Coordination Chemistry Reviews 441 (2021) 213977 Contents lists available at ScienceDirect Coordination Chemistry Reviews journal homepage: www.elsevier.com/locate/ccr Review Antitumour activity of coordination polymer nanoparticles Salvio Suárez-García a, Rubén Solórzano a,b, Ramon Alibés b, Félix Busqué b, Fernando Novio b,⇑, Daniel Ruiz-Molina a,⇑ a Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC and BIST, Campus UAB, Bellaterra, 08193 Barcelona, Spain b Departament de Química, Universitat Autònoma de Barcelona (UAB), Campus UAB, Cerdanyola del Vallès, 08193 Barcelona, Spain a r t i c l e i n f o a b s t r a c t Article history: Nanoscale coordination polymers (NCPs) have fascinated researchers over the last years. Their intrinsic Received 28 December 2020 theranostic properties of metal ions and organic ligands, the encapsulation of several drugs/biomolecules Accepted 11 April 2021 with excellent yields and the surface functionalisation, enhancing their biocompatibility and targeting, Available online 8 May 2021 have remarkably impacted in prospective drug delivery alternatives in medicine. Moreover, the proper- ties and characteristics of these nanoparticles (NPs) can be fine-tuned thanks to the synthetic flexibility of Keywords: coordination chemistry. For all these reasons, the number of examples published has grown exponen- Multifunctional nanoparticle tially over the last years, embracing different disciplines such as molecular electronics, sensors or nano- Coordination polymer Theranostic medicine, among others. Specifically, significant advances in antitumoural applications are reported, one Cancer therapy of the areas where this novel family of NPs has experienced a considerable advance. NCPs have accom- plished a high sophistication degree and efficiency as theranostic nanoplatforms (i.e., drug delivery car- riers and bioimaging probes) with long residence time in the bloodstream, targeting capacities and remarkable cellular internalisation. In this review, an introduction emphasizing the advantages of NPs for cancer treatment is included. Later on, the most representative examples of NCPs for antitumoural applications are described grouped into six mean representative areas: i) encapsulation approaches, ii) stimuli-responsive NCPs, iii) metal chemotherapy, iv) photodynamic therapy (PDT), v) unconventional therapeutic approaches and vi) theranostics. Particular emphasis is given to understand the encapsula- tion/release properties of these particles at the nanoscale and their interaction with biological environ- ments, highlighting any limitation and challenges that these systems are facing from a clinical translation perspective and envisioning possible future trends and areas that will deserve further atten- tion for the following years. Ó 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2. Encapsulation approaches in NCPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.1. Physical entrapment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.2. Chemical entrapment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3. Stimuli-responsive NCPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 3.1. pH-responsive . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 3.1.1. Metal node . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 3.1.2. Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 3.2. Photoactivation or redox stimuli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 3.3. Stimuli combination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 4. Metal chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 4.1. Platinum-based drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 4.1.1. Succinate (DSCP). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 4.1.2. Phosphonic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 ⇑ Corresponding authors. E-mail addresses: fernando.novio@uab.cat (F. Novio), dani.ruiz@icn2.cat (D. Ruiz-Molina). https://doi.org/10.1016/j.ccr.2021.213977 0010-8545/Ó 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). S. Suárez-García, Rubén Solórzano, R. Alibés et al. Coordination Chemistry Reviews 441 (2021) 213977 4.1.3. Gallate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 4.2. Copper-based drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 4.3. Other metal-based drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 5. Photodynamic therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 6. Unconventional approaches. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 7. NCPs for theranostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 7.1. MRI and chemotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 7.1.1. Gadolinium-based NCPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 7.1.2. Manganese-based NCPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 7.1.3. Iron-based NCPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 7.2. Other imaging/chemotherapy approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 7.3. Multi-mode imaging/therapy approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 7.3.1. MRI and optical imaging. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 7.3.2. MRI and PAI. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 7.3.3. Others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 8. Perspectives and future trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 1. Introduction sions (15%), iron-based polymer complexes (10%), micelles (5%), or other nanosystems (15%) [5]. Overall, nanomedicine stands nowa- The incorporation of nanoparticles (NPs) for antitumoral treat- days for more than 22% of all commercial drugs and continuously ment dates back to 1986, with the first evidence for their accumu- rising every day [6], from where oncology represents almost 35% lation into tumoural areas due to enhanced permeation and [7]. Since 1995, around 50 nano-based pharmaceuticals have been retention (EPR) effect. Due to their fast and uncontrolled growth, authorised by the FDA and are presently accessible for clinical tumoural cells generate poorly formed blood vessels with defects assays, and more than 60 are under clinical evaluation [8]. hundred nanometers in size that ensure significant contributions Beyond the examples of nanocarriers previously described, sev- of nutrients and oxygen (difficult to achieve with conventional eral other families of NPs have also been described in the literature. blood vessels, especially for large tumours). Those are the same Most of them are polymeric NPs and liposomes [9] or inorganic holes that facilitate the access of the NPs to the tumoural tissue systems such as metallic or ceramic NPs [10–12]. Worth emphasiz- [1], which once inside are consistently retained [2]. Other ing, porous NPs have high payloads, low toxicity, chemical robust- advantages for the use of NPs as drug carriers are: i) improvement ness and scalable production [13]. For instance, mesoporous silica of the drug pharmacokinetic profile, ii) enhanced chemical NPs (MSNs) with high empty volume and pore size between 2 and protection, iii) use of lipophilic drugs, iv) increase of the circulation 5 nm allows for high loading capacities and surface time concerning the free drug, and v) diminish prescriptions thus functionalisation (both internal and external) with different mole- less toxicity [3]. Thanks to all these benefits, exponentially increas- cules and biomolecules through one-pot reaction or after particle ing examples of nanoplatforms for antitumoural applications have formation (post-synthesis) [14]. An alternative family of porous been reported over the years, reaching in some specific cases the nanocarriers attracting growing interest is nanoscale metal–or- market [4]. Among them, the Food and Drug Administration ganic frameworks (NMOFs) [15]. Thanks to the wealth and syn- (FDA) has approved liposomes (35%) and nanocrystals (25%), emul- thetic flexibility of coordination chemistry, NMOFs can be Abbreviations: AA, anisamide; ADME, absorption, distribution, metabolism, and excretion; AIE, aggregation-induced emission enhancement; ALN, alendronate; AsPC-1, pancreatic cancer cell line; AZT, azidothymidine; A431, epidermoid carcinoma; BATA, bis–(alkylthio) alkene linker; BPEI, branched polyethyleneimine; BSA, Bovine Serum Albumin; BTB, 4,40 ,400 -benzene-1,3,5-triyl-tri-benzoic acid; CA, contrast agent; CBTA, cyclobutane-1,2,3,4-tetracarboxylic dianhydride; Ce6, chlorine e6; CD44+, CD44 overexpressing cancer cell line; CD44-, CD44 minimal-expressing cell line; CHG, S-(N-p-chlorophenyl- N-hydroxycarbamoyl)glutathione; CLSM, confocal laser scanning microscopy; CP, coordination polymer; CpG, cytosine triphosphate deoxynucleotide linked to guanine triphosphate deoxynucleotide ; NCP, coordination polymer nanoparticle; CPT, camptothecin; CT, computed tomography; CT-DNA, calf thymus DNA; CT26, colon cancer cell line; DAU, daunomycin; DHA, dihydroartemesinin; DLS, dynamic light scattering; DMCA, dual-mode contrast agent; DNA, deoxyribonucleic acid; DNP, dipeptide NPs; DOX, doxorubicin; dpac, dipyrido[3,2-a:20 ,30 -c](6,7,8,9- tetrahydro)phenazine; dpg, dipyrido[3,2-d:20 ,30 -f]quinoxaline; DPN, dip-pen nanolithography; DSP, c,c,t-(diamminedichlorodisuccinato)Pt(IV); Fc, 1,10 -dicarboxyl ferrocene, FDA, U.S. Food and Drug Administration; EPR, enhanced permeability and retention effect; ECM, tumour extracellular matrix; EDA, ethylenediamine; EGCG, epigallocatechin- 3-gallate; GA, gallic acid; GcMP, gemcitabine monophosphate; GMP, guanosin monophosphate; GSH, glutathione; GT, genetherapy; HOPO, 3-hydroxy-4-pyridinone; HCT116, human colorectal cells; HeLa, cervical cancer cells; Hemin, Fe-containing porphyrin; Hep-2, laryngeal cancer cell line; Hep G2, human liver cancer cell line; HT29, human colon cancer cell line; HmA, hexahistidine-metal nanoassemblies; H460, lung cancer cell line; ICG, indocyanine green; IC50, half maximal inhibitory concentration; ip, imidazo [4,5-f]1,10-phenanthroline; i.v., intravenous; MCF-7, human breast adenocarcinoma cells; MDR, multidrug resistant; miRNA, micro ribonucleic acid; MRI, magnetic resonance imaging; MSNs, mesoporous silica NPs; MTX, methotrexate; N-BP, Nitrogen containing bisphosphonates; NCI-H446/60, human lung cancer cells; NIR, near-infrared; NMOF, nanoscale metal–organic framework; NP, nanoparticle; OCa, ovarian cancer; OxPt, oxaliplatin; PA, piperazine; PAI, photoacoustic imaging; PAT, photoacoustic tomography; PDA, polydopamine; PDT, photodynamic therapy; PEG, polyethylene glycol; PEGMA, mPEG-grafted poly(methacrylate); PEG-PBHE-PS, poly(ethylene glycol)-b-poly(2- hydroxyethyl methacrylate-Boc-histidine)-b-poly(styrene); PEO, poly(ethylene-oxide); PET, positron emission tomography; pHis-PEG, poly-L-histidine-PEG; PPT, photother- mal therapy; PVP, polyvinylpyrrolidone; QD, quantum dot; rhod, rhodamine; RI, radioimaging; RGD, arginylglycylaspartic acid; RNA, ribonucleic acid; ROX, reactive oxygen species; r1, longitudinal relaxation value; r2, transversal relaxation value; SEM, scanning electron microscopy; siRNA, small interfering ribonucleic acid; SKOV-3, ovarian cancer cell line; SPECT, single-photon emission computed–tomography; SPIONs, superparamagnetic iron oxide NPs; TA, tannic acid; TCPP, meso-tetrakis(4-carboxyl)- 21H,23H-porphirine; TNTs, titania nanotubes; TPPGC, chloro(triphenylphosphine)gold(I); TPZnPc, tetra(4-carboxyphenoxy)-phthalocyaninatozinc(II); T1, longitudinal relaxivity; T2, transversal relaxivity; T1w, T1 weighted imaging contrast; T2w, T2 weighted imaging contrast; ZnPc, zinc phthalocyanine, 4T1, breast cancer cell line 2 S. Suárez-García, Rubén Solórzano, R. Alibés et al. Coordination Chemistry Reviews 441 (2021) 213977 Fig. 1. Main synthetic methodologies for the synthesis of porous and crystalline metal–organic frameworks (MOFs). a) the controlled diffusion of the separated components into the selected solvents with different densities leads to slowing the coordination reaction speed. The diffusion–reaction becomes useful for growing good-shaped and good-quality single crystals; b) hydro-/solvothermal approach to form 1D, 2D, and 3D coordination polymers (CPs). The precursors are added and mixed in a specific solvent within a sealed container. The application of temperature leads to reach the suitable conditions for the formation of crystals after a given period. Fig. 2. Main synthetic methodologies used for the synthesis of nanoscale coordination polymers (NCPs). a) lab-on-a-chip device where the starting materials are injected into the inlet and slowly diffuse to the mixing and reaction area, yielding the final product that is collected at the end of the device; b) use of atomic force microscopy (AFM) nanolithography (Dip-Pen) for the direct synthesis of NCPs on surfaces using femtolitre droplets, both mixing the reactant directly on the surface or previously in the ink holder; c) one-pot synthesis reaction; d) and assisted with microwave radiation that locally increase the temperature with low dissipation; e) the energy received from ultrasound radiation allows for acoustic cavitation formation that generates a localised increase in temperature and pressure. The figure shown in panel b is adapted from Ref. [25] with permission of the copyright holder. obtained with different geometries, dimensions, functionalities mainly by a one-pot reaction of organic ligands, metal ions and a and exceptionally high loadings thanks to their remarkable poros- co-solvent that promotes a fast precipitation (Fig. 2c), a process ity (from 1000 up to 10,000 m2/g) [16]. Beyond encapsulation that can be assisted by external stimuli such as microwave within the pores, it is also possible to attach the drug to the consti- (Fig. 2d) or ultrasounds (Fig. 2e) [176]. tutive metal ions of the polymeric network [17–20], which in turn The resulting NPs are usually amorphous and less porous than may be simultaneously used as contrast agents (CAs) [21]. There NMOFs, with a spherical shape to lessen the interfacial free are specific synthetic strategies to control the crystallinity and energy and average dimensions regulated by the addition rate porosity of the final products, usually using methods that accu- of the co-solvent [29]. Moreover, the synthesis is fully repro- rately control some parameters such as diffusion (Fig. 1a) or pres- ducible and scalable, in addition, to exhibit the following charac- sure and temperature (solvothermal) (Fig. 1b). teristics: i) excellent colloidal stabilities, ii) multifunctional Alternatively to NMOFs, nanoscale coordination polymers properties [30], iii) encapsulation of several drugs with excellent (NCPs) have also raised increasing interest since first reported by yields and control release, and iv) control of the surface function- Mirkin [22] and Wang [23] back in 2005. Various approaches have ality, improving their biocompatible character (Fig. 3c) [31,32]. A been used for their synthesis, ranging from the use of sophisticated representative example compiling most of such potentialities was lab-on-a-chip devices [24] (Fig. 2a) or Dip-Pen Nanolithography given by Novio et col., who reported NCPs containing carboxyl (DPN) [25,26] (Fig. 2b) to other methods [27] as reverse micro- ended ligands favouring improved thermal and colloidal stabili- emulsions [28]. However, the most shared and simple approach ties (Fig. 3a). Moreover, surface carboxyl groups were function- is the synthesis of the NPs using out-of-equilibrium conditions, alised with different functional groups through well-known 3 S. Suárez-García, Rubén Solórzano, R. Alibés et al. Coordination Chemistry Reviews 441 (2021) 213977 Fig. 3. a) representative out-of-equilibrium synthesis of NCPs using caffeic acid, bis-imidazol linker (1,4-Bis(imidazol-1-ylmethyl)benzene) (Bix) ligands and a metal salt; b) scanning electron microscopy (SEM) images showing different synthetic batches of nanoparticles (NPs) with tuned dimensions by controlling the reaction mixing speed; c) schematic representation of NCPs advantages: feasibility to incorporate different surface functionalities to favour their colloidal stability, signalling and targeting abilities, drug entrapment, and control release, imaging, biocompatibility or their integration into more complex hybrid systems. SEM images are reproduced from Ref. [33] with permission of the copyright holder. peptide coupling reactions [33]. This strategy endowed enhanced brain through intravenous (i.v.) injection requires crossing biocompatibility and colloidal stability [34] or hybrid composites the blood–brain barrier. In this case, small NPs must be used. formation [35]. All of this is favoured by the attachment of speci- Nevertheless, if the NPs are administered intranasally, the fic molecules on the particle surface (i.e., peptides, antibodies, or sizes can be larger. aptamers, among others), increasing the active targeting to cancer ii) Colloidal stability. NCPs must demonstrate excellent colloidal tissues [36]. stability in water and physiological conditions. Colloidal dis- Concerning the area of application, NCPs have become relevant persions of NCPs have to be achieved, thus avoiding aggrega- in different fields such as gas adsorption and separation processes tion and agglomeration processes, which will hamper their [37], catalysis [38], sensor devices [39], photoluminescence [40], final application. This colloidal stability have to be long energy harvesting and conductivity [41]. Each one of these applica- enough to ensure the performance of the NCPs. tions requires specific characteristics and stabilities though that of iii) Biocompatibility and biodegradability. The biocompatibility nanomedicine is probably one of the most restrictive. For the suc- will be directly related to the metals and organic ligands cesful application in this area, NCPs must fulfill specific needs that employed NCPs and must be tested in healthy tissues to are listed next: ensure their safety. To reduce potential side effects, a careful predesign should be considered. How the NCPs decompose i) Size. The final diameter of the NCPs must be in the nm range. will significantly affect their potential use in biomedicine. The size will influence the biodistribution and clearance of For example, the leaching of harmful metals can induce their the developed systems. Smaller NPs (<20 nm) can be easily accumulation in some organs causing pathologies in the and quickly cleaned from the body, while bigger NPs medium-long term. The biodegradability of the NCPs is also (>100 nm) can be retained for longer circulation times. The of vital importance and all the species from the NCP decom- required sizes will depend on the administration route and position must be safe and adequately metabolised/cleared also on the final target tissue. For example, reaching the by the organism. 4 S. Suárez-García, Rubén Solórzano, R. Alibés et al. Coordination Chemistry Reviews 441 (2021) 213977 Fig. 4. Representation of the two approaches used to encapsulate active drugs in NCPs: a) physical entrapment; b) chemical entrapment. iv) Shape and robustness. The most frequent round shaped mor- 2.1. Physical entrapment phology of NCPs facilitates its circulation through the blood- stream and properly biodistribution in the whole organism. The physical entrapment of organic/inorganic luminescent dyes What is even more important is the robustness of the NCPs. and magnetic NPs with good encapsulation yields was already The degree of rigidity/softness will facilitate its internaliza- reported back in 2009 [42]. The same authors also showed how tion through the organism and its final clearance. NCPs could encapsulate anticancer drugs with efficiencies up to v) Functionalisation. The presence of ready-to-use functional 21%, released with time [45]. In another work, Gao et col. reported groups as anchoring points on the surface of NCPs turns Fe-based NCPs coated with silica to increase their stability in phys- out to be very useful. In most cases, the NCPs are not intrin- iological environments, allowing for a sustained drug release of sically tumour-selective, and the EPR effect is not enough to several days in response to slight pH modifications [46]. Moreover, ensure its effective accumulation in the tumoural area. To functionalisation of the silica with folic acid provided the NPs with avoid harmful effects in healthy tissues, the surface of NCPs targeting properties against cancer cells. Liang et col. also reported must be decorated with specific moieties (e.g., antibodies, triblock copolymer nanowires bearing a complex of b-cyclodextrin, peptides and active pharmacological molecules, among and 4,40 -bipyridine in the presence of Ni(II), which incorporated others), ensuring its selective recognition and locally limit- the Nile red dye as organic cargo [47]. Recent designs furthermore ing its effect. Other functionalities can be added to improve included nanogels containing doxorubicin (Dox) obtained upon the properties of the developed NCPs, such as biocompatibil- coordination of Fe(III) with dopamine-base gelatin polymeric ity and colloidal stability (e.g., PEGylation or protein corona materials [48]. These novel nanogels exhibited excellent cytocom- formation). patibility and efficient penetration into the cell membrane. Inter- estingly, this nanoformulation showed a delayed drug efficacy in 2. Encapsulation approaches in NCPs comparison to free Dox. Encapsulation within NCPs takes place mostly through two dif- 2.2. Chemical entrapment ferent strategies (or a combination of both), which are schemati- cally depicted in Fig. 4. In the first of the approaches (physical As commented before, an alternative approximation to physical entrapment), encapsulation inside the nanostructure occurs along entrapment consists in the direct incorporation of active drugs the particle assembly modulated by the chemical nature of the (metal ions or organic ligands) as constitutive units of the poly- metals and ligands [42]. The second approach (chemical entrap- meric backbone with smart release responses in front of external ment) consists in the incorporation of the active drug or imaging stimuli (e.g., pH, enzymatic action, a reducing environment or probe as a constitutive building block of the NCP [43]. This can light). In this sense, Xing et col. reported the formation of different be achieved using two different methodologies: i) incorporation NPs combining methotrexate (MTX) and S-(N-p-chlorophenyl-N- of bio-active metal ions as connecting building blocks (e.g., Fe, hydroxycarbamoyl)glutathione (CHG, the human glyoxalase I inhi- Zn, Mn, Ag, Gd) or ii) incorporation of drugs as organic ligands. bitor) with Zn or Fe ions. The stabilisation of the NPs was achieved Consequently, the drug release in both entrapment approaches by coating with another coordination polymer (CP) layer made of occurs through different pathways: i) NP disintegration due to its Zn ions and 1,4-bis(imidazol-1-ylmethyl)benzene (bix) [49], silica, surface degradation, ii) diffusion of the active drugs through the or a lipid bilayer [50]. The differential robustness and degradation polymeric matrix, or iii) a combination of both [44]. Both of the coatings were used to fine-tune the drug release profile in approaches are explained in more detail next. front of varying physiological conditions. Later on, Yan et col. 5 S. Suárez-García, Rubén Solórzano, R. Alibés et al. Coordination Chemistry Reviews 441 (2021) 213977 demonstrated the formation of curcumin- and Zn(II)-based NCPs extracellular environments in cancer cells. The different examples with preferential accumulation in tumours and controlled are categorised next by families of metal ions and/or ligands. degradation in physiological environments [51]. Li et col. reported Fe-induced DNA self-assemblies with tunable Fe:nucleotide ratios [52]. These systems were efficiently uptaken by the cells, showing 3.1.1. Metal node a predominant presence in endosomes or lysosomes. Besides, DNA Iron. Gao et col. reported NCPs encapsulating Dox hydrochloride delivery was possible by using the immunostimulatory CpG. Fan et (40% drug loading content) made of Fe ions coordinated to col. developed NCPs made of tryptophan-phenylalanine dipeptide 1,10 -(1,4-butanediyl)bis(imidazole) and subsequently coated with with Zn(II) ions [53]. The synthesised NCPs showed fluorescence silica [46]. The NPs revealed the sustained release of the drug for in the visible range and excellent stability and biocompatibility. more than a few days, notably faster at low pHs. Fe(III)-gallic acid Worth to mention, these NPs were able to incorporate Dox through (GA) NCPs encapsulating up to 93.5% of Dox, which was released at p-p stacking that could be released in vitro (50% in 24 h, pH 6.0) as the lower pH of the lysosomes, were also stated [61]. Not only that, monitored by fluorescence. Finally, Bertleff-Zieschang et col. but the NPs also exhibited an efficient in vivo tumour growth inhi- reported the self-assembly of different flavonoids and Fe(III) ions bition. In another example, Xu et col. proposed core–shell Fe3O@ as films or microcapsules with high antioxidant activity retained salphen-In(III) CP [62]. At pH 5.0, the Fe3O4 core slowly released for several cycles [54]. Fe ions. These ions coordinated with the released salphen ligands No disregard for the examples above, Pt(IV)-based CPs are with- as active drugs, exhibiting IC50 values competitive with pharma- out doubt one of the most visible cases of chemical entrapment as ceutical Mn(II)-salen drugs. pioneered by Lin et col. (vide infra) [55]. Other authors such as Copper. Bai et col. described the polymerisation of histidine, Dox Yuanfeng et col. described PEG-coated NCPs made of Zn(II) and and Cu(II) with high drug loadings and pH-dependence release (pH alendronate (ALN) to deliver the prodrug c,c,t-(diamminedichloro 5.0) due to the dissociation of the coordination bonds [63]. Finally, disuccinato)Pt(IV) (DSP) [56]. In vivo biodistribution studies Wang et col. reported the production of NCPs based on Cu(II) and demonstrated a preferential platinum delivery in metastatic than dioxocyclam, which were dissociated at low pH [64]. in healthy bones (4-fold), reducing side toxicity effects. The bene- Other metal ions. Wang et col. described the formation of titania fits of these NPs was confirmed by Adarsh et col. who showed a dif- nanotubes (TNTs) loaded with active ibuprofen, vancomycin, or Ag ferent and more effective action mechanism than cisplatin and the NPs [65]. The systems were fabricated using bix and Zn(II) (os- free Pt(IV) prodrug [43]. teoblastic proliferation) or Ag(I) ions (antibacterial), allowing for Another family of effective chemical entrapment is that repre- the release of the cargo at low pH due to degradation of the NCP. sented by antitumour nitrogen-containing bisphosphonates (N- Alternatively, Zn-based hexahistidine NPs with low cytotoxicity, BPs), which inhibit matrix metalloproteinase activity and down- fast internalisation and high loading capacities (up to 53%) were regulate integrins [57]. The main limitation of N-BP was its quick described by Huang et col. [66]. Specifically, the antitumoural renal clearance and strong bone binding. To avoid this, different camptothecin (CPT) encapsulation resulted in more effective per- N-BPs, including pamidronate or zoledronate, were also used in formance than the free drug. Interestingly, the formed NCPs combination with Ca(II) ions, which were further coated with showed a sustained release at pH 4.5. Yang et col. also published cationic lipid bilayers to increase their stability [58]. The formed NPs made of a cisplatin Pt(IV) prodrug bearing two carboxylic NCPs were gradually destroyed under physiological conditions groups, poly-L-histidine-PEG and Ca(II), Co(II), Ni(II), Hf(IV) and with a sustained release, from a few to 120–140 h. The in vitro Tb(III) ions [67]. While stable at neutral pH, a fast release was cytotoxicity assays on H460 cell lines revealed very low IC50 values observed at low pH, favouring in vitro and in vivo therapeutic (4.5–1.0 mM) upon integrating the lipid bilayers with the cell effects at low doses (Fig. 5). membrane [59]. To end this section, we would like to point out a novel approx- imation recently reported consisting in the chemical modification 3.1.2. Ligands of drug-based ligands that are cleaved under physiological condi- Phenol family. Using different templates, Ejima et col. reported tions. So far, it has been mainly used to synthesise efficient NCPs non-toxic tannic acid (TA) and Fe(III) capsules that decomposed platforms to treat AIDS/HIV [60]. The strategy consisted of func- in acidic pHs [68]. Interestingly, the reported NCPs exhibited per- tionalizing azidothymidine (AZT, an anti-HIV drug) with a chelat- meability, stiffness, good degradability [69] and Dox encapsulation ing catechol group, incorporating a spacer cleavable under [70]. For instance, pH-dependent capsules made by reaction of TA enzymatic hydrolysis. Worth to mention that this approach could with Al(III), Mn(II), or Gd(III) showed an effective cell internalisa- be extended to antitumoural applications, ensuring bigger encap- tion carrying several anticancer drugs (irinotecan, topotecan, or sulation yields and better control of the release kinetics. verapamil). Beyond TA, catechols have also been successfully used. Li et col. reported the combination of Fe(III) ions, hydrocaffeic acid, Dox and dopamine-modified hyaluronic acid [71]. The phenolic- 3. Stimuli-responsive NCPs based NCPs showed tumour growth inhibition without recurrence, thanks to the Dox release at the low pH in endosomes/lysosomes Another critical issue is developing responsive NPs that selec- or near-infrared (NIR) induced phototherapy [72]. Combinations tively deliver the drug in a controlled ON-OFF manner. Next, the of polyethyleneglycol (PEG), catechol-functionalized hyaluronic different approaches described in the literature are revised. acid and Dox showed pH-induced drug release and targeting for CD44+ cancer cells. These results were improved, supported by additional protein corona effects [73]. Park et col. used this 3.1. pH-responsive same approach to coat yeast cells without losing their biological activity [74]. pH stimuli is relevant mainly due to two reasons. First, coordi- In an interesting work, oleic acid emulsions containing Dox nation bonds can be sensitive to pH variations, especially at low were coated with a PEG holding catechol groups and Fe(III) ions pH, where protonation of the ligand takes place. Second, such sen- that respond to pH [75]. The obtained NPs exhibited high sitivity can be used to target the release, while reducing side cytotoxicity in human breast cancer cells, good permanence in effects, taking advantage of the variations within intra- and the bloodstream and a stealth-like response. 6 S. Suárez-García, Rubén Solórzano, R. Alibés et al. Coordination Chemistry Reviews 441 (2021) 213977 Fig. 5. a) one-pot synthesis of PEGylated NCPs and b) application as pH-responsive anticancer therapy favoured by the enhanced permeation and retention (EPR) effect. Reproduced from Ref. [67] with permission of the copyright holder. pH-sensitive ligands. An acid-sensitive imine linker together 3.3. Stimuli combination with Hf(IV) was used by Liu et col. to obtain NCPs capable of encapsulating chloro(triphenylphosphine)gold(I) (TPPGC) [76]. The combination of two or more stimuli allows for better con- The NPs exhibited excellent stability in physiological conditions trol of the cargo release. In this sense, Li et col. described the forma- and were degraded in acidic environments, releasing the drug tion of chemically and colloidally stable Zn(II) and histidine- in vitro and in vivo. Moreover, the chemotherapy was fully containing dipeptide NCPs [84]. The NPs showed the release of implemented with the radiosensitisation of the Hf ions without Ce6 (encapsulation yield higher than 50%) in front of both pH- compromising the toxicity nor the biodegradability. The same and GSH. The NPs also exhibited excellent in vivo circulation life- imine-based linker was reacted with Mn(II) ions and PEG by Liu times and antitumour accumulation and efficacy with very low et col. to obtain NPs encapsulating collagenase that degraded at toxicity. In the example shown in Fig. 6, Liu et col. described the low pH, exhibited high tumour accumulation and photodynamic formation of MnO2 NPs coated with the Hf(IV) and the Pt(IV) pro- effects [77]. Finally, Nador et col. have synthesised NPs made of drug DSP CP and PEG [85]. The presence of the Hf(IV) ions ensured Co(II) ions and a bis-catechol ligand bearing pH-dependent imine the radiotherapy, the MnO2 NPs, the magnetic resonance imaging group [78]. The NPs were stable at neutral pH but degraded and (MRI), and the Pt(IV) prodrug the chemotherapy once released in aggregated at pH 5.0. the reductive intracellular environments. The system was evalu- ated in vivo, showing features as chemotherapeutic with no appre- ciable side toxicity. Continuing with the examples, core–shell NPs combining PEG- 3.2. Photoactivation or redox stimuli poly(4-vinylpyridine), folic acid and the Ir(III)-2-phenylquinoline complex were shown to interact with histidine intracellularly, Zhang et col. fabricated NCPs by the combination of Zn(II) and a releasing the iridium complex that acts as an active drug and a bis(imidazole) ligand encapsulating fluorescein, tetracycline (an- phosphorescent emitter [86]. The reaction of Eu(III) or Tb(III) ions tibiotic), or Dox [79]. The encapsulated cargos were selectively with guanosine 50 -monophosphate (GMP) resulted in NPs with released upon UV light irradiation thanks to the presence of a pho- controlled release of N-methyl mesoporphyrin IX (NMM), as fol- tocleavable o-nitrobenzyl unit. Accordingly, cytotoxic effects in lowed by fluorescence [87,88]. GMP was also reacted with lan- HeLa cells were further substantial upon irradiation. In another thanides by Gao et col. to report NCPs that responded to example, Liu et col. described the reaction of the singlet-oxygen dipicolinic acid, ethylene diamine tetraacetic acid, pH and Cu(II) sensitive bis-(alkylthio) alkene linker (BATA) with Hf(IV) ions to or Hg(II) ions [89]. To finish with this section, Bai et col. synthesised generate NCPs loaded with the photosensitiser chlorin e6 (Ce6) NCPs with a disulfide-Dox prodrug and Cu(II) that responded to the and Dox [80]. Therefore, red light induced both the formation of simultaneous presence of the reductive/acidic environments of singlet oxygen and the drug release after ligand rupture and NP tumoural cells [90]. degradation. Moreover, in vivo distribution showed good tumour accumulation and synergistic chemo/phototherapy more effi- 4. Metal chemotherapy ciently than independently administered drugs. Finally, Hu et col. described NCPs using Zn(II) and a photoswitchable diarylethene 4.1. Platinum-based drugs ligand (UV or visible), representing a new paradigm for light- triggered release [81]. Undoubtedly, one of the utmost active metal ions used for the On the other side, GA and Fe(III) based NCPs with redox- assembly of NCPs is platinum. In fact, cisplatin and other Pt(II) controlled degradation, and therefore tunable drug release, was anticancer drugs, such as carboplatin or oxaliplatin (OxPt), are reported by Cherepanov et col. [82]. Micelles made of PEG-poly(N already FDA-approved chemotherapeutics used for a long-time (2-hydroxypropyl)methacrylamide bearing 4-(methylthio)benzoyl treatment of several different cancers [91]. Due to this success, sci- groups and the [ethylenediamineplatinum(II)]2+ linker were shown entists also aimed to include in clinical experiments other Pt(II), Pt to effectively encapsulate curcumin [83]. Interestingly, after treat- (IV) prodrugs and photoactivatable Pt(IV) [92], with a wealth of ment with dithioerythritol, the drug release was favoured, mimick- optimism based on NPs for future platinum-based cancer drugs ing the intracellular glutathione (GSH). [93]. From all of them, Pt(IV) prodrugs are the ones mostly used 7 S. Suárez-García, Rubén Solórzano, R. Alibés et al. Coordination Chemistry Reviews 441 (2021) 213977 Fig. 6. Schematic representation of the theranostic and redox/pH responsive MnO2 NPs coated with a CP shell formed by Hf(IV) + c,c,t-(diamminedichlorodisuccinato)Pt(IV) (DSP). Drug release responds to a pH decrease, reductive environments, and endogenous tumour H2O2, enhancing cancer chemoradiotherapy. Moreover, these NPs are able to tumour-specific magnetic resonance imaging (MRI). Reproduced from Ref. [85] with permission of the copyright holder. Fig. 7. Schematic representation of the NCPs formation using the Pt(IV) prodrugs (top) shown in three leading families of Pt(IV) prodrugs used as synthons in the building of NCPs (bottom). to obtain NCPs combined with bis-chelating equatorial ligands able and 28.0 ± 2.6 wt%, respectively) with a robust synergistic effect to further coordinate with other metal ligands [94]. Beyond induc- to treat Pt-resistant OCa cells [96]. In vivo studies also showed per- ing the polymerisation, axial ligands can also introduce additional sistent circulation in the bloodstream and improved tumour properties and/or biological activity. Mainly three different fami- uptake, resulting in tumour growth inhibition (80%) and regression lies of ligands, schematically represented in Fig. 7, have been used (70%). with this aim. In another example, Zhao et col. used NCPs made of Zn(II) coor- dinated to alendronate (ALN) and a fatty acid-modified PEG to effi- 4.1.1. Succinate (DSCP) ciently deliver DSCP to the bone [56]. For this, particle size was A seminal work published in 2008 by Lin et col. described cyto- regulated by adjusting experimental parameters down to approxi- toxic effects in colon and breast cancer cells of NCPs synthesised mately 55 nm to extravasate into capillaries and accumulate into from terbium metal ions and the DSCP ligand [55]. Further coating metastatic bones. Besides, to efficiently inhibit tumour growth, with a silica layer functionalised with a silyl-derived peptide RGD these NPs also reduced osteoclastic bone destruction with no sig- provided both cell targeting properties and controlled release of nificant toxicity. More recently, a new biodegradable NCP family the cisplatin prodrug. Later on, the silica coating was replaced by incorporating Fe(III) and DSCP, which was liberated in the presence a lipid bilayer, bearing the active targeting molecule anisamide of GSH, was reported [97]. Interestingly, the Fe(III) ions were (AA), which improved the biocompatibility and cytotoxicity in reduced into Fe(II), which enforced an amplified intracellular human cell lung cancer cells [95]. The same group has also oxidative stress via the Fenton reaction. Further decoration of the reported NCPs loaded with GMP and carboplatin (8.6 ± 1.5 wt% NPs with PEG and the cyclo[Arg-Gly-Asp-D-Phe-Lys(mpa)] peptide 8 S. Suárez-García, Rubén Solórzano, R. Alibés et al. Coordination Chemistry Reviews 441 (2021) 213977 Fig. 8. a) synthesis of Zn-Pt(IV) and b) SEM image of Zn-Pt(IV) NCPs; c) in vitro platinum release kinetics and agarose gel electrophoresis of a pBluescript II plasmid DNA treated with the NCPs, the free prodrug and blanks (inset). Reproduced from Ref. [43] with permission of the copyright holder. Fig. 9. Graphic illustration of the fabrication, composition and effect of Pt-based NCPs, showing the endocytosis and release of OxPt and GMP, and the OxPt and GMP based DNA replication disruption. Reproduced from Ref. [99] with permission of the copyright holder. (cRGD) enabled an excellent targeting effect against avb3-integrin, cells, cervical cancer, and human adenocarcinoma. Such improve- which is commonly overexpressed in tumoural cells, showing ment does not come from a differential Pt cell uptake but a higher outstanding biosafety and biodegradability. DNA bonding. The results showed how the nanostructuration Even though successful, previous examples lacked mechanistic could adjust the bioavailability of different species to enhance details that justify its effectiveness, the reason why some of us the therapeutic action compared to the free drug. decided to gain more in-depth knowledge on how nanostructura- tion modulates the mechanism of actuation of platinum-based 4.1.2. Phosphonic acid drugs. For this, we designed NCPs made of a Pt(IV) prodrug, Zn NCPs made of biphosphonic acids containing cisplatin and OxPt (II) and bix ligand (Fig. 8) [43]. with high drug loadings (~48 and ~45 wt%, respectively) and a The formed NPs (with a size around 200 nm) exhibited excel- coating combining lipids and PEG were reported by Lin et col. lent permanency in physiological media and sustainable control [98]. These NCPs revealed low activation of the mononuclear drug release. Moreover, Pt(IV)-based NCPs demonstrated enhanced phagocyte system and, therefore, a considerable blood circulation cytotoxicity with respect to free Pt(IV) prodrug in neuroblastoma time that allowed for their use to treat subcutaneous tumour mur- 9 S. Suárez-García, Rubén Solórzano, R. Alibés et al. Coordination Chemistry Reviews 441 (2021) 213977 Fig. 10. a) representation of NCP@pyrolipid NPs, including PEG in the coating layer; b) intravenous (i.v.) injection and tissue distributions of Pt released from NCP@pyrolipid; c) tumour development inhibition curve after i.v. injection of phosphate-buffered saline (PBS), NCP, porphysome, or NCP@pyrolipid to the human head and neck cancer SQ20B subcutaneous xenograft murine models. Reproduced from Ref. [100] with permission of the copyright holder. ine models with higher efficacy than free drugs. This approach was models by generating a strong tumour-specific immune response likewise useful to combine different chemotherapeutic approaches combined with the PDT effect [102]. Significant immunotherapy within a single nanocarrier. For instance, Zn(II)-based NCPs with effects were also obtained using lipid-coated NCPs that systemati- OxPt and gemcitabine monophosphate (GcMP) ensured a synergis- cally delivered a combination of OxPt and dihydroartemesinin tic effect in pancreatic cancer mouse models (Fig. 9) [99]. In addi- (DHA). This system effectively induced cell death through the syn- tion to minimal mononuclear phagocyte system uptake and ergism of ROS and the anti-PD-L1 antibody in murine colorectal prolonged bloodstream circulation, these NPs ensured the co- cancer tumours [103]. delivery of both anticancer drugs with different action mechanisms Different examples of RNA-bearing NPs have also been to concurrently disrupt several anticancer mechanisms. described. For instance, self-assembled NCPs with the cisplatin Yet again, Lin et col. described core–shell NCPs containing high prodrug coated with a cationic lipid layer occluding siRNAs have loads of cisplatin and a pyrolipid (photosensitiser) for combined been reported to target three multidrug resistants (MDR) genes chemo-/photodynamic therapy (PDT) [100]. These NPs showed that overcome cisplatin-resistance ovarian cancer cells [104,105]. superior and efficient tumour reversion in head and neck Cell viability studies showed an improved chemotherapeutic effi- cancer-induced mouse models (83% tumour reduction) compared cacy by downregulating the expression of MDR genes while the to administering the non-encapsulated anticancer drugs in vivo local administration reduced tumour dimensions of subcu- (Fig. 10). taneous xenografts. Finally, non-toxic NCPs based on Pt(IV)(en)2- Another emergent area where NCPs point to success is in bis(phosphonic acid) [en = ethylenediamine] and microRNA immunotherapy for cancer treatment [101]. With this aim, previ- (miRNA) were coated with a self-assembled lipid bilayer [106]. ous NCP-pyrolipid nanoformulations were combined with the Subsequently, the resulting system was functionalised with PEG PD-L1 antibody to treat subcutaneous CT26 and HT29 mouse chains, avoiding the clearance by phagocytes. 10 S. Suárez-García, Rubén Solórzano, R. Alibés et al. Coordination Chemistry Reviews 441 (2021) 213977 4.1.3. Gallate was delivered through a pH-sensitive release in the tumour Beyond succinic and phosphonic acid, the tendency over the microenvironment facilitated via microvesicle-mediated intercel- last few years has been the introduction of gallate groups, favour- lular transfer. Moreover, the release was traced by the fluorescence ing the coordination with metals and providing additional anti- of the released AQ4N or Dox upon protonation. Thus, these NCPs cancer properties. In this direction, in 2017, Caruso et col. were capable of loading phthalocyanine and induced the PDT reported PEG-modified NPs (100 nm) with antifouling and high ‘‘on-demand”, which facilitated a hypoxic atmosphere and trig- drug loadings [107]. The NPs exhibited long in vivo circulation gered the decrease of AQ4N, increasing therapeutic efficiency. times (half-life of 18 h) and better (up to four times) antitumour activity in a human prostate cancer xenograft mouse model com- 4.3. Other metal-based drugs pared with the prodrug or cisplatin. One year later, Chen et col. reported the protection of phagocytic enzyme myeloperoxidase Many Ru(II)-based inorganic and organometallic complexes (MPO) from degradation by coating with pPt/PEG polyphenols have relevant therapeutic action [120], though only a few are NCPs. [108]. The NPs, which exhibited excellent in vivo blood circulation Higuchi et col. reported supramolecular NCPs combining bis(ter- and tumour retention, improved the efficacy as the Pt ion produced pyridine) with Ru(II)/Fe(II) that significantly inhibited the growth H2O2 that MPO intercellularly catalysed into the active HOCl. In of cell lung cancer lines (NCI-H460) thanks to metal/phosphate another successful example, a combination of chemo- ion interactions with the DNA [121]. Raja et al. used Co(NO3)2 photothermal therapy (PTT) with multimodal photoacoustic (PA)/ and isonicotinic hydrazine that interacted with calf thymus DNA MRI/positron emission tomography (PET) imaging was achieved and bovine serum albumin (BSA) [122]. This system exhibited by using NPs made of the Pt prodrug polyphenol and Gd(III) ions. strong radical scavenging potency and cytotoxicity against Hep-2, In these NPs, coated with the pH/sensitive PEG-based block copoly- Hep G2, HeLa and A431 cancer cell lines (two/three times higher mers, the Pt drug release was activated under NIR irradiation or in when compared to cisplatin). Correlation of the binding ability of the characteristic acidic pH of tumours. The results showed cobalt complexes, DNA and inhibition values were, later on, con- enhanced MR signal, exhibiting an excellent tumour accumulation firmed [123], as well as Cu(II) and Zn(II) [124]. Different sub- and eradication with low power NIR laser irradiation [109]. Finally, stituents and other structural changes influenced the activity, the combination of epigallocatechin-3-gallate (EGCG, a Pt(IV) pro- bringing invaluable information to the strategy of efficient agents drug bearing phenol groups) and polyphenol modified PEG block for targeting nucleic acids. In another family of examples, arsenic copolymers, using Fe(III) as a metal node, yielded NPs with a rele- and bismuth-based polymers were shown to be very effective vant cellular internalisation. Cisplatin was also used to increase the (low IC50 values), inhibiting the growth of the human prostate cells intracellular H2O2 necessary to generate reactive oxygen species while exhibiting low toxicity towards normal human cells (Fig. 11) (ROS) through the Fenton reaction of the Fe(III) ions and, therefore, [125,126]. a chemodynamic/chemotherapy anticancer efficacy [110]. Researchers also studied the anticancer activity of La(III), Sr(II) The examples previously reported, though successful, still [127] and In (III)-based [128] NCPs. On top of that, some precious exhibited intrinsic resistance to some tumours and mainly adverse metal-containing polymers also showed engaging anticancer activ- side effects. For this reason, more efficient metal-based therapeutic ities following mechanisms different from those of Pt-based poly- agents, some of them being currently running clinical trials, are mers [129]. However, their use has been scarcely explored as rigid actively being searched nowadays [111]. Growing developments chelation is required to achieve stability [130]. Finally, the nanos- based on Ru, Cu, Zn, Au, or In complexes have received intensive tructuration of kinetically inert coordination complexes for anti- attention over the last years [112–114]. cancer agents, such as Rh(III) or Ir(III) [131], could open interesting investigations for anticancer activity. To conclude this 4.2. Copper-based drugs section, Huang et col. rationally designed NCPs incorporating GSH-responsive NO donor and Fe ions [132]. Degradation of the In the case of copper, there are enough examples to configure a NO donor in the presence of GSH in tumour cells (~10 mM) quickly specific section. One of the first reports appeared back in 2011; reacted with H2O2 and O–2 anions to form peroxynitrite anion Arunachalam et col. reported NCPs made of copper ion and bipyr- (ONOO–) and, therefore, enhanced the chemodynamic efficacy idyl/polyethyleneimine ligands that killed NCI-H460 human lung (Fig. 12). cancer cells [115]. One year later, Wang et col. reported Cu- aminobenzoate NPs with IC50 values of 17.5 ± 4.9 and 30.7 ± 1.3 lg/mL at 72 h for HeLa and NCI-H446 cells, respectively [116]. 5. Photodynamic therapy These toxicities were related to the released Cu(II) ions from NCPs and/or direct interaction of the NPs with the cells. Other Cu-based PDT lies in the administration of photosensitiser in a tumour NCPs containing 1,10-phenanthroline and L-arginine induced the area, which under light activation generates singlet oxygen (1O2) apoptosis of MCF-7 mammary carcinoma cells, most likely due to that activates cell apoptosis/necrosis and immunity [133]. One the formation of DNA/RNA complexes [117]. of the main advantages of using NPs for this therapy is that the More recent efforts aim for the integration of different strate- photosensitiser is accumulated in the tumour cells. Therefore, irra- gies and drug combinations pursuing synergistic antitumoural diation can selectively generate a local amount of ROS, preserving effects. In this sense, Wu et col. designed multifunctional NCPs that surrounding tissues. In the case of CPs, most of the examples so far consisted on hyaluronic acid (targeting), AQ4N (chemotherapeu- reported are NMOFs [134–137], with some interesting NCPs tic), gossypol (chemotherapeutic agent and a self-carrier) and Cu reported. For instance, nanostructuration has been found to solve (II) as connecting node and antitumour enhancer [118]. These the low solubility and selectivity of Zn phthalocyanine-based NPs (88.7 ± 7.4 nm) exhibited excellent drug encapsulation effi- photosensitisers [138]. Zhao et col. designed NCPs from the coordi- ciencies (70–100%) and tumour-targeting abilities mediated by nation between phthalocyanines and Zn(II) [139]. The resulting hyaluronic acid receptors and pH. In vivo experiments showed that systems were coated via self-assembly of a lipid bilayer that gener- the NPs accumulated and released drugs specifically at the tumour ated PDT in MCF-7 cell cultures and cholesterol derivatives that region, favouring a considerable decrease of the administered dose ensured responses to acidic tumour microenvironments. In and any related side effect. Liu et col. reported AQ4N-Cu(II) NPs another example, Chen et col. reported NCPs embracing DNA combining now banoxantrone and Dox [119]. The anticancer drug coordinated to Ca(II) with AS1411 DNA G quadruplexes and 11 S. Suárez-García, Rubén Solórzano, R. Alibés et al. Coordination Chemistry Reviews 441 (2021) 213977 Fig. 11. Encapsulation of phenylarsine oxide (PAO) into a biodegradable block copolymer containing pendant thiol groups (or not) on the hydrophobic part; i.e., [PEO-b-P (CCLC6-SH)]PEO-b-P(CCLC6-SH) and PEO-b-P(CCLC6) micelles. The upload process takes place upon solvent polarity changes, while arsenic was entrapped chemically (reaction with the thiol groups) or physically in the polymer that did not contain the thiol groups. The detachment of PAO from PEO-b-P(CCLC6-S-PAO) took place by direct hydrolysis in aqueous media or by glutathione (GSH) triggered arsenic release. Reproduced from Ref. [126] with permission of the copyright holder. Fig. 12. a) synthesis of Fe(III)-BNCP NPs; b) tentative mechanism for the NO chemodynamic activity of these NPs in tumour cells. Reproduced from Ref. [132] with permission of the copyright holder. pHis-PEG, and the additional incorporation of the photosensitiser resulting from the coordination of Zn(II) ions with an amphiphilic Ce6 and an Fe-containing porphyrin (hemin) [140]. With further amino acid [141]. The final NCPs were coated with an anti-nucleolin PEG modification, the nanostructure demonstrated cell internalisa- aptamer (AS1411), which improved cancer cell-targeted capability in tion and intranuclear ROS activity. Simultaneously, the PDT effect different cancer cells. In vivo assays showed a significant was improved through the inhibition of anti-apoptotic protein B- accumulation into tumours through the EPR effect, aptamer interac- cell lymphoma 2 expression. Interestingly, endogenous tumour tion with tumour markers and NIR-induced PDT. The nanoassembly H2O2 could decompose the DNAzyme function (Fig. 13). could also disassemble inside the acidic tumours containing GSH, so In a similar approach, Chu et al. assembled porphyrin/ the porphyrin/G-quadruplex tandem was more effective while G-quadruplex complexes (with NIR light responses) on NCPs reducing the 1O2 consumption of the GSH. 12 S. Suárez-García, Rubén Solórzano, R. Alibés et al. Coordination Chemistry Reviews 441 (2021) 213977 Fig. 13. a) scheme of Ca-AS1411/Ce6/hemin@pHis-PEG (CACH-PEG) NCPs; b) time-dependent in vivo fluorescence imaging of 4T1 tumour-bearing-mice after i.v. injection (right column: ex vivo imaging of different organs and tumour took after 24 h post-injection from a representative mouse); c) Viability of 4T1 cells treated (72 h) with different concentrations of AS1411 or CACH-PEG; d) viability of 4T1 cells incubated with CAC-PEG or CACH-PEG and irradiated with 660 nm light (5 mW/cm2, 30 min) with and without 100 lM H2O2. L stands for a sample exposed to a 660 nm LED irradiation at a density of 5 mW/cm2. Reproduced from Ref. [140] with permission of the copyright holder. 6. Unconventional approaches Changing the approach, Mirkin et col. reported the synthesis of NCPs, based on the reaction of Fe(NO3)3 and 3-hydroxy-4- One of the significant difficulties in treating cancer comes from pyridinone (HOPO) conjugated with DNA as biocompatible the extracellular matrix that prevents the tumour diffusion of gene-regulation agents [143]. The resulting nanoconjugates drugs and favours hypoxic environments unsatisfactory for effi- showed the ability to enter cells and target a known cancer- cient treatments. Therefore, developing strategies to degrade the related mRNA transcript (SKOV-3 ovarian-cancer cells) that modi- extracellular matrix is expected to improve existing cancer thera- fied protein expression without the need for transfection agents, pies. With this aim, Liu et al. encapsulated collagenase in PEG- generating an efficient gene knockdown. Alternatively, Liu et col. coated NCPs made of Mn ions and a benzoic-imine ligand sensitive described biodegradable NCPs for radioisotope therapy in clinical to pH. These NPs efficiently accumulate in the tumour and release cancer treatments [144]. The proposed nanosystem consisted on collagenase thanks to the acidic pH that degraded collagen and PEG-modified NCPs obtained by the one-pot reaction of Hf(IV) ions minimise the extracellular matrix [77]. Wang et al. recently pub- and tetrakis (4-carboxyphenyl) porphyrin (TCPP). These NPs could lished an interesting idea to combat metastatic cancer by regulat- be simply labelled with 99mTc(IV) (radioisotope with a half-life of ing the immune system using vaccine-like microparticles made of 6.0 h) that emit c rays, resulting in NPs feasible for SPECT imaging. epigallocatechin-3-gallate (EGCG) and Al(III) metal ions and encap- The results revealed efficient in vivo tumour retention and elimina- sulating tumour cells (Fig. 14) [142]. tion with moderate doses of 99mTc. On top of that, the NPs were 13 S. Suárez-García, Rubén Solórzano, R. Alibés et al. Coordination Chemistry Reviews 441 (2021) 213977 Fig. 14. a) schematic representation of tumour cells coated with an EGCG/Al layer (TL@EGCG/Aln); b) expected coordination modes within the NP; c) SEM micrographs of uncoated B16 cells and different coating tumour cells. Reproduced from Ref. [142] with permission of the copyright holder. biodegradable and easily excreted without significant long-term Agents (DMCAs) NCPs to facilitate the understanding of diagnostic body accumulation, indicating their promising effect for cancer images by suppressing MRI artefacts and ambiguities, have been radioisotope therapy. Interestingly, the NCPs allowed for improved effectively obtained. Yang et col. developed multifunctional Gd efficacy and fewer side effects than currently used radioisotopes (III)-based NCPs combining 1,10 -dicarboxyl ferrocene, coated with (half-lives of days). silica to improve water stabilisation and superficial amination Hybrid NPs combining gold nanosystems and a CP obtained by [150]. Surface amine groups allowed for the covalent coupling of reaction of (pq)2Ir(Hdcbpy) with Dy(OOCCH3)3 have been reported a fluorescent rhodamine dye (RBITC) and an arginine-glycine- [145]. The hybridisation of both induced an evident redshift of the aspartic acid (RGD) peptide resulting in water-stable NCPs with local surface plasmon resonance peak. Furthermore, these hybrid low cytotoxicity and dual-mode T1w/T2w in vivo imaging (Fig. 15). NPs also exhibited PAI-induced NIR-driven PTT and MRI in vivo. Finally, in another work, Li et col. described the formation of hybrid 7.1.2. Manganese-based NCPs NPs by combining DNA and Fe(II) ions that released DNA in vitro Lin et col. reported Mn-bisphosphonate NCPs with remarkable and in vivo [52]. loads of zoledronate (63 wt%) and Mn(II) ions (13 wt%) [151]. The NPs were further coated with lipids, PEGylated and functional- ized with anisamide to enable specificity to cancer cells, biocom- 7. NCPs for theranostics patibility and control over the drug release. In vitro MRI assays evidenced the efficacy of these NCPs as an efficient CA and vali- There are a plethora of examples describing the use of NCPs as dated the targeting ability and apoptosis in breast/pancreatic can- imaging systems [146]. One of the cornerstones in cancer research cer cells. In its place, manganese dioxide (MnO2) NPs coated with a nowadays is the combination of drug efficacy with tumour moni- Hf-cisplatin-PEG shell showed a redox/pH/H2O2-responsive cancer toring in real-time to increase the safety of the treatment [147]. treatment [85]. The NPs exhibited tumour activity wherein the oxygen level was elevated due to the presence of the MnO2 core 7.1. MRI and chemotherapy and displayed fast renal clearance. Moreover, a remarkable tumour growth inhibition was noticed after the combined chemoradio- MRI is an effective non-invasive procedure that allows for therapy treatment without appreciable toxicity. In another exam- excellent imaging resolution and body penetration. Commonly, ple, Zhao et al. synthesised redox-sensitive mesoporous NCPs MRI requires the administration of external CAs to enhance image made of Mn(II) and dithiodiglycolic acid. The NPs encapsulated resolution and efficacy. Next, we revise examples of NCPs grouped Dox and were protected with polydopamine (PDA) and PEG according to the metal ion used. [152]. The disulfide linkage (SS) present in the dithiodiglycolic ligand was cleaved by GSH, leading to degradation of NCPs and 7.1.1. Gadolinium-based NCPs Dox release (Fig. 16). Moreover, the NCPs demonstrated a Zhu et col. developed biodegradable gadolinium NCPs loaded concentration-dependent MRI contrast larger than clinically tested with Dox stable at neutral pH but responsive to pH modifications Gd CAs, providing efficient in vivo tumour accumulation. The NCPs [148]. The presence of the CD44 receptor in the NPs facilitated exhibited good stability in the physiological environments and the selective internalisation and trapping within acidic partitions stable blood circulation after i.v. injection. of HeLa cells. Once there, the NPs disassembled, releasing Gd ions Yan et col. reported NCPs loaded with the photosensitive drug and fluorescent Dox used for real-time monitoring. Ma et al. engi- Ce6 using an amphiphilic amino-acid ligand coordinated with neered NPs for theranostics merging amphiphilic pluronic F127 Mn(II) ions [153]. The NCPs showed significant drug loading capac- and a peptide-amphiphile with drugs located into the hydrophobic ity, high intrinsic biocompatibility, strong stability and PDT dam- micelle cores and chelated with Gd(III) MRI CAs [149]. Experiments age by releasing Ce6 upon coordination of GSH with Mn(II). on tumour-bearing mice using Dox demonstrated them as efficient Moreover, MRI was used to verify the antitumor efficacy in vivo therapeutic agents. Recently, examples of Dual-Mode Contrast (Fig. 17). 14 S. Suárez-García, Rubén Solórzano, R. Alibés et al. Coordination Chemistry Reviews 441 (2021) 213977 Fig. 15. Fc-Gd@SiO2(RBITC)–RGD NCPs synthesis and their use as in vivo targeted dual-mode T1- and T2-weighted magnetic resonance imaging (MRI). Reproduced from Ref. [150] with permission of the copyright holder. Fig. 16. Synthesis of Dox-loaded NCPs with glutathione (GSH)-triggered degradation. Reproduced from Ref. [152] with permission of the copyright holder. Fig. 17. Assembly and disassembly of FMCNPs for MRI-guided phtodynamic therapy (PDT). Reproduced from Ref. [153] with permission of the copyright holder. 15 S. Suárez-García, Rubén Solórzano, R. Alibés et al. Coordination Chemistry Reviews 441 (2021) 213977 by in vitro and in vivo MRI experiments. In vivo intratumoural injec- tion confirmed an antitumour activity combined with laser treat- ment (PTT) and monitored by the positive change in the MRI of the tumour. Following a very successful approach, some of us reported NPs upon the reaction of a bis-imidazol (bix) ligand with different metal ions and phenol groups completing the coordination sphere. While the bis-imidazol ensures the polymerisation, the caffeic ligand confers: i) high robustness enforced by supramolecular hydrogen bonds without modifying the morphology and encapsu- lation abilities and ii) carboxylate groups located on at the surface of the NPs functionalised using peptide coupling reactions (Fig. 19). Moreover, these NPs exhibit high drug loading capacities, low cyto- toxicity, efficient cell internalisation and control over the colloidal stability, becoming an excellent platform for their use as theranos- tic devices. The MRI properties of this novel platform were tested using three different metal ions (Fe(III), Gd(III) and Mn(II)), being the Fe-based NPs the ones showing enhanced in vitro phantoms and ex vivo dual-mode T1/T2 contrast [157]. Fig. 18. Synthesis and application of PDAs@CP3-Dox. Reproduced from Ref. [155] In vivo MRI studies of the NPs in a murine glioblastoma model with permission of the copyright holder. also showed a remarkable permanence for the simultaneous recording of T1 values comparable to commercial CAs and an addi- tional T2 signal. Moreover, a subsequent gradual clearance denoted 7.1.3. Iron-based NCPs their good biodegradability Fig. 20 [157]. Beyond MRI, fluorescent Zhao et col. described the synthesis of amphiphilic polymeric multichannel imaging was also demonstrated. For this, fluorescein micelles encapsulating Dox and cross-linked through coordination isothiocyanate (FITC), 1-pyrenebutanoic acid hydrazide (PBH) or bonds [154]. The presence of Fe(III) ions provided T1-weighted Alexa FluorÒ 568 (A568) were covalently linked to a catechol (T1w) MRI signals, while the acid-sensitive coordination bond of ligand. The NPs had good in vitro internalisation, retaining their the drug allowed for its release and effective elimination of the characteristic fluorescence without significant dye leakage 4T1 tumour in a mouse model. Lu et col. also developed PDA NPs (Fig. 20) [158]. with Fe ions for T1/T2 MRI and chemo-/photothermal therapy Finally, this platform was used to encapsulate different active [155]. The in vivo performance of these NPs showed low toxicity materials taking advantage of its chemical flexibility. For and excellent biocompatibility. In addition, the chemotherapy instance, hybrid NCPs encapsulating superparamagnetic iron was facilitated by delivering Dox on demand in response to NIR oxide NPs (SPIONs) acting as both T1/T2 CAs and efficient drug and by heat (Fig. 18). Following the efficient use of phenols, Mu release systems were reported [159]. The NPs not only exhibited et col. described the preparation of ultrasmall BSA-coated GA–Fe an efficient cellular uptake but a ten-fold efficacy versus the free (III) NCPs that showed excellent biocompatibility and NIR drug in front of the human breast adenocarcinoma (MCF-7) cell absorption [156]. The NCPs provide good T1w contrast as validated line [33]. Fig. 19. Formation of NCPs based on bis-imidazol (L1, bix) and caffeic acid (L2) ligands. This approach allows for the fabrication of an extensive family of NCPs with different metal nodes, while carboxylates at the surface can be functionalised using peptide coupling reactions. Reproduced and adapted from Ref. [157] with permission of the copyright holder. 16 S. Suárez-García, Rubén Solórzano, R. Alibés et al. Coordination Chemistry Reviews 441 (2021) 213977 Fig. 20. a) SEM images; b) size histogram and in vivo T1w/T2w image; c) before and d) post i.v. injection of Fe-NCP; e) in vivo images using a confocal laser scanning microscopy of HeLa cells incubated with Co-NCP system for 2 h with NCP3-FITC-A568 (top) and the corresponding control (non-functionalised NCP). Different single-channel projections were displayed (FITC (green), A568 (red), the nuclear stain (Hoechst, blue)) and the merge of all the channels. Scale bars are 20 mm. Reproduced from Ref. [157] and [158] with permission of the copyright holder. 7.2. Other imaging/chemotherapy approaches the i.v. administration of the NCPs allowed for the inhibition of tumour growth. Interestingly, these NCPs showed very low Fluorescent Zr-porphyrin NCPs loaded with Dox showed in vivo in vivo toxicity and excellent clearance through the renal system. efficient accumulation in tumours combined with laser irradiation Recently, we have described the modification of previously with residual side effects in healthy tissues [160]. In an additional reported MRI-based NCPs [157] by adding In(III) and Cu(II) and example, Ban et al. synthesised amphiphilic hyperbranched poly- their respective radioisotopes [163]. In this case, the PDA-like coat- triazoles containing Cu ions with aggregation-induced emission ing employed allowed for forming a functionalisable platform to (AIE) enhancement used as a fluorescent probe [161]. The resulting incorporate PEG and folic acid for its specific targeting in CT26 nanocarrier was useful for cancer therapy in response to a redox tumour-bearing mice. stimulus that dissociated disulfide bonds and released the Cu com- plex units. As shown in other sections, radioimaging has also been 7.3. Multi-mode imaging/therapy approaches used for the monitoring of NCPs. In this sense, Liu et col. reported renal-clearable NCPs coordinating W(VI) ions with PEG- 7.3.1. MRI and optical imaging. functionalised GA and subsequently radiolabeled with 64Cu for Yin et col. have developed NCPs using Gd(III) and Ru[4,40 - PET imaging (Fig. 21) [162]. The application of radiotherapy after (COOH)2bipyridyl(bpy)]2+ 3 with low toxicity and imaging ability Fig. 21. a) synthesis W-GA-PEG NCPs and b) schematic of 64Cu-labeled W-GA-PEG NCPs that enables positron emission tomography (PET) imaging and the radio-sensitising function of W(VI) for cancer radiotherapy. Reproduced from Ref. [162] with permission of the copyright holder. 17 S. Suárez-García, Rubén Solórzano, R. Alibés et al. Coordination Chemistry Reviews 441 (2021) 213977 Fig. 22. Schematic synthesis and theranostic applications of Ir-Gd NCPs. Reproduced from Ref. [165] with permission of the copyright holder. to differentiate tumours from other tissues thanks to a combina- and radio-sensitisation [171]. The NCPs were further coated with tion of high MRI contrast and red fluorescence emission [164]. In PDA and PEGylated, showing excellent eradication of tumours another example, Yang et col. stated stable and low toxicity NCPs thanks to synergistic photothermal and radiation therapy in with Ir(III) (luminescent) and magnetic Gd(III) ions (MRI probe) in vivo model experiments, without appreciable toxicity and effi- [165]. The NPs exhibited an efficient uptake by HeLa cells, while cient excretion. Liu et col. described Zn(II)-dipicolylamine NCPs the efficient production of 1O2 under visible irradiation allowed loading ICG and therapeutic genes to accomplish a fluorescence/ for PDT therapy of cancer cells (Fig. 22). Similarly, Yang et al. PAI-guided combination of phototherapy (PTT) and gene therapy reported NCPs through the coordination between Mn(II) ions and [172]. In a 4T1 xenograft mouse model, PTT and gene therapy com- IR825, a NIR dye, followed by PDA coating and PEGylation [166]. bined reduced the tumours with minimum side effects and, nota- In vivo results demonstrated its efficacy as T1 CA after gradual bly, without recurrence after three weeks. Finally, Yin et col. uptake by the tumour, high PTT efficacy and rapid renal excretion, reported NCPs using Ru[4,40 -(COOH)2bpy]2+ 3 , Gd(III) and Yb(III) that minimising any long-term toxicity concern. Upon irradiation, allowed for red fluorescence, MRI and CT imaging with 3D spatial tumours on mice with the NPs were entirely removed without resolution and the 1O2 production of the LRu for the efficient treat- reappearance in 60 days. ment of Hep G2 tumour-bearing mice [173]. Recently, G.-G. Yang With a similar strategy, Qin et al. integrated diagnostic and et al. described the formation of NCPs through the coordination therapeutic components into a single NCP. The ratio of coordinated of quercetin (a heat shock protein inhibitor) with Fe(II) ions Gd(III) and Fe(II) ions with polyphenols (i.e., TA) influenced the col- [174]. The NCPs showed specific accumulation in tumours due to loidal stability in an aqueous solution. These NPs revealed pho- the EPR effect. After the application of temperature, complete tothermal interconversion and longitudinal relaxivity that tumour ablation was achieved without damaging the surrounding depended on the composition [167]. Those NPs (~23 nm) with a healthy tissues. Additionally, these NCPs provided high resolution boosted Gd/Fe molar ratio exhibited an r1 and r2/r1 ratio values and depth tumour imaging, thanks to the combination of PAI and of 9.3 mM1 s1 and 1.26, respectively, and high photothermal MRI. Worth to mention, this nanosystem presented high renal effectiveness. The in vivo assays in mice bearing EMT-6 tumours clearance ability, highlighting its safe clinical application and effec- demonstrated the effective boost of tumour indicators and tumour tiveness for cancer treatment. growth suppression via PTT. 7.3.2. MRI and PAI. 8. Perspectives and future trends Examples of NCPs systems able to give contrast in both MRI and PAI have been newly described. For example, Guo et col. designed a According to the excellent results reported over the last years, ground-breaking imaging agent combining an Fe3O4 nanocluster the use of NCPs with antitumoural activity can be considered in node and a carbocyanine-Gd(III) outer coating [168]. On top of an embryonic development stage and still very promising. Most that, folic acid-conjugated PEG chains were combined to improve of the reported developments use metal chemotherapy and its the biodistribution and in vivo targeted delivery. Jin et al. reported combination with other active drugs (multifunctional nanodrugs) ultra-small Fe-GA NCPs functionalised with PEG, displaying strong and/or CAs for imaging purposes (MRI, CT, SPECT/PET, and fluores- NIR absorbance, T1 MR contrasting capability and high stability in cence, among others). All of this, along with new therapeutic devel- various physiological environments [169]. Then, i.v. injection fol- opments such as PDT, PTT, or PA, allow us to predict that the lowed by photoacoustic tomography (PAT) and MRI bimodal imag- blossom of these nanocarriers is yet to come. A schematic compi- ing revealed tumour targeting without apparent toxicity. lation of the most relevant anticancer NCPs revised is shown in Interestingly, labelling with 64Cu isotope also allowed for PET scan- Table 1, while Table 2 summarises NCPs combining diagnostic ning. Finally, Hu et al. synthesised NCPs using PDA and Fe ions and therapeutic abilities. All-in-all, NCPs are strong prospective loaded with indocyanine green (ICG) for PAI/MRI and PTT cancer candidates to treat cancer thanks to their chemical versatility treatment [170]. ICG molecules increased remarkably the optical and the endless combination catalog available to mature novel absorption of PDA NCPs in the NIR region and diminish their fluo- nanomedicines with enhanced therapies. The interrogation that rescence emission, thus improving the PAI contrast and stimulat- one poses then is: What steps are required from now on to achieve ing their photothermal conversion. Moreover, the Fe(III) ions such an ambitious objective? coordinated with the PDA NCPs served for T1 MRI. In a mouse From our unassertive point of view, there are some main 4T1 breast tumour model, these NCPs showed PAI/MRI dual- research areas that, in the short-medium term, deserve deep atten- modal imaging and highly powerful PTT with noticeable therapeu- tion to successfully design the nanoplatforms of tomorrow if we tic performance and minimum side effects. want them to reach clinical phases. Those are described next: 7.3.3. Others  The first one is to devote more attention to the chemical compo- Yang et al. reported core–shell NCPs containing Mn(II) ions and sition of the NPs. In all examples reported, there is always a IR825 dye for MRI and CT imaging, respectively, and Hf(IV) for CT rational design but few delve into the exact chemical composi- 18 Table 1 S. Suárez-García, Rubén Solórzano, R. Alibés et al. Reported examples classified by the therapeutic activity of the NCPs. Therapeutic modality Active Metal Ligand Coating Drug loaded Cancer Ref. Metal Node Type Metal chemotherapy Pt Zn(II) DSP, 1,4-Bis(imidazol-1-ylmethyl)benzene — DSP Breast, Cervix, [43] Neuroblastoma Tb(III) DSP Silica coating DSP Colon [55] Pt Zn(II) DSP fatty acid-modified PEG ALN Breast [56] Pt Zr(IV), DSP Lipid coating DSP Lung [95] La(III) Pt Zn(II) Carboplatin-bis(phosphonic acid) Lipid coating Carboplatin-bis(phosphonic Ovarian [96] acid) prodrug + GcMP Pt Fe(III) DSCP cRGD functionalized PEG Glioma [97] Pt Zn(II) Bisphosphonic acids containing cisplatin and oxaliplatin Lipid coating Cisplatin + oxaliplatin prodrugs Pancreatic, [98,104,105] prodrugs Ovarian Pt Zn(II) Bisphosphonic acids containing oxaliplatin prodrug Lipid coating Oxaliplatin prodrug + GcMP Pancreatic [99] Pt Zn(II) cis,cis,trans-[Pt(NH3)2Cl2(OCONHP(O)(OH)2)2], pyropheophorbide-lipid conjugate Cisplatin prodrug Head and Neck [100] Pt Zn(II) Pt(dach)(oxalate)(bisphosphoramidic acid) Lipid coating oxaliplatin Colorectal [103] prodrug + dihydroartemesinin (DHA) Pt Zn(II) PtIV(en)2-bis(phosphonic acid) PEG functionalized lipid bilayer miRNA Colorectal [106] Pt Fe(III) Platinum prodrug polyphenols PEG polyphenols Cisplatin prodrug Glioblastoma [108] Pt Gd(III) Platinum prodrug polyphenols block copolymers PEG-PDI-PDPA (PEG-PDI- Cisplatin prodrug Glioblastoma [109] C20) Pt Fe(III) Platinum prodrug polyphenols epigallocatechin-3-gallate (EGCG), Cisplatin prodrug Hepatic [110] polyphenol modified block copolymer (PEG-b-PPOH) Cu Cu(II) 2,20-bipyridyl, branched polyethyleneimine — — Lung [115] Cu Cu(II) Cu-3,5-bis(pyridin-3-ylmethylamino)benzoate — — Cervix, Breast, [116] 19 Lung Cu Cu(II) 1,10-phenanthroline and L-arginine — — Breast [117] Cu Cu(II) AQ4N + gossypol hyaluronic acid AQ4N + gossypol Prostate [118] Cu Cu(II) AQ4N, DOX AQ4N + Dox + phthalocyanine Hepatic [119] Fe Ru(II), bis(terpyridine) derivatives — — Lung [121] Fe(II) Ru Co(II) 2-oxo-1,2-dihydroquinoline-3-carbaldehyde (isonicotinic) — — Hepatic, Cervix, [122] hydrazine Skin Co Co(II) BPEI, dpq, ip — — Breast [123] Cu Cu(II), oxalic acid, N,N0 -bis[2-(dimethylamino)ethyl]oxamide — — — [124] Zn(II) Co As(III) methoxy poly(ethylene oxide)-block-poly[a-(6-mecaptohexyl — — Breast [126] amino)carboxylate-e-caprolactone] [PEO-b-P(CCLC6-SH)] 1,3,5-benzenetribenzoic acid (H3BTB) and 4,40 ,40 0 -(1,3,5- Coordination Chemistry Reviews 441 (2021) 213977 As La(III), — — Endometrial [127] Sr(II) triazine-2,4,6-triyl)tribenzoic acid (H3TATB) carcinoma La, Sr In(III) 5-hydroxyisophthalic acid (H3hip) — — Lung [128] In Fe(II) 1,5-bis[(l-proline-1-yl)diazen-1-ium-1,2-diol-O2-yl]-2,4- — — Hepatic [132] dinitrobenzene, [BPDB] Non-Metal Zn(II) 1,4-bis(imidazol-1-ylmethyl)benzene (bix) — Dox, SN-38, Leukaemia [44] chemotherapy CPT, or DAU Ca(II) Pamidronate, Zoledronate Lipid coating Pamidronate, Zoledronate Lung [58,59] Cu(II) PEG113-PBHEm-PSn triblock copolymer — Dox Cervix [63] Photodynamic Zn(II) tetra(4-carboxyphenoxy)-phthalocyaninatozinc(II) Lipid coating — Breast [139] therapy Ca(II) AS1411 DNA G quadruplexes including Ce6 dye + hemin — — Breast [140] Zn(II) porphyrin/G-quadruplex complexes and amphiphilic amino anti-nucleolin aptamer (AS1411) Cervical [141] acids S. Suárez-García, Rubén Solórzano, R. Alibés et al. Table 2 Use of reported NCPs as theranostic systems. Imaging Cancer Metal Ligands Coating Therapy Ref. modality Type MRI Breast MnO2, Hf(IV) DSP Hf-DSP Chemotherapy, [85] radiotherapy Cervix Gd(II) pluronic F127 and a peptide-amphiphile poly(ethylene-oxide) (PEO) + peptides Chemotherapy [149] Glioblastoma, Breast Gd(II) 1,10 -dicarboxyl ferrocene (Fc) rhodamine and RGD functionalized Silica — [150] coating Breast, Pancreatic Mn(II) Zoledronic acid PEG-functionalized Lipid coating Chemotherapy [151] Breast, cervix, Mn(II) dithiodiglycolic acid PEGylated PDA Chemotherapy [152] osteosarcoma Breast Fe(III) Catechol functionalized amphiphilic polymers Polymeric coating Chemotherapy [154] Breast Fe(III) Gallic acid BSA coating PTT [156] Glioblastoma Fe(III), Gd(III), Mn Caffeic acid, 1,4-Bis(imidazol-1-ylmethyl)benzene — — [157] (II) Breast Gd(III), polyphenols — PTT [167] Fe(III) Dual-mode MRI Cervix Fe(III) PDA — Chemotherapy, PTT [155] 20 MIR/NIR Cervix, Breast Mn(II) IR825 NIR dye PEGylated PDA PTT [166] MRI/Fluorescence Breast Mn(II) amphiphilic amino-acid, Chlorin e6 — PDT [153] Hepatic Gd(III) Ru[4,40 -(COOH)2bipyridyl(bpy)]2+ 3 — — [164] MRI/ Cervix Ir(II), Gd(III) 2-phenylquinoline; 3-carboxy-2,20 -bipyridyl-30 - polyvinylpyrrolidone (PVP) — [165] Phosphorescence carboxylate MRI/PAI Cervix Fe2O4, Gd(III) carbocyanine Folic acid-conjugated PEG — [168] Breast Fe(III) Indocyanine green (ICG)–loaded polydopamine (PDA) — PTT [170] Breast Fe(II) quercetin — Chemotherapy, PTT [174] MRI/PAI/PET Breast, glioblastoma Fe(III) Gallic acid PEG PTT [167] MRI/Fluorescence/CT Hepatic Gd(III), Yb(III) Ru[4,40 -(COOH)2bpy]2+ 3 — PDT [173] Coordination Chemistry Reviews 441 (2021) 213977 MRI/NIR/CT Cervix, Breast Mn(II), Hf(IV) Mn/Hf-IR825 PEGylated PDA PTT, Radiotherapy [171] Fluorescence/PAI Breast Zn(II) dipicolylamine PTT, gene therapy [172] Fluorescence Hepatic Zr(II) Porphyrin — Chemotherapy, PDT [160] Adenocarcinoma Cu(II) amphiphilic hyperbranched polytriazoles — Chemotherapy [161] PET Breast W(IV) PEG functionalized gallic acid — Radiotherapy [162] S. Suárez-García, Rubén Solórzano, R. Alibés et al. Coordination Chemistry Reviews 441 (2021) 213977 tion. The difficulty is evident. Many of them are amorphous and Acknowledgments without a well-defined chemical composition, as these NPs are obtained far from chemical equilibrium. Furthermore, many of This work was supported by grants RTI2018-098027-B-C21, them are obtained in a single reaction step together with PID2019-106403RB-I00 and RED2018-102471-T from the Spanish lipid/polymeric coatings, targeting molecules, PEG, or other bio- Government funds and by the European Regional Development molecules. Thus, although a positive macroscopic effect can be Fund (ERDF). The ICN2 is funded by the CERCA programme/Gener- identified in most cases, it is quite difficult (if not impossible) alitat de Catalunya. The ICN2 is supported by the Severo Ochoa to establish a retroactive analysis that allows us to show an Centres of Excellence programme, funded by the Spanish Research effective correlation between the real chemical composition Agency (AEI, grant no. SEV-2017-0706). R. S. thanks the Ministerio versus the therapeutic effect. de Educación, Cultura y Deporte for the predoctoral grant  Second, several in vivo experiments have validated these NPs FPU14/03170. S.S.-G. acknowledges the support from MINECO with: i) an excellent biodistribution with preferential retention BES-2015-071492 grant. Special thanks to Dr. Javier Saiz-Poseu in tumours mostly (EPR effect), ii) a suitable biodegradation from 3D Science Visuals (Instagram: 3dscivisuals) for contributing profile that allows for the desired measurement and/or effects with graphic design and scientific illustrations. while avoiding toxic accumulation over long periods of time, iii) improvement of IC50 and image concerning free drugs and CAs and iv) the nanostructuration favours targeting and protec- tion of the NPs while avoiding side effects. Therefore, further References studies are required to understand and fine-tune the interaction [1] R.K. Jain, T. Stylianopoulos, Delivering nanomedicine to solid tumors, Nat. of NCPs with the biological media and tissues, control the in vivo Rev. Clin. Oncol. 7 (2010) 653–664. biodistribution kinetics, diffusion and degradation of the NPs, [2] R.K. Jain, Delivery of molecular and cellular medicine to solid tumors, Adv. and control over the pharmacokinetics and efficiency of the car- Drug Deliv. Rev. 64 (2012) 353–365. [3] I. Brigger, C. Dubernet, P. Couvreur, Nanoparticles in cancer therapy and riers. Worth to mention, more effort is needed to efficiently diagnosis, Adv. Drug. Deliv. Rev. 64 (2012) 24–36. study the different administration routes available to reach [4] S.D. Steichen, M. Caldorera-Moore, N. Peppas, A review of current the tumor area efficiently. The most-reported administration nanoparticle and targeting moieties for the delivery of cancer therapeutics, Eur. J. Pharm. Sci. 48 (2013) 416–427. route is i.v., which allows for a quick biodistribution through the [5] S.R. D’Mello, C.N. Cruz, M.L. Chen, K.M. Tyner, The evolving landscape of drug bloodstream. Nevertheless, other administration routes are being products containing nanomaterials in the United States, Nat. Nanotechnol. 12 exponentially tested, such as intranasally. In this last route, other (2017) 523–529. [6] P. Evers, Nanotechnology in Medical Applications: The Global Market, BCC aspects become relevant, for example, the mucoadhesion interac- Research (Business Communications Company (BCC) Inc., Wellesley, MA, USA, tion with NCPs that could induce its retention, hampering its suc- 2017. cessful administration in the final location. The administration [7] R.A. Petros, J.M. Desimone, Strategies in the design of nanoparticles for route could be selected depending on the type of tumour and therapeutic applications, Nat. Rev. Drug Discovery 9 (2010) 615–627. [8] C.L. Ventola, Progress in nanomedicine: approved and investigational its location. For example, brain-located tumours could be treated nanodrugs. P&T: a Peer-reviewed, J. Formul. Manage. 42 (2017) 742–755. by administering NCPs via the intranasal pathway, avoiding cross- [9] T.M. Allen, P.R. Cullis, Liposomal drug delivery systems: From concept to ing the blood-brain barrier. Each administration route has its clinical applications, Adv. Drug Deliv. Rev. 65 (2013) 36–48. [10] S.E. Lohse, C.J. Murphy, Applications of colloidal inorganic nanoparticles: advantages and disadvantages and its selection must be done from medicine to energy, J. Am. Chem. Soc. 134 (2012) 15607–15620. accordingly to different issues: i) tumour location (e.g., brain, [11] M. Arruebo, Drug delivery from structured porous inorganic materials, Wiley lungs, bladder), ii) NCPs features (e.g., size, stability, tissue interac- Interdiscip. Rev. Nanobiotechnology 4 (2012) 16–30. [12] D. Peer, J.M. Karp, S. Hong, O.C. Farokhzad, R. Margalit, R. Langer, Nanocarriers tions) and iii) side effects and toxicity. as an emerging platform for cancer therapy, Nature Nanotech. 2 (2007) 751–  The variety of diseases and illnesses faced so far is very diverse. 760. Perhaps the idea of concentrating ourselves in those where [13] A. Baeza, D. Ruiz-Molina, M. Vallet-Regí, Expert Opin. Drug Deliv. 14 (2017) 783–796. these systems have more potential would promote the area [14] M. Kim, H. Na, Y. Kim, S.R. Ryoo, H.S. Cho, K.E. Lee, H. Jeon, R. Ryoo, D.H. Min, since there would be more synergism between different groups Facile synthesis of monodispersed mesoporous silica nanoparticles with towards a common target. ultralarge pores and their application in gene delivery, ACS Nano 5 (2011) 3568–3576.  Finally, as far as we know, none of these systems is currently in [15] L. Yuan, Z. Yanli, C. Xiaoyuan, Bioengineering of metal-organic frameworks the clinical phases. If the preclinical results are so interesting, for nanomedicine, Theranostics 9 (2019) 3122–3133. why has translation not occurred yet? More rigorous testing is [16] P. Horcajada, C. Serre, M. Vallet-Regí, M. Sebban, F. Taulelle, G. Férey, Metal– necessary to assess the clinical relevance and reproducibility organic frameworks as efficient materials for drug delivery, Angew. Chem. 118 (2006) 6120–6124. when synthesised from different sources and following good [17] R. Anand, F. Borghi, F. Manoli, I. Manet, V. Agostoni, P. Reschiglian, R. Gref, S. manufacturing practice protocols. Moreover, additional com- Monti, Host-guest interactions in Fe(III)-trimesate MOF nanoparticles loaded mitments for the clinical implementation must be stretched, with doxorubicin, J. Phys. Chem. B 118 (2014) 8532–8539. [18] M. Giménez-Marqués, T. Hidalgo, C. Serre, P. Horcajada, Nanostructured always in close collaboration with clinicians aware of the real metal–organic frameworks and their bio-related applications, Coord. Chem. needs of patients. Rev. 307 (2015) 1–19. [19] C. Wen, J. Wang, C. Chengchao, C. Wei, W. Chunsheng, L. Gang, Metal-organic framework-based stimuli-responsive systems for drug delivery, Adv. Sci. 6 All-in-all, although there is still work ahead, the results (2019) 1801526. obtained to date are very promising, especially considering that [20] L. Wang, M. Zheng, Z. Xie, Nanoscale metal–organic frameworks for drug the blossom of these systems is relatively recent. In fact, the scien- delivery: a conventional platform with new promise, J. Mater. Chem. B 6 (2018) 707–717. tific community involved in this discipline grows exponentially [21] K. Böll, A. Zimpel, O. Dietrich, S. Wuttke, M. Peller, Clinically approved MRI every day, which allows us to face these new challenges with a contrast agents as imaging labels for a porous iron-based MOF nanocarrier: a very positive attitude of success in the medium-long term. systematic investigation in a clinical MRI setting, Adv. Ther. 3 (2020) 1900126. [22] M. Oh, C.A. Mirkin, Chemically tailorable colloidal particles from infinite Declaration of Competing Interest coordination polymers, Nature 438 (2005) 651–654. [23] X. Sun, S. Dong, E. Wang, Coordination-induced formation of submicrometer- The authors declare that they have no known competing finan- scale, monodisperse, spherical colloids of organic-inorganic hybrid materials at room temperature, J. Am. Chem. Soc. 127 (2005) 13102–13103. cial interests or personal relationships that could have appeared [24] J. Puigmartí-Luis, Microfluidic platforms: A mainstream technology for the to influence the work reported in this paper. preparation of crystals, Chem. Soc. Rev. 43 (2014) 2253–2271. 21 S. Suárez-García, Rubén Solórzano, R. Alibés et al. Coordination Chemistry Reviews 441 (2021) 213977 [25] M. Guardingo, P. González-Monje, F. Novio, E. Bellido, F. Busqué, G. Molnár, A. [54] N. Bertleff-Zieschang, M.A. Rahim, Y. Ju, J.A. Braunger, T. Suma, Y. Dai, S. Pan, Bousseksou, D. Ruiz-Molina, Synthesis of nanoscale coordination polymers in F. Cavalieri, F. Caruso, Biofunctional metal-phenolic films from dietary femtoliter reactors on surfaces, ACS Nano 10 (2016) 3206–3213. flavonoids, Chem. Commun. 53 (2017) 1068–1071. [26] E. Bellido, P. González-Monje, M. Guardingo, F. Novio, A. Sánchez, M. Montero, [55] W.J. Rieter, K.M. Pott, K.M.L. Taylor, W. Lin, Nanoscale coordination polymers G. Molnar, A. Bousseksou, D. Ruiz-Molina, Nanoscale coordination polymers for platinum-based anticancer drug delivery, J. Am. Chem. Soc. 130 (2008) obtained in ultrasmall liquid droplets on solid surfaces and its comparison to 11584–11585. different synthetic volume scales, RSC Adv. 6 (2016) 76666–76672. [56] H. Yuanfeng, H. Yanjuan, H. Ziyuan, Y. Jiang, X. Sun, Y. Shen, W. Chu, C. Zhao, [27] M. Guardingo, F. Busqué, D. Ruiz-Molina, Reactions in ultra-small droplets by Bisphosphonate-functionalized coordination polymer nanoparticles for the tip-assisted chemistry, Chem. Commun. 52 (2016) 11617–11626. treatment of bone metastatic breast cancer, J. Control. Release 264 (2017) 76– [28] A. Bousseksou, G. Molnár, L. Salmon, W. Nicolazzi, Molecular spin crossover 88. phenomenon: recent achievements and prospects, Chem. Soc. Rev. 40 (2011) [57] J.R. Green, Bisphosphonates: preclinical review, Oncologist 9 (2004) 3–13. 3313–3335. [58] S. Wang, J. Della Rocca, W. Lin, R.C. Huxford-Phillips, S.A. Kramer, D. Liu, [29] I. Imaz, D. Maspoch, C. Rodríguez-Blanco, J.M. Pérez-Falcón, J. Campo, D. Ruiz- Coercing bisphosphonates to kill cancer cells with nanoscale coordination Molina, Valence-tautomeric metal-organic nanoparticles, Angew. Chem. Int. polymers, Chem. Commun. 48 (2012) 2668–2670. Ed. 47 (2008) 1857–1860. [59] E. Alvarez, A.G. Marquez, T. Devic, N. Steunou, C. Serre, C. Bonhomme, C. [30] F. Novio, J. Simmchen, N. Vázquez-Mera, L. Amorín-Ferré, D. Ruiz-Molina, Gervais, I. Izquierdo-Barba, M. Vallet-Regi, D. Laurencin, F. Mauri, P. Coordination polymer nanoparticles in medicine, Coord. Chem. Rev. 257 Horcajada, A biocompatible calcium bisphosphonate coordination polymer: (2013) 2839–2847. towards a metal-linker synergistic therapeutic effect?, CrystEngComm 15 [31] K.M.L. Taylor-Pashow, J. Della Rocca, Z. Xie, S. Tran, W. Lin, Postsynthetic (2013) 9899–9905. modifications of iron-carboxylate nanoscale metalorganic frameworks for [60] R. Solórzano, O. Tort, J. García-Pardo, T. Escribà, J. Lorenzo, M. Arnedo, D. Ruiz- imaging and drug delivery, J. Am. Chem. Soc. 131 (2009) 14261–14263. Molina, R. Alibés, F. Busqué, F. Novio, Biomater. Sci. 7 (2019) 178–186. [32] S.M. Cohen, Postsynthetic methods for the functionalization of metal-organic [61] K. Han, W.Y. Zhang, J. Zhang, Z.Y. Ma, H.Y. Han, pH-responsive nanoscale frameworks, Chem. Rev. 112 (2012) 970–1000. coordination polymer for efficient drug delivery and real-time release [33] F. Novio, J. Lorenzo, F. Nador, K. Wnuk, D. Ruiz-Molina, Carboxyl group (- monitoring, Adv. Healthc. Mater. 6 (2017) 1–9. CO2H) functionalized coordination polymer nanoparticles as efficient [62] S. Xu, J. Liu, D. Li, L. Wang, J. Guo, C. Wang, C. Chen, Fe-Salphen complexes platforms for drug delivery, Chem. Eur. J. 20 (2014) 15443–15450. from intracellular pH-triggered degradation Of Fe3O4@Salphen-InIII CPPs for [34] F. Novio, D. Ruiz-Molina, Hydrophobic coordination polymer nanoparticles selectively killing cancer cells, Biomaterials 35 (2014) 1676–1685. and application for oil–water separation, RSC Adv. 4 (2014) 15293–15296. [63] L. Bai, F. Song, X.H. Wang, J.Y.Q. Cao, X. Han, X.L. Wang, Y.Z. Wang, Ligand- [35] P. Gonzalez-Monje, F. Novio, D. Ruiz-Molina, Covalent grafting of metal-drug coordination based micelles for efficient intracellular doxorubicin coordination polymers on surfaces: the case of hybrid valence tautomeric delivery, RSC Adv. 5 (2015) 47629–47639. interphases, Chem. Eur. J. 21 (2015) 10094–10099. [64] B. Wang, M. Jacquet, K. Wang, K. Xiong, M. Yan, J. Courtois, G. Royal, pH- [36] Y. Bi, F. Hao, G. Yan, L. Teng, R.J. Lee, J. Xie, Actively targeted nanoparticles for induced fragmentation of colloids based on responsive self-assembled copper drug delivery to tumor, Curr. Drug Metab. 17 (2016) 763–782. (II) metallopolymers, New J. Chem. 42 (2018) 7823–7829. [37] J. Duan, W. Jin, S. Kitagawa, Water-resistant porus coordination polymers for [65] T. Wang, X. Liu, Y. Zhu, Z.D. Cui, X.J. Yang, H. Pan, K.W.K. Yeung, S. Wu, Metal gas separation, Coord. Chem. Rev. 332 (2017) 48–74. ion coordination polymer-capped pH-triggered drug release system on [38] Y.-B. Huang, Q. Wang, J. Liang, X. Wang, R. Cao, Soluble metal-nanoaprticle- titania nanotubes for enhancing self-antibacterial capability of Ti Implants, decorated porous coordination polymers for the homogenization of ACS Biomater. Sci. Eng. 3 (2017) 816–825. heterogeneous catalysis, J. Am. Chem. Soc. 138 (2016) 10104–10107. [66] W. Huang, P. Hao, J. Qin, S. Luo, T. Zhang, B. Peng, H. Chen, X. Zan, [39] J. Deng, F. Wu, P. Yu, L. Mao, On-site sensors based on infinite coordination Hexahistidine-metal assemblies: a promising drug delivery system, Acta polymer nanoaprticles: Recent progress and future challenge, Appl. Mater. Biomater. 90 (2019) 441–452. Today 11 (2018) 338–351. [67] Y. Yang, L. Xu, W. Zhu, L. Feng, J. Liu, Q. Chen, Z. Dong, J. Zhao, Z. Liu, M. Chen, [40] E.S. Sebastian, A. Rodríguez-Diéguez, J.M. Seco, J. Cepeda, Coordination One-pot synthesis of pH-responsive charge-switchable PEGylated nanoscale polymers with intriguing photoluminescence beahavior: The promising coordination polymers for improved cancer therapy, Biomaterials 156 (2018) avenue for greatest long-lasting phosphors, Eur. J. Inorg. Chem. 2018 (2018) 121–133. 2155–2174. [68] H. Ejima, J.J. Richardson, K. Liang, J.P. Best, M.P. Van Koeverden, G.K. Such, J. [41] J.-S.M. Lee, K. Otake, S. Kitagawa, Transport properties in porous coordination Cui, F. Caruso, One-step assembly of coordination complexes for versatile film polymers, Coord. Chem. Rev. 421 (2020) 213447. and particle engineering, Science 341 (2013) 154–157. [42] I. Imaz, J. Hernando, D. Ruiz-Molina, D. Maspoch, Metal-organic spheres as [69] M.A. Rahim, H. Ejima, K.L. Cho, K. Kempe, M. Müllner, J.P. Best, F. Caruso, functional systems for guest encapsulation, Angew. Chem. Int. Ed. 48 (2009) Coordination-driven multistep assembly of metal-polyphenol films and 2325–2329. capsules, Chem. Mater. 26 (2014) 1645–1653. [43] N.N. Adarsh, C. Frias, T.M. Ponnoth Lohidakshan, J. Lorenzo, F. Novio, J. Garcia- [70] Y. Ping, J. Guo, H. Ejima, X. Chen, J.J. Richardson, H. Sun, F. Caruso, pH- Pardo, D. Ruiz-Molina, Pt(IV)-based nanoscale coordination polymers: responsive capsules engineered from metal-phenolic networks for anticancer Antitumor activity, cellular uptake and interactions with nuclear DNA, drug delivery, Small 11 (2015) 2032–2036. Chem. Eng. J. 340 (2018) 94–102. [71] J. Li, C. Zhang, S. Gong, X. Li, M. Yu, C. Qian, H. Qiao, M. Sun, A nanoscale [44] L. Amorín-Ferré, F. Busqué, J.L. Bourdelande, D. Ruiz-Molina, J. Hernando, F. photothermal agent based on a metal-organic coordination polymer as a Novio, Encapsulation and release mechanisms in coordination polymer drug-loading framework for effective combination therapy, Acta Biomater. 94 nanoparticles, Chem. Eur. J. 19 (2013) 17508–17516. (2019) 435–446. [45] I. Imaz, M. Rubio-Martínez, L. García-Fernández, F. García, D. Ruiz-Molina, J. [72] Y. Ju, J. Cui, H. Sun, M. Müllner, Y. Dai, J. Guo, N. Bertleff-Zieschang, T. Suma, J. Hernando, V. Puntes, D. Maspoch, Coordination polymer particles as potential J. Richardson, F. Caruso, Engineered metal-phenolic capsules show tunable drug delivery systems, Chem. Commun. 46 (2010) 4737–4739. targeted delivery to cancer cells, Biomacromolecules 17 (2016) 2268–2276. [46] P.F. Gao, L.L. Zheng, L.J. Liang, X.X. Yang, Y.F. Li, C.Z. Huang, A new type of [73] Y. Ju, Q. Dai, J. Cui, Y. Dai, T. Suma, J.J. Richardson, F. Caruso, Improving pH-responsive coordination polymer sphere as a vehicle for targeted targeting of metal-phenolic capsules by the presence of protein coronas, ACS anticancer drug delivery and sustained release, J. Mater. Chem. B 1 (2013) Appl. Mater. Interfaces 8 (2016) 22914–22922. 3202–3208. [74] J.H. Park, K. Kim, J. Lee, J.Y. Choi, D. Hong, S.H. Yang, F. Caruso, Y. Lee, I.S. Choi, [47] G. Liang, H. Ni, S. Bao, F. Zhu, H. Gao, Q. Wu, Synthesis and characterization of A cytoprotective and degradable metal-polyphenol nanoshell for single-cell nanowire coils of organometallic coordination polymers for controlled cargo encapsulation, Angew. Chem. Int. Ed. 53 (2014) 12420–12425. release, J. Phys. Chem. B 118 (2014) 6339–6345. [75] Q.Q. Besford, Y. Ju, T.Y. Wang, G. Yun, P.V. Cherepanov, C.E. Hagemeyer, F. [48] C. Fan, D.A. Wang, Novel gelatin-based nano-gels with coordination-induced Cavalieri, F. Caruso, Self-assembled metal-phenolic networks on emulsions as drug loading for intracellular delivery, J. Mater. Sci. Technol. 32 (2016) 840– low-fouling and pH-responsive particles, Small 14 (2018) 1–9. 844. [76] J.Liu,H.Wang,X.Yi,Y. Chao,Y.Geng,L.Xu,K.Yang, Z.Liu,pH-sensitive dissociable [49] L. Xing, Y. Cao, S. Che, Synthesis of core–shell coordination polymer nanoscalecoordinationpolymerswithdrugloadingforsynergisticallyenhanced nanoparticles (NCPs) for pH-responsive controlled drug release, Chem. chemoradiotherapy, Adv.Funct. Mater. 27 (2017) 1–10. Commun. 48 (2012) 5995–5997. [77] J. Liu, L. Tian, R. Zhang, Z. Dong, H. Wang, Z. Liu, Collagenase-encapsulated [50] R.C. Huxford, K.E. deKrafft, W.S. Boyle, D. Liu, W. Lin, Lipid-coated nanoscale pH-responsive nanoscale coordination polymers for tumor coordination polymers for targeted delivery of antifolates to cancer cells, microenvironment modulation and enhanced photodynamic nanomedicine, Chem. Sci. 3 (2012) 198–204. ACS Appl. Mater. Interfaces 10 (2018) 43493–43502. [51] X. Yan, Y. Li, Q. Zou, C. Yuan, S. Li, R. Xing, Amino acid coordination-driven [78] F. Nador, F. Novio, D. Ruiz-Molina, Coordination polymer particles with self-assembly for enhancing both biological stability and tumor accumulation ligand-centred pH-responses and spin transition, Chem. Commun. 50 (2014) of curcumin, Angew. Chem. Int. Ed. 57 (2018) 17084–17088. 14570–14572. [52] M. Li, C. Wang, Z. Di, H. Li, J. Zhang, W. Xue, M. Zhao, K. Zhang, Y. Zhao, L. Li, [79] Y. Zhang, Y. Guo, S. Wu, H. Liang, H. Xu, Photodegradable coordination Engineering multifunctional DNA hybrid nanospheres through coordination- polymer particles for light-controlled cargo release, ACS Omega 2 (2017) driven self-assembly, Angew. Chem. Int. Ed. 58 (2019) 1350–1354. 2536–2543. [53] Z. Fan, L. Sun, Y. Huang, Y. Wang, M. Zhang, Bioinspired fluorescent dipeptide [80] J. Liu, G. Yang, W. Zhu, Z. Dong, Y. Yang, Y. Chao, Z. Liu, Light-controlled drug nanoparticles for targeted cancer cell imaging and real-time monitoring of release from singlet-oxygen sensitive nanoscale coordination polymers drug release, Nat. Nanotechnol. 11 (2016) 388–394. enabling cancer combination therapy, Biomaterials 146 (2017) 40–48. 22 S. Suárez-García, Rubén Solórzano, R. Alibés et al. Coordination Chemistry Reviews 441 (2021) 213977 [81] X.G. Hu, X. Li, S.I. Yang, Novel photochromic infinite coordination polymer [107] Y. Dai, J. Guo, T.-Y. Wang, Y. Ju, A.J. Mitchell, Th. Bonnard, J. Cui, J.J. particles derived from a diarylethene photoswitch, Chem. Commun. 51 Richardson, Ch.E. Hagemeyer, K. Alt, F. Caruso, Self-Assembled nanoparticles (2015) 10636–10639. from phenolic derivatives for cancer therapy, Adv. Healthc. Mater. 6 (2017) [82] P.V. Cherepanov, M.A. Rahim, N. Bertleff-Zieschang, M.A. Sayeed, A.P. 1700467. O’Mullane, S.E. Moulton, F. Caruso, Electrochemical behavior and redox- [108] Y. Dai, S. Cheng, Zh. Wang, R. Zhang, Z. Yang, J. Wang, B.C. Yung, Z. Wang, O. dependent disassembly of gallic acid/FeIIIMetal-phenolic networks, ACS Appl. Jacobson, C. Xu, Q. Ni, G. Yu, Z. Zhou, X. Chen, Hypochlorous acid promoted Mater. Interfaces 10 (2018) 5828–5834. platinum drug chemotherapy by myeloperoxidase-encapsulated therapeutic [83] S. Buwalda, B. Nottelet, A. Bethry, R.J. Kok, N. Sijbrandi, J. Coudane, Reversibly metal phenolic nanoparticles, ACS Nano 12 (2018) 455–464. core-crosslinked PEG-P(HPMA) micelles: platinum coordination chemistry [109] Z. Yang, Y. Dai, L. Shan, Z. Shen, Z. Wang, B.C. Yung, O. Jacobson, Y. Liu, W. for competitive-ligand-regulated drug delivery, J. Colloid Interface Sci. 535 Tang, S. Wang, L. Lin, G. Niu, P. Huang, X. Chen, Tumor microenvironment- (2019) 505–515. responsive semiconducting polymer-based self-assembling [84] S. Li, Q. Zou, Y. Li, C. Yuan, R. Xing, X. Yan, Smart peptide-based nanotheranostics, Nanoscale Horiz. 4 (2019) 426–433. supramolecular photodynamic metallo-nanodrugs designed by [110] Z. Ren, S. Sun, R. Sun, G. Cui, L. Hong, B. Rao, A. Li, Z. Yu, Q. Kan, Z. Mao, A multicomponent coordination self-assembly, J. Am. Chem. Soc. 140 (2018) metal–polyphenol-coordinated nanomedicine for synergistic cascade cancer 10794–10802. chemotherapy and chemodynamic therapy, Adv. Mater. 32 (2020) 1906024. [85] J. Liu, Q. Chen, W. Zhu, X. Yi, Y. Yang, Z. Dong, Z. Liu, Nanoscale-coordination- [111] U. Ndagi, N. Mhlongo, M.E. Soliman, Metal complexes in cancer therapy – an polymer-shelled manganese dioxide composite nanoparticles: A multistage update from drug design perspective, Drug Des. Devel. Ther. 11 (2017) 599– redox/pH/H2O2-responsive cancer theranostic nanoplatform, Adv. Funct. 616. Mater. 27 (2017) 1605926. [112] A. Bindoli, M.P. Rigobello, G. Scutari, C. Gabbiani, A. Casini, L. Messori, [86] Y. Wang, Y. Wu, F. Li, D. Chen, Folic acid-modified iridium(III) coordination Thioredoxin reductase: a target for gold compounds acting as potential polymeric nanoparticles facilitating intracellular release of a phosphorescent anticancer drugs, Coord. Chem. Rev. 253 (2009) 1692–1707. residue capable of nuclear entry, Inorg. Chem. Commun. 40 (2014) 143–147. [113] I. Kostova, Ruthenium complexes as anticancer agents, Curr. Med. Chem. 13 [87] F. Pu, E. Ju, J. Ren, X. Qu, Multiconfigurable logic gates based on fluorescence (2006) 1085–1107. switching in adaptive coordination polymer nanoparticles, Adv. Mater. 26 [114] P.C. Bruijnincx, P.J. Sadler, New trends for metal complexes with anticancer (2014) 1111–1117. activity, Curr. Opin. Chem. Biol. 12 (2008) 197–206. [88] F. Pu, J. Ren, X. Qu, ‘‘Plug and Play” logic gates based on fluorescence [115] R.S.Kumar,V.S.Periasamy,C.P.Paul,A.Riyasdeen,S.Arunachalam,M.A.Akbarsha, switching regulated by self-assembly of nucleotide and lanthanide ions, ACS Cytotoxic effect of a polymer-copper(II) complex containing 2,20-bipyridyl Appl. Mater. Interfaces 6 (2014) 9557–9562. ligand on human lungcancer cells,Med. Chem.Res. 20 (2011) 726–731. [89] R.-R. Gao, S. Shi, Y.-J. Li, M. Wumaier, X.-C. Hu, T.-M. Yao, Coordination [116] K. Wang, X. Ma, D. Shao, Z. Geng, Z. Zhang, Z. Wang, Coordination-induced polymer nanoparticles from nucleotide and lanthanide ions as a versatile assembly of coordination polymer submicrospheres: promising antibacterial platform for color-tunable luminescence and integrating boolean logic and in vitro anticancer activities, Cryst. Growth Des. 12 (2012) 3786–3791. operations, Nanoscale 9 (2017) 9589–9597. [117] J. Lakshmipraba, S. Arunachalam, A. Riyasdeen, R. Dhivya, S. Vignesh, M.A. [90] L. Bai, X.H. Wang, F. Song, X.L. Wang, Y.Z. Wang, ‘‘AND” Logic gate regulated Akbarsha, R.A. James, DNA/RNA binding and anticancer/antimicrobial pH and reduction dual-responsive prodrug nanoparticles for efficient activities of polymer-copper(II) complexes, Spectrochim. Acta - Part A Mol. intracellular anticancer drug delivery, Chem. Commun. 51 (2015) 93–96. Biomol. Spectrosc. 109 (2013) 23–31. [91] L. Kelland, The resurgence of platinum-based cancer chemotherapy, Nat. Rev. [118] S. Shen, Y. Wu, K. Li, Y. Wang, J. Wu, Y. Zeng, D. Wu, Versatile hyaluronic acid Cancer 7 (2007) 573–584. modified AQ4N-Cu(II)-gossypol infinite coordination polymer nanoparticles: [92] T.C. Johnstone, K. Suntharalingam, S.J. Lippard, The next generation of multiple tumor targeting highly efficient synergistic chemotherapy, and real- platinum drugs: targeted Pt(II) agents, nanoparticle delivery, and Pt(IV) time self-monitoring, Biomaterials 154 (2018) 197–212. prodrugs, Chem. Rev. 116 (2016) 3436–3486. [119] D. Zhang, M. Wu, Z. Cai, N. Liao, K. Ke, H. Liu, M. Li, G. Liu, H. Yang, X. Liu, J. Liu, [93] X. Duan, C. He, S.J. Kron, W. Lin, Nanoparticle formulations of cisplatin for Chemotherapeutic drug based metal-organic particles for microvesicle- cancer therapy, WIREs Nanomed. Nanobiotechnol. 8 (2016) 776–791. mediated deep penetration and programmable pH/NIR/hypoxia activated [94] N. Graf, T.E. MokhtariIoannis, A. Papayannopoulos, S.J. Lippard, Platinum(IV)- cancer photochemotherapy, Adv. Sci. 5 (2018) 1700648. chlorotoxin (CTX) conjugates for targeting cancer cells, J. Inorg. Biochem. 110 [120] L. Zeng, P. Gupta, Y. Chen, E. Wang, L. Ji, H. Chao, Z.S. Chen, The development (2012) 58–63. of anticancer ruthenium(II) complexes: from single molecule compounds to [95] R.C. Huxford-Phillips, S.R. Russell, D. Liu, W. Lin, Lipid-coated nanoscale nanomaterials, Chem. Soc. Rev. 46 (2017) 5771–5804. coordination polymers for targeted cisplatin delivery, RSC Adv. 3 (2013) [121] J. Li, T. Murakami, M. Higuchi, Metallo-supramolecular polymers: versatile 14438–14443. DNA binding and their cytotoxicity, J. Inorg. Organomet. Polym. Mater. 23 [96] C. Poon, X. Duan, C. Chan, W. Han, W. Lin, Nanoscale coordination polymers (2013) 119–125. codeliver carboplatin and gemcitabine for highly effective treatment of [122] D.S. Raja, N.S.P. Bhuvanesh, K. Natarajan, Novel water soluble ligand bridged platinum-resistant ovarian cancer, Mol. Pharm. 13 (2016) 3665–3675. cobalt(II) coordination polymer of 2-oxo-1,2-dihydroquinoline-3- [97] J. Liu, M. Wu, Y. Pan, Y. Duan, Z. Dong, Y. Chao, Z. Liu, B. Liu, Biodegradable carbaldehyde (isonicotinic) hydrazone: evaluation of the DNA binding, nanoscale coordination polymers for targeted tumor combination therapy protein interaction, radical scavenging and anticancer activity, Dalton with oxidative stress amplification, Adv. Funct. Mater. 30 (2020) 1908865. Trans. 41 (2012) 4365–4377. [98] D. Liu, C. Poon, K. Lu, C. He, W. Lin, Self-assembled nanoscale coordination [123] S. Nehru, S. Arunachalam, R. Arun, K. Premkumar, Polymer-Cobalt(III) polymers with trigger release properties for effective anticancer therapy, Nat. complexes: structural analysis of metal chelates on DNA interaction and Commun. 5 (2014) 4182. comparative cytotoxic activity, J. Biomol. Struct. Dyn. 32 (2014) 1876–1888. [99] C. Poon, C. He, D. Liu, K. Lu, W. Lin, Self-assembled nanoscale coordination [124] M. Jiang, Y.T. Li, Z.Y. Synthesis, Structure, cytotoxic activities, and DNA- polymers carrying oxaliplatin and gemcitabine for synergistic combination binding of 1-D copper(II) and Zinc(II) coordination polymers, J. Coord. Chem. therapy of pancreatic cancer, J. Control. Release 201 (2015) 90–99. 65 (2012) 1858–1871. [100] C. He, D. Liu, W. Lin, Self-assembled core-shell nanoparticles for combined [125] C.E. Carraher, M.R. Roner, N. Pham, A. Moric-Johnson, Group VA polyesters chemotherapy and photodynamic therapy of resistant head and neck cancers, containing thiodiglycolic acid-synthesis and preliminary cancer activity, J. ACS Nano 9 (2015) 991–1003. Macromol. Sci. Part A Pure Appl. Chem. 51 (2014) 547–556. [101] P. Velpurisiva, A. Gad, B. Piel, R. Jadia, P. Rai, Nanoparticle design strategies for [126] Q. Zhang, M.R. Vakili, X.F. Li, A. Lavasanifar, X.C. Le, Polymeric micelles for effective cancer immunotherapy, J. Biomed. 2 (2017) 64–77. GSH-triggered delivery of arsenic species to cancer cells, Biomaterials 35 [102] C. He, X. Duan, N. Guo, C. Chan, C. Poon, R.R. Weichselbaum, W. Lin, Core-shell (2014) 7088–7100. nanoscale coordination polymers combine chemotherapy and photodynamic [127] Y. Wang, L. Duan, X. Luo, Q. Deng, J. Xie, J. Jin, K. Zhang, Two new metal therapy to potentiate checkpoint blockade cancer immunotherapy, Nat. coordination polymers: anticancer activity in endometrial carcinoma, Inorg. Commun. 7 (2016) 1–12. Nano-Metal Chem. 48 (2018) 257–261. [103] X. Duan, C. Chan, W. Han, N. Guo, R.R. Weichselbaum, W. Lin, [128] D. Shu, W. Chen, Synthesis, structure, and in vitro anti-lung cancer activity on Immunostimulatory nanomedicines synergize with checkpoint blockade an in-based nanoscale coordination polymer, Main Group Met. Chem. 41 immunotherapy to eradicate colorectal tumors, Nat. Commun. 10 (2019) (2018) 129–133. 1899. [129] L.A. Ostrovskaya, L.V. Zhilitskaya, K.A. Abzaeva, D.B. Korman, V.A. Rikova, M. [104] C. He, D. Liu, W. Lin, Self-assembled nanoscale coordination polymers M. Fomina, M.G. Voronkov, N.V. Bluhterova, Polyacrylates of noble metals as carrying SiRNAs and cisplatin for effective treatment of resistant ovarian potential antitumor drugs, Biophysics (Oxf) 59 (2014) 642–645. cancer, Biomaterials 36 (2015) 124–133. [130] I. Romero-Canelón, P.J. Sadler, Next-generation metal anticancer complexes: [105] C. He, C. Poon, C. Chan, S.D. Yamada, W. Lin, Nanoscale coordination polymers multitargeting via redox modulation, Inorg. Chem. 52 (2013) 12276–12291. codeliver chemotherapeutics and siRNAs to eradicate tumors of cisplatin- [131] Y. Geldmacher, M. Oleszak, W.S. Sheldrick, Rhodium(III) and iridium(III) resistant ovarian cancer, J. Am. Chem. Soc. 138 (2016) 6010–6019. complexes as anticancer agents, Inorg. Chim. Acta 393 (2012) 84–102. [106] C. Chan, N. Guo, X. Duan, W. Han, L. Xue, D. Bryan, S.C. Wightman, N.N. [132] Y. Hu, T. Lv, Y. Ma, J. Xu, Y. Zhang, Y. Hou, Z. Huang, Y. Ding, Nanoscale Khodarev, R.R. Weichselbaum, W. Lin, Systemic MiRNA delivery by nontoxic coordination polymers for synergistic NO and chemodynamic therapy of liver nanoscale coordination polymers limits epithelial-to-mesenchymal cancer, Nano Lett. 19 (2019) 2731–2738. transition and suppresses liver metastases of colorectal cancer, [133] P. Agostinis, K. Berg, K.A. Cengel, T.H. Foster, A.W. Girotti, S.O. Gollnick, S.M. Biomaterials 210 (2019) 94–104. Hahn, M.R. Hamblin, A. Juzeniene, D. Kessel, M. Korbelik, J. Moan, P. Mroz, D. 23 S. Suárez-García, Rubén Solórzano, R. Alibés et al. Coordination Chemistry Reviews 441 (2021) 213977 Nowis, J. Piette, B.C. Wilson, J. Golab, Photodynamic therapy of cancer: an [156] X. Mu, C. Yan, Q. Tian, J. Lin, S. Yang, BSA-assisted synthesis of ultrasmall update, CA Cancer J. Clin. 61 (2017) 250–281. gallic acid-Fe(III) coordination polymer nanoparticles for cancer theranostics, [134] K. Lu, C. He, W. Lin, Nanoscale metal-organic framework for highly effective Int. J. Nanomed. 12 (2017) 7207–7223. photodynamic therapy of resistant head and neck cancer, J. Am. Chem. Soc. [157] S. Suárez-García, N. Arias-Ramos, C. Frias, A.P. Candiota, C. Arús, J. Lorenzo, D. 136 (2014) 16712–16715. Ruiz-Molina, F. Novio, Dual T1/T2 nanoscale coordination polymers as novel [135] Q. Guan, Y.A. Li, W.Y. Li, Y.B. Dong, Photodynamic therapy based on nanoscale contrast agents for MRI: A preclinical study for brain tumor, ACS Appl. Mater. metal-organic frameworks: from material design to cancer nanotherapeutics, Interfaces 10 (2018) 38819–38832. Chem. Asian J. 13 (2018) 3122–3149. [158] F. Nador, K. Wnuk, J. García-Pardo, J. Lorenzo, R. Solorzano, D. Ruiz-Molina, F. [136] R. Chen, J. Zhang, J. Chelora, Y. Xiong, S.V. Kershaw, K.F. Li, P.K. Lo, K.W. Cheah, Novio, Dual-fluorescent nanoscale coordination polymers via a mixed-ligand A.L. Rogach, J.A. Zapien, C.-S. Lee, Ruthenium(II) complex incorporated UiO- synthetic strategy and their use for multichannel imaging, ChemNanoMat 4 67 metal-organic framework nanoparticles for enhanced two-photon (2018) 183–193. fluorescence imaging and photodynamic cancer therapy, ACS Appl. Mater. [159] M. Borges, S. Yu, A. Laromaine, A. Roig, S. Suárez-García, J. Lorenzo, D. Ruiz- Interfaces 9 (2017) 5699–5708. Molina, F. Novio, Dual T1/T2 MRI contrast agent based on hybrid [137] K. Lu, C. He, W. Lin, A chlorin-based nanoscale metal-organic framework for SPION@coordination polymer nanoparticle, RSC Adv. 5 (2015) photodynamic therapy of colon cancers, J. Am. Chem. Soc. 137 (2015) 7600– 86779–86783. 7603. [160] W. Liu, Y.M. Wang, Y.H. Li, S.J. Cai, X.B. Yin, X.W. He, Y.K. Zhang, Fluorescent [138] L.P. Roguin, N. Chiarante, M.C. García Vior, J. Marino, Zinc(II) phthalocyanines imaging-guided chemotherapy-and-photodynamic dual therapy with as photosensitizers for antitumor photodynamic therapy, Int. J. Biochem. Cell nanoscale porphyrin metal-organic framework, Small 13 (2017) 1–8. Biol. 114 (2019) 105575. [161] Q. Ban, J. Du, W. Sun, J. Chen, S. Wu, J. Kong, Intramolecular copper- [139] Z. Huang, L. Huang, Y. Huang, Y. He, X. Sun, X. Fu, X. Xu, G. Wei, D. Chen, C. containing hyperbranched polytriazole assemblies for label-free cellular Zhao, Phthalocyanine-based coordination polymer nanoparticles for bioimaging and redox-triggered copper complex delivery, Macromol. Rapid enhanced photodynamic therapy, Nanoscale 9 (2017) 15883–15894. Commun. 39 (2018) 1800171. [140] Y. Yang, W. Zhu, L. Feng, Y. Chao, X. Yi, Z. Dong, K. Yang, W. Tan, Z. Liu, M. [162] S. Shen, D. Jiang, L. Cheng, Y. Chao, K. Nie, Z. Dong, C.J. Kutyreff, J.W. Engle, P. Chen, G-quadruplex-based nanoscale coordination polymers to modulate Huang, W. Cai, et al., Renal-clearable ultrasmall coordination polymer tumor hypoxia and achieve nuclear-targeted drug delivery for enhanced nanodots for chelator-free 64Cu-labeling and imaging-guided enhanced photodynamic therapy, Nano Lett. 18 (2018) 6867–6875. radiotherapy of cancer, ACS Nano 11 (2017) 9103–9111. [141] J.-Q. Chu, D.-X. Wang, L.-M. Zhang, M. Cheng, R.-Z. Gao, C.-G. Gu, P.-F. Lang, [163] S. Suárez-García, T.V.F. Esposito, J. Neufeld-Peters, M. Bergamo, H. Yang, K. P.-Q. Liu, L.-N. Zhu, D.-M. Kong, Green layer-by-layer assembly of porphyrin/ Saatchi, P. Schaffer, U.O. Häfeli, D. Ruiz-Molina, C. Rodríguez-Rodríguez, F. G-quadruplex-based near-infrared nanocomposite photosensitizer with high Novio, Hybrid metal-phenol nanoaprticles with polydopamine like coating biocompatibility and bioavailability, ACS Appl. Mater. Interfaces 12 (2020) for PET/SPECT/CT imaging, ACS Appl. Mater. Interfaces 13 (2021) 10705– 7575–7585. 10718. [142] X. Wang, J. Liang, C. Zhang, G. Ma, C. Wang, D. Kong, Coordination [164] Y.M. Wang, W. Liu, X.B. Yin, Self-limiting growth nanoscale coordination microparticle vaccines engineered from tumor cell templates, Chem. polymers for fluorescence and magnetic resonance dual-modality imaging, Commun. 55 (2019) 1568–1571. Adv. Funct. Mater. 26 (2016) 8463–8470. [143] C.M. Calabrese, T.J. Merkel, W.E. Briley, P.S. Randeria, S.P. Narayan, J.L. Rouge, [165] Y. Lu, F. Xue, H. Yang, M. Shi, Y. Yan, L. Qin, Z. Zhou, S. Yang, Phosphorescent D.A. Walker, A.W. Scott, C.A. Mirkin, Biocompatible infinite-coordination- coordination polymer nanoparticles as a three-in-one platform for optical polymer nanoparticle-nucleic-acid conjugates for antisense gene regulation, imaging, T1-weighted magnetic resonance imaging, and photodynamic Angew. Chem. Int. Ed. 54 (2015) 476–480. therapy, J. Phys. Chem. C 119 (2015) 573–579. [144] Y. Chao, C. Liang, Y. Yang, G. Wang, D. Maiti, L. Tian, F. Wang, W. Pan, S. Wu, K. [166] Y. Yang, J. Liu, C. Liang, L. Feng, T. Fu, Z. Dong, Y. Chao, Y. Li, G. Lu, M. Chen, Z. Yang, Z. Liu, Highly effective radioisotope cancer therapy with a non- Liu, Nanoscale metal-organic particles with rapid clearance for magnetic therapeutic isotope delivered and sensitized by nanoscale coordination resonance imaging-guided photothermal therapy, ACS Nano 10 (2016) 2774– polymers, ACS Nano 12 (2018) 7519–7528. 2781. [145] Q. Yang, Z. Zhou, L. Cui, H. Yang, C. Yan, X. Zhou, S. Yang, L. Pan, X. Zhang, [167] J. Qin, G. Liang, Y. Feng, B. Feng, G. Wang, N. Wu, Y. Zhao, J. Wei, Synthesis of Coordination polymer hybridized au nanocages: a nanoplatform for dual- gadolinium/iron–bimetal–phenolic coordination polymer nanoparticles for modality imaging guided near-infrared driven photothermal therapy in vivo, theranostic applications, Nanoscale 12 (2020) 6096–6103. J. Mater. Chem. B 5 (2017) 8761–8769. [168] Q. An, J. Liu, M. Yu, J. Wan, D. Li, C. Wang, C. Chen, J. Guo, Multifunctional [146] S. Suárez-García, R. Solórzano, F. Novio, R. Alibés, F. Busqué, D. Ruiz-Molina, magnetic Gd3+-based coordination polymer nanoparticles: combination of Coordination polymers nanoaprticles for bioimaging, Coord. Chem. Rev. 432 magnetic resonance and multispectral optoacoustic detections for tumor- (2021) 213716. targeted imaging in vivo, Small 11 (2015) 5675–5686. [147] E.-K. Lim, T. Kim, S. Paik, Nanomaterials for theranostics: recent advances and [169] Q. Jin, W. Zhu, D. Jiang, R. Zhang, C.J. Kutyreff, J.W. Engle, P. Huang, W. Cai, Z. future challenges, Reviews 115 (2015) 327–394. Liu, L. Cheng, Ultra-small iron-gallic acid coordination polymer nanoparticles [148] Z. He, P. Zhang, Y. Xiao, J. Li, F. Yang, Y. Liu, J.R. Zhang, J.J. Zhu, Acid-degradable for chelator-free labeling of 64Cu and multimodal imaging-guided gadolinium-based nanoscale coordination polymer: a potential platform for photothermal therapy, Nanoscale 9 (2017) 12609–12617. targeted drug delivery and potential magnetic resonance imaging, Nano Res. [170] D. Hu, C. Liu, L. Song, H. Cui, G. Gao, P. Liu, Z. Sheng, L. Cai, Indocyanine green- 11 (2018) 929–939. loaded polydopamine-iron ions coordination nanoparticles for [149] J. Ma, H. Dong, H. Zhu, C.W. Li, Y. Li, D. Shi, Deposition of gadolinium onto the photoacoustic/magnetic resonance dual-modal imaging-guided cancer shell structure of micelles for integrated magnetic resonance imaging and photothermal therapy, Nanoscale 8 (2016) 17150–17158. robust drug delivery systems, J. Mater. Chem. B 4 (2016) 6094–6102. [171] Y. Yang, Y. Chao, J. Liu, Z. Dong, W. He, R. Zhang, K. Yang, M. Chen, Z. Liu, Core- [150] H. Yang, C. Qin, C. Yu, Y. Lu, H. Zhang, F. Xue, D. Wu, Z. Zhou, S. Yang, RGD- shell and co-doped nanoscale metal-organic particles (NMOPs) obtained via conjugated nanoscale coordination polymers for targeted T1- and T2- post-synthesis cation exchange for multimodal imaging and synergistic weighted magnetic resonance imaging of tumors in vivo, Adv. Funct. Mater. thermo-radiotherapy, NPG Asia Mater. 9 (2017) e344. 24 (2014) 1738–1747. [172] C. Chu, E. Ren, Y. Zhang, J. Yu, H. Lin, X. Pang, Y. Zhang, H. Liu, Z. Qin, Y. Cheng, [151] D. Liu, C. He, C. Poon, W. Lin, Theranostic nanoscale coordination polymers for X. Wang, W. Li, X. Kong, X. Chen, G. Liu, Zinc(II)-dipicolylamine coordination magnetic resonance imaging and bisphosphonate delivery, J. Mater. Chem. B nanotheranostics: toward synergistic nanomedicine by combined 2 (2014) 8249–8255. photo/gene therapy, Angew. Chem. Int. Ed. 58 (2019) 269–272. [152] J. Zhao, Y. Yang, X. Han, C. Liang, J. Liu, X. Song, Z. Ge, Z. Liu, Redox-sensitive [173] Y.M. Wang, W. Liu, X.B. Yin, Multifunctional mixed-metal nanoscale nanoscale coordination polymers for drug delivery and cancer theranostics, coordination polymers for triple-modality imaging-guided photodynamic ACS Appl. Mater. Interfaces 9 (2017) 23555–23563. therapy, Chem. Sci. 8 (2017) 3891–3897. [153] H. Zhang, K. Liu, S. Li, X. Xin, S. Yuan, G. Ma, X. Yan, Self-assembled minimalist [174] G.-G. Yang, D.-J. Zhou, Z.-Y. Pan, J. Yang, D.-Y. Zhang, Q. Cao, L.-N. Ji, Z.-W. multifunctional theranostic nanoplatform for magnetic resonance imaging- Mao, Multifunctional low-temperature photothermal nanodrug with in vivo guided tumor photodynamic therapy, ACS Nano 12 (2018) 8266–8276. clearance, ROS-Scavenging and anti-inflammatory abilities, Biomaterials 216 [154] K. Xin, M. Li, D. Lu, X. Meng, J. Deng, D. Kong, D. Ding, Z. Wang, Y. Zhao, (2019) 119280. Bioinspired coordination micelles integrating high stability, triggered cargo [176] N. N. Adarsh, F. Novio, D. Ruiz-Molina, Coordination Polymers Built from 1,4- release, and magnetic resonance imaging, ACS Appl. Mater. Interfaces 9 Bis(Imidazol-1-Ylmethyl)Benzene: From Crystalline to Amorphous, Dalton (2017) 80–91. Transactions 45 (2016) 11233–11255. [155] Y. Chen, K. Ai, J. Liu, X. Ren, C. Jiang, L. Lu, Polydopamine-based coordination nanocomplex for T1/T2 dual mode magnetic resonance imaging-guided chemo-photothermal synergistic therapy, Biomaterials 77 (2016) 198–206. 24