iron

                  (Ferumoxytol)          oxide injected dose:

                                         2.6 mg per kg of

                                         body weight);

                                         imaging with high

                                         sensitivity &

                                         specificity in

                                         detecting small

                                         lymph nodes (even 2

                                         nm)
                                                                                                              227
Prostate cancer   Hafnium oxide NPs      Size: 50 nm; liquid,    Targeting & therapy   Phase I & II ongoing

                  (NBTXR3)               intra-tumoral           (radiotherapy)        (estimated

                                         injection; non-                               completion year

                                         pyrogen, sterile;                             2020)


                                                                                                                        113 | Page
             white aqueous

             dispersion; negative

             surface charge; stable

             in aqueous solution at

             pH 6-8; able to

             deposit high energy

             within tumors;

             chemically inert in

             cellular & subcellular

             systems; therapy

             activated by intensity

             modulated

             radiotherapy
                                                                               228
Silica NPs   Size: sub-8 nm;           Targeting & imaging   Phase I ongoing

             intravenous               (PET/MRI)             (estimated

             injection; targeting of


                                                                                     114 | Page
(64Cu-NOTA-             prostate-specific                              completion year

PSMAi-PEG-Cy5.5-        membrane antigen                               2021)

C' dots)                (PSMA); specific

                        uptake at prostate

                        specific (PC-3) cells
                                                                                           104
Magnetic iron oxide     Size: 15.74 nm;          Targeting & imaging   Phase I completed

NPs, conjugated with    surface charge:          (MRI)                 (2015)

dual peptides           −58.06 ± 1.72 mV;

targeting luteinizing   preferential binding

hormone-releasing       & accumulation in

hormone receptor        PC-3 cells; 2 times

(LHRH-R) &              enhanced

urokinase-type          cytotoxicity; 10 times

plasminogen             lesser dose required;

activator receptor      possess double-

(uPAR)


                                                                                                 115 | Page
                                          receptor targeting and

                                          imaging capability




                                                                                                           229
Cervical cancer   Ultrasuperparamagne     Size: 30 nm;             Targeting & imaging   N/A completed

                  tic nanoparticle iron   intravenous                                    (2019)

                  oxide (Ferumoxtran-     injection; increased

                  10)                     MRI sensitivity to

                                          detect lymph nodes

                                          metastasis
                                                                                                           88
                  Gd NPs (AGuIX),         Size: 4.5 nm;            Theranostic agent     Phase I ongoing

                  grafted with            improved                 (imaging, targeting & (2019)

                  additional DOTA         longitudinal             therapy)

                  chelates,               relaxivity (4.87 s−1



                                                                                                                 116 | Page
                     complexation of         mM−1 & r2/ r1 of

                     bismuth                 1.46); a contrast of

                                             4.26 Hounsfield unit

                                             mM−1 (close to those

                                             of clinically used CT

                                             contrast agents)
                                                                                                                 230
Multiple sclerosis   Ultra                   Size: 17-31 nm;          Targeting & imaging   Phase I completed

                     superparamagnetic       intravenous injection;   (MRI)                 (2019)

                     nanoparticle iron       contrast agent for

                     oxide (Ferumoxytol)     brain MRI; ultrahigh-

                                             field MRI & phase

                                             contrast; highly

                                             sensitive
                                                                                                                 231
Pancreatic cancer    Ultrasuperparamagne     Size: 17-31 nm;          Targeting & imaging   Phase IV completed

                     tic nanoparticle iron   targeting of bombesin (MRI)                    (2012)

                     oxide (Ferumoxytol)     receptors; relaxivity:


                                                                                                                       117 | Page
                                            70 mM-1s-1;

                                            identification of

                                            small/undetectable

                                            lymph nodes

                                            metastasis
                                                                                                            232
Non-small cell lung   Polymeric NPs, with   Size: 100 nm;        Targeting & therapy   Phase II completed

cancer                a hydrophobic         biocompatible;                             (2016)

                      polylactic acid       demonstrated dose

                      polymeric core,       linear

                      encapsulating DOX     pharmacokinetic

                      & hydrophilic PEG     profile; prolonged

                      corona decorated      persistence

                      with small molecule

                      prostate-specific

                      membrane antigen




                                                                                                                  118 | Page
                    (PSMA) targeting

                    ligands (BIND-014)
                                                                                                                    233
Relapsed or         Polyethylenimine         Size: 72 nm; rod-       Targeting & therapy   Phase I/II recruitment

refractory B cell   NPs, comprised of        shaped;                 (RNAi)                status (2014)

malignancies        small interfering        polydispersity index:

                    RNA–mediated             0.197; positive

                    suppression of           surface charge;

                    hypusinated              inhibits tumor

                    eukaryotic translation   progression in a

                    initiation factor 5A     number of B-cell

                    (eIF5A) & plasmid-       malignancies

                    based overexpression

                    of a non-hypusinable

                    eIF5A mutant

                    (SNS01-T)




                                                                                                                          119 | Page
                                                                                                               234
Relapsed or           Lipid NP, composed    Size: >100 nm;           Targeting &           Phase I completed

refractory leukemia   of cationic           liquid, intramuscular    immunotherapy         (2017)

                      DOTIM/cholesterol     injection; cationic;

                      liposomes & plasmid   with

                      DNA (JVRS-100)        immunostimulatory

                                            properties; enhanced

                                            humoral & cell-

                                            mediated immune

                                            responses
                                                                                                               235
Parkinson's disease   Gold nanocrystals,    Single crystallized in   Therapy & diagnosis   Phase II ongoing

                      modified with         the face centred cubic                         (estimated

                      montmorillonite       lattice; with a                                completion year

                                            preferential growth                            2020)

                                            direction along the

                                            (111) plane; specific

                                            surface: 327–579


                                                                                                                     120 | Page
                                         m2/g; large specific

                                         pore volumes ~0.7

                                         cm3/g; pore

                                         diameters: 0–10 nm;

                                         synthesized

                                         propargylamines with

                                         82–94 % yield &

                                         100 % selectivity

Central venous     Impregnated with      Size: 50 nm; 10−9        Targeting & therapy   Phase IV completed   236,237



catheter related   silver NPs (AgTive)   mol/l required for                             (2008)

infections                               bactericidal activity;

                                         concentration of

                                         0.8 % in an active

                                         surface of 450 cm2/g

                                         polyurethane




                                                                                                                       121 | Page
CONCLUSION AND FUTURE PERSPECTIVE

Nanotheranostics refers to the use of nanomaterials capable of providing concurrent

diagnostics and therapeutics at the disease sites. In this review, we have discussed the key

properties of different nanomaterials, and how these nanomaterials are designed and tuned to

meet the selectivity and specificity of the target disease. The specific properties of the

nanomaterials in terms of feasibility, drawbacks and their potential applications in

nanotheranostics were presented.

Both solid and liquid cancerous tumors are different in regard to their tumor vascularity and

heterogeneity, which require different diagnostic treatment and targeting strategies. Au

nanostructures are biocompatible and permit facile surface functionalization for wide

biological applications. In addition, Au nanostructures serve as a good photothermal

transducer. Conjugation of a photosensitizer on the Au-based nanoplatform could generate

high singlet oxygen and activate PDT. Most of the nanomaterials presented here are stimuli-

responsive, able to kick-start the sequential theranostic effects and release the

chemotherapeutic drugs only when reaching tumor sites. If the potential side effects of each

drug are well-understood, future studies can be expected on the co-delivery of drug

combinations in a single platform for broader pharmacological applications.

Inorganic nanomaterials are relatively stable over large ranges of pH and temperature, yet,

concerns are raised over their low biodegradation and biosafety issues. Modification of

different molecules (targeting and imaging contrast agents, drugs) on the surface of the

inorganic nanomaterials permits diverse applications of the nanomaterials. However, the

characterization and fairly weak fundamental understanding of the structure-function

correlations often restrict its predictive functions in nanotheranostics. Polymeric and lipid

NPs are usually used as nano-vehicles for delivering therapeutics and diagnostics agents to

the tumor sites, thanks to their biocompatibility and biostability features. Generally, the poor


                                                                                       122 | Page
spatial resolution, shallow tissue penetration and relatively low quantum yield are some of the

challenges of NIR-emissive polymeric NPs in theranostics. Since each drug varies in their

surface area and solubility, their loading mechanism into lipid NPs sometimes remain

challenging. Knowledge of the drug loading mechanism allows optimal formulation of the

nanocarrier system with theranostic properties and minimal limitations or potential side

effects.

Being one of the most interesting and versatile materials, graphene and its derivatives offer a

relatively simple but highly integrated and multifunctional nanotheranostic platform for

biomedical applications. Nevertheless, more systemic investigations are required to better

understand its behavior, biodegradability and toxicological profiles in complex biological

environment.

Concerning nanotheranostic applications in liquid tumors, researches are still in its infancy

compared to solid tumor. Most of the approaches done thus far are directed to the diagnosis

and treatment of blood cancers, such as lymphoma and leukemia. It is surprising to note that

although the physico-chemical scenario of blood cancers is different to solid tumors, the same

types of nanomaterials are being used. This can be clearly observed in the use of metal NPs

for thermal ablation in both solid and liquid tumors. In solid tumors, the nanomaterial is

anchored to the surface of the tumor leading to an effective and non-invasive ablation,

whereas in liquid tumor, the target element is in constant circulation and this can lead to

ablation of adjacent tissue. The same phenomenon is observed with the use of polymeric and

lipid NPs as drug delivery systems in both solid and liquid tumor, where it is not clear the

different requirements in terms of blood-brain barrier penetration, stability and renal

clearance. This question needs to be solved and more work should be carried out in order to

push the nanotheranostics for in vivo applications in circulating tumors.




                                                                                      123 | Page
For neurodegenerative diseases, all the nanotheranostic strategies have been applied for the

diagnosis and treatment of Alzheimer disease and interestingly the selection of the

nanomaterial is based on the therapeutic strategy (inhibition of Aβ aggregation and Cu2+ ions

chelation). In both cases, fluorescence imaging modality is selected as a cost-effective and

simple alternative to MRI and PET. Moreover, both therapy strategies have proven to be

effective in in vivo therapy of Alzheimer disease, although it would be important to develop

them also for the other neurodegenerative diseases.

The NPs used for the theranostics of autoimmune diseases can be colloidal-based or organic-

based. The nanomaterials are mostly designed for targeting of the scavenger receptor present

on the activated macrophages. The NPs permit prolonged circulation in the bloodstream and

subsequently controlled release of the therapeutic drugs at the inflammation sites. Safety

concern (biodistribution in non-targeted tissues, potential inflammation, biodegradability,

biocompatibility and clearance) is the biggest obstacle that hampers the clinical application of

most of the nanomedicine of RA.

For cardiovascular diseases, the research is mainly focused on the non-invasive imaging

modalities such as MRI and NIR fluorescence for detection of atherosclerotic plaque. The

pursuit of therapeutic agents for atherosclerosis and its potential impact remains an open field

for research. Currently, there is less information about the dose, pharmacokinetics, long-term

side effects and toxicology of the NPs employed in most of the studies. Future research

should also be emphasized on more detailed biocompatibility (such as blood-half-life) and

immunogenicity evaluation of the NPs, as well as development towards precision drug

delivery and early detection of atherosclerotic plaque.

Inorganic NPs as antibacterial agents still face drawbacks such as non-specific biological

toxicity or potential long-term in vivo retention. Applications of metal-free antibacterial

agents are limited by poor stability and biocompatibility, complicated synthetic steps, and


                                                                                       124 | Page
limited material structural tunability. Besides, the long-term biosafety of antibacterial

nanomaterials is another big concern as it usually associated with possible risks including

excessive or insufficient heating, undesired diffusion and potential impact on the immune

system.

Continuous and multiple pharmacological and physical approaches have been developed to

overcome biological and physiological barriers of the nanomaterials in complex biological

systems. The ideal size of the NPs is highly dependent on the cancer type, tumor site and the

stage of the diseases. Overall, NPs with a tunable size between 10-100 nm is the most

favorable in the development of cancer theranostics, mainly due to enhanced cellular uptake,

biodistribution, blood circulation half-life, cellular uptake, tumor penetration and targeting at

this size range.

The pH value, antioxidant levels and enzymatic activity belong to endogenous stimuli; while

light, ultrasound and magnetic are some of the examples of external stimuli. Theranostic

applicability of external stimuli-responsive nanomaterials is less dependent on tumor type or

pathological properties. Such nanomaterials can be applied at the diseases site in a controlled

manner, but the efficacy is severally compromised in metastasized lesions. In contrast,

theranostic efficacy of endogenous stimuli-sensitive nanomaterials is highly heterogeneous

between different types of tumors/diseases. Moreover, staging (a process to determine if

cancer has spread within the organ or to other parts of the body) is important to determine the

stage of the cancer/disease. The design of nanomaterials (dose requirements, efficacy, side

effects, etc.) must be tuned according to the pathological properties of tumors/diseases.

Safety, efficiency and controllability are the major criteria in biomedical applications. Eco-

toxicological, biosafety and biocompatibility evaluation must be conducted for theranostic

nanomaterials, taking into account factors including route of administration/exposure,

biodistribution, biodegradability, long-term exposure, etc. The morphology, size distribution,


                                                                                       125 | Page
nature of interfaces (charges and surface chemistry) and colloidal stability of the

nanomaterials in different media might influence the nanotoxicity of nanomaterials. The

interaction of NPs with cell organelles also requires further studies as it plays a critical role in

impacting the biogenesis and biological activities.

No theranostic nanomaterials have been approved by the FDA for commercialization to date,

mainly due to significant heterogeneity in the design, synthesis, safety and efficacy of the

nanomaterials in clinical trials. The behavior of the nanomaterials in the dynamic

physiological and pathological alterations in vivo is not well-defined too. Most of the current

nanomaterials are in various phases of clinical trials, though the future perspective is brilliant.

Future research should be focused on improving the clinical relevance and translational

feasibility of nanomaterials for theranostic applications. The strength and limitations of each

nanomaterial, particularly the potential side effects/toxicities, should be comprehensively

understood upon developing them with robust efficacy and clinical benefit. Understanding of

pharmacokinetic profile of nanomaterials in humans should be emphasized, along with

clinical translation in appropriate animal models. After all the concerted efforts from

multidisciplinary teams of chemist, pharmacists, physicists and engineers, it is believed that

nanomaterials promise revolutionary potential as theranostic agents for a variety of clinical

applications and improving the quality of life of the population.

AUTHOR INFORMATION

Corresponding authors
*
    E-mail: Kasturi.Muthoosamy@nottingham.edu.my
*
    E-mail: arben.merkoci@icn2.cat

ORCID

Xin Yi Wong: 0000-0002-8673-9345

Amadeo Sena-Torralba: 0000-0003-1340-1383


                                                                                         126 | Page
Ruslan Alvarez Diduk: 0000-0002-9876-1574

Kasturi Muthoosamy: 0000-0003-3752-5794

Arben Merkoçi: 0000-0003-2486-8085

ACKNOWLEDGMENTS

This work was supported by the Fundamental Research Grant Scheme (FRGS), Ministry of

Higher Education (MOHE), Malaysia [FRGS/1/2016/STG07/UNIM/02/1]. This work is also

funded by the CERCA Program/ Generalitat de Catalunya. ICN2 acknowledges the support

of the Spanish MINECO for the Project MAT2017-87202-P and through the Severo Ochoa

Centers of Excellence Program under Grant SEV2201320295.

VOCABULARY

nanotheranostics, development of nanomedicine approaches for advanced theranostics

(combined therapeutic and imaging/diagnostic features); nanomaterials, materials with one

or more external dimensions in the nanoscale (sizes range from about 1-100 nm);

photothermal therapy, thermal ablation of cancer cells with the use of photoabsorbing

agents that could efficiently transfer the absorbed light energy into heat, subsequently leading

to cell death; photodynamic therapy, an externally activatable treatment with the use of

photosensitizer molecules to generate cytotoxic singlet or reactive oxygen species to kill

cancer cells via oxidative stress; passive targeting, delivery of nanoparticles via enhanced

permeability and retention effect in tumor or any leaky vasculature and anatomic barrier;

active targeting, delivery of nanoparticles to the tissue of interest based on molecular,

ligand/receptor or antibody-antigen recognition. More focused delivery with reduced

potential side effects, toxicity and cost of drug/delivery; graphene, single-layered carbon

atoms packed into a two-dimensional honeycomb lattice.




                                                                                      127 | Page
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