biomolecules Review Nano-Based Approved Pharmaceuticals for Cancer Treatment: Present and Future Challenges Francisco Rodríguez 1,† , Pablo Caruana 1,† , Noa De la Fuente 2 , Pía Español 3 , María Gámez 4 , Josep Balart 5 , Elisa Llurba 3 , Ramón Rovira 3 , Raúl Ruiz 1 , Cristina Martín-Lorente 6 , José Luis Corchero 7, * and María Virtudes Céspedes 1, * 1 Grup d’Oncologia Ginecològica i Peritoneal, Institut d’Investigacions Biomédiques Sant Pau, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; frodriguezl@santpau.cat (F.R.); pcaruana@santpau.cat (P.C.); raulruizpalacios17@gmail.com (R.R.) 2 Servicio de Cirugía General y del Aparato Digestivo, Hospital HM Rosaleda, 15701 Santiago de Compostela, Spain; ndelafuente@hmhospitales.com 3 Department of Obstetrics and Gynecology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, 08041 Barcelona, Spain; mespanoll@santpau.cat (P.E.); ellurba@santpau.cat (E.L.); rroviran@santpau.cat (R.R.) 4 Department of Pharmacy, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; mgamezl@santpau.cat 5 Department of Radiation Oncology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; jbalart@santpau.cat 6 Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; cmartinl@santpau.cat 7 Institut de Biotecnologia i de Biomedicina and CIBER-BBN, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain * Correspondence: jlcorchero@ciber-bbn.es (J.L.C.); mcespedes@santpau.cat (M.V.C.); Tel.: +34-93-5812148 (J.L.C.); +34-93-400000 (ext. 1427) (M.V.C.) Citation: Rodríguez, F.; Caruana, P.; † These authors contributed equally to this work. De la Fuente, N.; Español, P.; Gámez, M.; Balart, J.; Llurba, E.; Rovira, R.; Abstract: Cancer is one of the main causes of death worldwide. To date, and despite the advances Ruiz, R.; Martín-Lorente, C.; et al. in conventional treatment options, therapy in cancer is still far from optimal due to the non-specific Nano-Based Approved systemic biodistribution of antitumor agents. The inadequate drug concentrations at the tumor site led Pharmaceuticals for Cancer to an increased incidence of multiple drug resistance and the appearance of many severe undesirable Treatment: Present and Future side effects. Nanotechnology, through the development of nanoscale-based pharmaceuticals, has Challenges. Biomolecules 2022, 12, 784. emerged to provide new and innovative drugs to overcome these limitations. In this review, we https://doi.org/10.3390/ provide an overview of the approved nanomedicine for cancer treatment and the rationale behind biom12060784 their designs and applications. We also highlight the new approaches that are currently under Academic Editor: Bahman Anvari investigation and the perspectives and challenges for nanopharmaceuticals, focusing on the tumor Received: 10 May 2022 microenvironment and tumor disseminate cells as the most attractive and effective strategies for Accepted: 2 June 2022 cancer treatments. Published: 4 June 2022 Keywords: nanomedicine; cancer therapy; nanotechnology; approved nanopharmaceuticals; Publisher’s Note: MDPI stays neutral targeted therapy with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction More than ten million people are diagnosed with cancer annually [1]. Cancer com- Copyright: © 2022 by the authors. prises a wide diversity of diseases, all of them characterized by numerous cellular physio- Licensee MDPI, Basel, Switzerland. logical systems leading to abnormal and non-stop cell growth in a specific tissue location, This article is an open access article forming the tumor [2]. distributed under the terms and After cancer diagnosis, combined therapies are commonly used, applying different conditions of the Creative Commons modalities such as surgery followed by chemotherapy and/or radiotherapy. Currently, Attribution (CC BY) license (https:// and despite the advances in conventional treatment options, cancer therapy is still far creativecommons.org/licenses/by/ from optimal. Conventional chemotherapeutic drugs are non-selective small molecules 4.0/). Biomolecules 2022, 12, 784. https://doi.org/10.3390/biom12060784 https://www.mdpi.com/journal/biomolecules Biomolecules 2022, 12, 784 2 of 27 that distribute all over the body without discriminating healthy from damaged tissues [3]. This lack of specificity is translated into the appearance of many severe undesirable side effects and multiple drug resistances [4]. Nanomedicine offers a versatile platform of bio- compatible and biodegradable drug-delivery systems (DDS) that can deliver conventional chemotherapeutic drugs in vivo, increasing their bioavailability and concentration around tumor tissues, improving their pharmacokinetics and release profile, and minimizing side effects [5]. The lipid-based and protein-based DDS are the majority of nanopharmaceuticals approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for cancer treatment. Innovations in liposome technology, and the incorpo- ration of micelles, polymeric nanomaterials, and inorganic-based nanoparticles, together with the application of targeting with a plethora of ligands, have provided a new generation of nanopharmaceuticals under evaluation in clinical trials, alone or in combination with conventional treatments [6]. Importantly, the recent discoveries of new molecular and cellular targets involved in cancer progression and metastasis are emerging as key factors in nanopharmaceutical development and underscore the importance of continuous feedback between basic and clinical fields. It will choose the best options to overcome the biomedical and technical chal- lenges and will provide the rationale for developing more effective nanopharmaceuticals for cancer therapy. In addition, nanopharmaceutical production, costs, and toxic effects limit the use of nanoparticles in clinical practice. Their toxicity profile requires further extensive research, being one of the most relevant issues required for the eventual approval of nanopharmaceuticals. In this review, we will provide an overview of the approved and marketed nanophar- maceuticals for cancer treatment and the rationale behind their design and application. Moreover, we highlight the new approaches in DDS development and the nanopharmaceu- ticals that are currently under clinical trials and discuss their advantages, limitations, and future perspectives. 2. Rationale of Nanopharmaceutical Development for Cancer Therapy Many antitumor agents are available in the market and have been extensively used in clinic. However, these conventional therapies are mainly based on systemically admin- istered non-selective chemotherapeutics of small molecular size (<6 nm) that are below the renal filtration cut-off (around 7 nm). They are excreted through the kidney, which results in a short circulation time and in a wide biodistribution all over the body without discriminating healthy from damaged tissues, especially targeting those tissues that have a high replacement rate such as intestinal lining and immune cells [7]. This lack of specificity is translated into many severe undesirable side effects in patients, such as anemia, appetite loss, constipation, bleeding, diarrhea, fatigue, fertility issues, and hair loss, as the most prevalent signs of toxicity [8]. In addition, low-weight chemotherapeutics have other limitations apart from systemic toxicity, such as low response rates, the development of re- sistances, and the absence of tumor selectivity. Consequently, all the intrinsic limitations of conventional cancer therapies and the alarmingly high number of deaths in cancer disease have prompted the development of nanomedicine. This field is intensively working on the application of nanotechnology for the development of more effective and safer cancer treatments in the nanoscale range (desirably between 8–100 nm). Since the 1950s, DDS have been explored as alternative engineered platforms for the improvement of cancer chemotherapy. DDS, as nanovehicles, are of several material types, forms, and natures. They offer targeted versions of current anticancer drugs, enhancing antitumor efficacy due to a controlled release at the target site. DDS overcome the non-specific systemic distribu- tion and the inadequate drug concentrations in the tumor site, the intolerable cytotoxicity in healthy tissue, and drug resistance [4,8]. Biomolecules 2022, 12, 784 3 of 27 3. Targeting Tumor Microenvironment in Cancer Therapy In the past, tumors were considered as a whole population of cancer cells. The cancer treatment was based on targeting the highly proliferating tumor cells using mainly cytostatic agents designed to target the intrinsic cancer cell mechanisms. However, during cancer progression, tumors become highly heterogeneous, containing different cellular populations characterized by distinct molecular features and different responsivity to therapies. This heterogeneity is provided by many bulk cancer cells, as well as a small population of cancer stem cells (CSCs) and the tumor microenvironment (TME). TME is comprised of the non-cancerous cells and the factors and proteins produced by them, which ultimately support the growth of cancer cells [9]. All of them are critical components, influencing initiation, progression, and metastasis, as well as promoting the resistance of cancer cells to therapies, eventually resulting in patient relapse [10]. This heterogeneity is the main cause that limits the therapeutic value of many drugs [4], and it is further associated with a fatal disease [10,11]. To date, many efforts have been made to understand these multicomponent scenarios and design efficient and precise therapies to target the different compartments in order to increase the clinical impact of cancer treatments [12]. 3.1. Targeting Cancer Stem Cells in TME In the last decade, the CSCs hypothesis has gained attention for targeted intervention in cancer therapy. These cancer cells contribute to tumor initiation, growing, resistance, metastasis, and relapse [13,14]. CSCs have been defined as a subset of tumor cells with the ability to self-renew and differentiate into non-CSC highly proliferative cancer cells within the tumor mass [15]. In in vivo experimental model systems CSCs have the ability to initiate tumors and sustain constant tumorigenesis. CSCs share several of their defining features with normal stem cells, including relative quiescence, active DNA repair systems, aggressive proliferation, and drug resistance [16]. These processes are principally regulated by the WNT/β-catenin, transforming growth factor-β, Hedgehog, and Notch signals [14]. Three origins have been postulated for CSCs: (a) (epi)genetic changes such as methylation, demethylation, mutations, and rearrangement in the stem/progenitor cell population (niche) or even in differentiated cells [17]; (b) spontaneous oncogenic reprogramming in somatic cells; and (c) TME activation through providing extracellular cues [18]. CSCs are identified from the expression of several cell surface markers, and these markers are tumor-type dependent and conform to a signature; thus, the different markers are combined to isolate a bonafide cell population with high numbers of CSCs. However, the gold standard method to unveil the tumor-initiating capabilities of CSCs is the use of limiting dilution in xenograft animals to form tumors (see detailed reviews of CSCs in [19,20]). To date, several studies have been able to prove the existence of CSCs in tumors, and their tumorigenicity has been demonstrated in several cancers, including brain, liver, lung, colon, breast, ovarian, pancreas, prostate, melanoma, head, neck, and bladder [21,22]. Furthermore, their frequency increases upon tumor progression, being different from one cancer to another [23,24]. Several CSCs markers such as CD44, ALDH1 CD133, and CXCR4 have been identified in different tumors and are targets for therapeutic interventions [24]. CSCs are also able to resist conventional therapies such as chemotherapy and radio- therapy [25]. Such resistance is given by the increased expression of drug transporters (e.g., ATP-binding cassette (ABC) membrane transporters), the maintenance of a slow di- viding state (quiescence), and efficient DNA repair mechanisms [26]. Moreover, CSCs have enhanced epithelial to mesenchymal (EMT) properties, enhanced expression and activation of several survival signaling pathways, and increased immune-evasion and DNA-repair mechanisms [25]. Furthermore, the functional properties of CSCs during cancer expansion and the responses to the therapeutic approaches are defined by the TME [27,28]. The plasticity of CSCs through transformation into proliferative cancer cells is possibly under the control of signals from both CSCs and the TME. Cancer-associated fibroblasts are among the most influential cells for promoting both the differentiation of CSCs and the dedifferentiation Biomolecules 2022, 12, 784 4 of 27 of non-CSCs to a CSC-like phenotype. Interestingly, CSCs can also alter the cellular microenvironment in favor of cancer progression, influencing stromal cells through the release of extracellular vesicles [29]. The elimination of CSCs, based on their preferential expression of markers and/or their supporting elements, is thought to be better in efficiently antitumor therapy. CSC targeting has allowed for the creation of novel technologies and therapies that can target tumor progression at earlier stages of pathogenesis [30–33]. To date, no approved nanophar- maceutical is used to eliminate these populations, but some of them are in preclinical and clinical trials [34]. 3.2. Targeting Tumor Stroma in TME Tumors are complex systems that comprise malignant cancerous cells and the so-called tumor stroma formed by the non-cancerous cells such as fibroblasts, immune cells, bone marrow-derived inflammatory cells, lymphocytes, and cells that form blood vessels, as well as the extracellular matrix (ECM). They also include the proteins produced by all the cells that also support the growth of the malignant cells [35]. The microenvironment of the tumor is an integral part of its physiology, structure, and functioning, and it is an essential aspect of the malignant process [36]. The interactions between the malignant and normal cells create the TME and play critical roles in cancer development, progression, and metastasis. The combination of cancer cell mutations (and other alterations) coupled with changes to the tumor stroma contributes to the tumor heterogeneity and drives tumorigenesis, resulting in fatal disease [37]. Over the years, most anticancer therapies have targeted malignant cancer cells specifically, while largely ignoring TME. Investigations are now focusing and are extensively exploited on the tumor microenvironment as a separate cancer-associated entity. Anticancer therapies should target both cancer cells and the stromal compartment to be effective and result in improved patient outcomes [36]. The use of experimental cancer models has shown the tumor architecture of TME and the complexity of cellular and noncellular interactions within a tumor [37]. The monitoring of changes in molecular and cellular profiles of the tumor microenvironment could be vital for identifying cell or protein targets in tumor progression, being useful for cancer prevention and therapeutic purposes [38]. 3.2.1. Angiogenic Targets Angiogenesis is the formation of new blood vessels and involves the migration, growth, and differentiation of endothelial cells to supply oxygenation and nutrients to tissues. An- giogenesis is highly activated in tumors [39]. However, the rapid growth of the tumor cells results in leaky and highly disoriented vascular structures and the inability of blood vessels to provide oxygenation and nutrients to tumor cells, leading to oxygen-deficient or hypoxic regions in the tumor. This situation results in a hypoxic tumor core, mak- ing it immune to chemotherapy and radiation treatments. The lack of oxygen can also cause glycolytic behavior in cells, inducing greater cell migration in-vivo and in-vitro [39]. Controlling the angiogenesis is a critical step in cancer progression, and the dissection of the molecular interactions of this process by the TME enhances prognoses and facilitates targeted therapy [40]. 3.2.2. Drug Chemoresistance Targets TME is also recognized as a key contributor to drug resistance in cancer treatment. When cancer develops, the stroma undergoes changes to become fibrotic and activated. The extracellular matrix (ECM) becomes denser and more rigid, thanks to new connective fibers, such as tenascin and fibronectin, which cancer cells can invade. Cancer-associated fibroblasts (CAFs), myofibroblasts, and mesenchymal stromal cells (MSCs) change shape and expression profiles and become more proliferative. Senthebane et al. [41] reported that components of TME, including CAFs and the ECM, are major contributors to chemore- sistance [41]. In response to chemotherapy or radiation therapy, CAFs and MSCs secrete Biomolecules 2022, 12, 784 5 of 27 different growth factors, cytokines, and chemokines that promote cancer cell survival, proliferation, invasion, and metastasis, leading to resistance. Dense fibrosis causes lim- ited access of cancer cells to therapeutic agents in three ways: creating an extracellular matrix (ECM) barrier that such agents cannot diffuse through; promoting the stromal cytochrome P450 (CYP)-mediated degradation of drugs; and increasing interstitial pressure that prevents therapeutic agents from entering the tumor [37,41]. Extensive work has been done to explore the interactions between cancer cells and the TME. The monitoring of the changes in the TME using their molecular and cellular profiles could be pivotal for identifying cells or protein targets for cancer prevention and therapeutic purposes. Discovery studies involving the laser capture microdissection of stroma [42], coupled with analyses of genetic mutations [43] and epigenetic changes [44], can uncover novel therapeutic targets. Drugs that target stromal components are in various stages of preclinical and clinical development. In most cases, the stroma-targeting drugs abrogate resistance to cancer cell-targeting therapies, leading to strong anticancer responses [45]. However, some future challenges must be considered: the unknown elements of the optimal composition of combinations comprising stromal-targeting and cancer-targeting agents or even the administration sequence should be defined for being offered to patients [45]. The order of drug administration is important because certain sequences can result in adverse effects. For example, when chemotherapy is administered after the initiation of an immune response, it could cause the death of immune cells, thereby reversing their cytotoxic effect. As we continue to better understanding the complex interactions between the heterogeneous milieu of cellular and non-cellular contributors to the TME, we will be able to improve stroma-targeting strategies and design more effective anticancer therapies. 3.3. Disseminated Tumor Cell Targets One of the major hallmarks of cancer is the dissemination of tumor cells to adjacent organs or to distal sites (or metastasis). Metastasis comprises approximately 90% of total cancer-related deaths [46]. Conventional cytostatic agents are successful at reducing pri- mary tumor size, but they have a poor effect on disseminated tumor cells. Several studies have described that metastasis-initiating cells (MICs) seem to be responsible to tumor growth in distant organs. MICs result from (i) a phenotype with intrinsic programs to sur- vive the stresses of the metastatic process, (ii) undergo epithelial–mesenchymal transitions, (iii) enter slow-cycling states for dormancy, (iv) escape immune surveillance in collabora- tion with the metastatic microenvironment, and (v) establish supportive interactions with organ-specific niches [47–49]. Thus, one of the most promising strategies to control cancer is focused on design- ing drugs that interfere with MICs (see detailed review in [48]). MICs overexpress the chemokine receptor CXCR4. The overexpression of this receptor in primary tumors has been described in 20 different cancer types and contributes to tumor growth, angiogenesis, metastasis, and therapy resistance. CXCR4-overexpressing tumors are likely to metastasize in an organ-specific and CXCL12-dependent manner, with the lung, liver, brain, kidney, skin, and bone marrow being the CXCL12-expressing organs [50,51]. Supporting this fact, the inhibition of the CXCL12/CXCR4 axis resulted in a reduced metastatic load in many cancer mouse models [52–54]. Metastatic CSCs overexpressing CXCR4 are clinically relevant targets; thus, their selective elimination could represent an advance in metastases control. A multitude of CXCR4-directed antagonists have been developed during the last decade. Among them, AMD3100 (Plerixafor), a low-weight molecule, is the unique compound approved by the FDA for the mobilization of hematopoietic stem cells and for the treatment of multiple myeloma and non-Hodgkin’s lymphoma [55]. Many other CXCR4 antagonists are being developed, and some of them are under clinical trials. No approved nanopharmaceutical is used to treat cancer stem cells. Biomolecules 2022, 12, 784 6 of 27 4. Modes of Targeting: From Size to Multicomplexity DDSs Because of the nanoscale size, nanovehicles tend to accumulate more in tumor tissues with respect to low-weight drugs due to the enhanced permeability and retention (EPR) effect [56]. This inherent targeting (referred to Passive targeting) is due to the tumoral leaky vasculature, different pH, and different local temperature, as well as a deficient lymphatic drainage system in tumors [57]. However, this passive mode of targeting can induce (a) multi-drug resistance (MDR) due to the high systemic dosage used to achieve a sufficient amount of drug at the tumor site to trigger a therapeutic response, (b) poor drug diffusion, and (c) accumulation in the liver and spleen [58]. Targeted drug-delivery systems (TDDS) are commonly used to overcome the lim- itations of low specificity, low therapeutic index, low absorption, short half-life, and a large volume of distribution by low-molecular-weight drugs and untargeted nanovehicles. Moreover, TDDS minimizes the adverse effects, reducing nephrotoxicity, neurotoxicity, and cardiotoxicity by making changes in the inappropriate disposition of the drug and reducing its presence in non-targeted areas [59]. At the same time, TDDS could also maximize the therapeutic efficacy of the drug by preventing its inactivation in circulation, avoiding the degradation of the drug before reaching the target site [60–63]. The functional targeted of nanovehicles can be achieved through two different strate- gies: (i) active targeting and (ii) stimuli-responsive targeting [64]. Active targeting con- figures the nanovehicle to target-specific cells after extravasation using the molecular recognition (ligand-receptor or antigen-antibody interactions) of the tumor cells through specific receptors that are overexpressed on them [65]. The ligand must have a high affinity for its receptor, and trigger receptor-mediated endocytosis, after which the intracellular release can be favored by acidic pH or enzyme [66]. These ligands can be either adsorbed onto the particle surface or covalently bound to one of the components of the nanoparticles, normally poly-(ethylene glycol). Different types of ligands can be used to target cancer cells, including, most commonly, folic acid, and peptides or protein-targeting moieties, such as antibodies, anti-body fragments, cell-penetrating peptides (CPPs), growth factors, or cytokines. This interaction is highly specific and strong, and antibodies seem to be the most effective ligands. The production of conventional antibodies is difficult and expensive; therefore, specifically, an amino acid sequence called the antigen-binding fragment (Fab), which univocally binds to antigens, is preferred because of it is safe against non-specific binding and can be easily engineered [67]. Finally, the small synthetic single-stranded RNA or DNA oligonucleotides (normally composed of 20–60 nucleotides), called aptamers, which can form specific shapes (helices or single-stranded loops), are a new type of ligands that are extremely versatile and can bind different kinds of targets—proteins, inorganic molecules, and cells with high selectivity. Their preparation is much simpler and cheaper than the antibodies, not showing any sign of toxicity [68,69]. On the other hand, stimuli-responsive targeting is intended as the localized release of drugs induced by a trigger that alters the structure of the nanocarrier [70]. This system is highly specific and can be activated “on-demand” at the desired site. Stimuli can be internal, such as variations in pH, redox conditions, and ionic strength, or external, such as temperature, ultrasounds, magnetic fields, and ultraviolet/near-infrared (UV/NIR) radiation [71]. DDS can be designed to be responsive to these stimuli and to achieve enhanced release of their cargo in the precise location [72]. Moreover, external stimuli such as local hyperthermia and UV/NIR light can act in the microenvironment, for example, by enhancing the permeability of blood vessels to favor tissue penetration, or ultrasounds can induce the release of contrast agents at the tumor site, while magnetic fields can locally drive DDS, thus triggering drug release via hyperthermia [73,74]. 5. Approved Nanopharmaceuticals for Clinical Uses in Cancer Therapy Figures 1 and 2 and Table 1 list the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA)-approved nanopharmaceuticals for cancer therapy. Biomolecules 2022, 12, 784 7 of 27 Among the DDS, the lipid-based platform, such as nanoliposomes, supplies a good number Biomolecules 2022, 12, 784 11 of of the total approved nanopharmaceuticals for cancer treatment [75]. To date, 56% of them are lipid-based nanoformulations, and the rest are included as protein-based (38%) and metallic-based nanoformulations (6%). Figure 1. Lipid-based approved and marketed nanopharmaceuticals FDA and/or EMA-approved Figure 1. Lipid-based approved and marketed nanopharmaceuticals FDA and/or EMA-approv nanomedicines from 1995 to 2022 (last accessed May 2022), cataloged by their nature, encapsulated nanomedicines from 1995 to 2022 (last accessed May 2022), cataloged by their nature, encapsulat drug, their mechanism of action, and their induced effects. drug, their mechanism of action, and their induced effects. DoxilTM and CaelyxTM are indicated for the treatment of ovarian cancer, AIDS-relat Kaposi’s sarcoma, and in combination with bortezomib, for the treatment of multiple m eloma. CaelyxTM and MyocetTM are also indicated for patients with metastatic breast canc [78]. Biomolecules 2022, 12, 784 Biomolecules 2022, 12, 784 8 of 27 Figure 2. Protein- and metallic-based approved and marketed nanopharmaceuticals. FDA and/or EMA-approved nanomedicines from Figure 2. Protein- 1995 and to 2022 (last accessed metallic-based approved May and2022), cataloged marketed by their nature, nanopharmaceuticals. FDA encapsulated drug, their mechanism EMA-approved of action, and nanomedicines fromtheir induced 1995 effects. to 2022 (last accessed May 2022), cataloged by th ture, encapsulated drug, their mechanism of action, and their induced effects. However, significant toxicities, such as myelosuppression, allergic reactions, n toxicity, and systemic toxicity, have mainly been due to solvents, limiting the effectiv of paclitaxel-based treatments. Both the absence of solvents and the receptor-med delivery result in decreased toxicity and increased antitumor activity [104,105] nanopharmaceutical form, nab-Paclitaxel, takes advantage of the increased delivery bumin to tumors via a receptor-mediated transport called transcytosis. Nab-Pac Biomolecules 2022, 12, 784 9 of 27 Table 1. Approved and marketed nanopharmaceuticals for cancer therapy. Nanoformulation Nanostructure ProductTM Nanotechnology Platform Drug Advantages TME Targeting Indication Company Approval (Year) PEGylatyed STEALTH ® ↑ blood circulation time Kaposi’s sarcoma, Doxil liposomes composed of Doxorubicin ↑ tumor uptake (EPR) Cancer and stroma cells ovarian Ca, multiple Ortho Biotech FDA (1995) MPEG-DSPE, HSPC, CHO. ↓ cardiotoxicity myeloma PEGylated liposomal Metastatic breast, Ca., ↑ blood circulation time ovarian Ca., Caelyx doxorubicin composed of Doxorubicin ↑ tumor uptake (EPR) Cancer and stroma cells Schering-Plough EMA (1996) MPEG-DSPE, Kaposi’s sarcoma, HSPC, CHO ↓ cardiotoxicity and multiple myeloma Citrate salt of daunorubicin ↓ protein binding encapsulated in non-pegylated ↑ blood circulation time DaunoXome Daunorubicin Cancer and stroma cells Kaposi’s sarcoma Galen FDA (1996) liposomes composed of DSPC ↑ tumor uptake (EPR) and CHO (2:1 MR) ↓ cardiotoxicity Liposomal doxorubicin Lipid based nanoparticles ↑ blood circulation time Myocet (non-PEGylated) composed of ↑ tumor uptake (EPR) Teva UK Doxorubicin Cancer and stroma cells Metastatic breast Ca. EMA (2000) PC, CHO, citric acid, ↓ cardiotoxicity and NaOH Liposomal mifamurtide (fully synthetic analogue of a ↑ blood circulation time Mepact component of Mycobacterium Mifamurtide ↑ tumor uptake (EPR) Macrophages Osteosarcoma Millenium EMA (2009) sp. cell wall) composed of ↓ toxicity POGP, DGPS, MS Gel containing Superficial and/or sustained release Biofrontera Bioscience Ameluz 5-aminolevulinic acid, E211, 5-aminolevulinic acid Cancer and stroma cells nodular basal cell EMA (2011) ↓ toxicity GmbH SoyPC, and PG carcinoma Liposomal vincristine ↑ blood circulation time Acute lymphoid Marqibo Vincristine ↑ tumor uptake (EPR) Cancer and stroma cells Spectrum FDA (2012) composed of SM and CHO ↓ toxicity leukaemia Nanoliposomes composed of ↑ blood circulation time Pancreatic Onivyde DSPC, CHO, Irinotecan ↑ tumor uptake (EPR) Cancer and stroma cells Ca., Merrimack FDA (2015) MPEG-2000-DSPE ↓ toxicity Colorectal Ca. ↑ blood circulation Nanoliposomes composed of Daunorubicin time, Acute myeloid Vyxeos Cancer and stroma cells Jazz Pharmaceuticals EMA (2018) DSPC, DEPG, and CHO Cytarabine ↑ accumulation in bone leukaemia marrow Biomolecules 2022, 12, 784 10 of 27 Table 1. Cont. Nanoformulation Nanostructure ProductTM Nanotechnology Platform Drug Advantages TME Targeting Indication Company Approval (Year) Covalent conjugate of L-asparaginase with mPEG, ↑ blood circulation time Acute lymphoblastic Les Oncaspar Pegaspargase Cancer cells FDA (1994) MSP, Na2HPO4, ↑ tumor uptake (EPR) leukaemia Laboratoires Servier Heptahydrate, and NaCl Recombinant cytotoxic protein ↑ blood circulation time composed of ↑ tumor uptake (EPR) Ontak Denileukin Diftitox Activated T-cells Cutaneous T-cell Les laboratoires Servier FDA (1999) diphtheria toxin fragments A ↑ selectivity lymphoma and B (Met1-Thr387)-His and ↓ severe toxicity human IL-2 (Ala1-Thr133) Protein-drug conjugates Polymeric matrix of Recordati Industria Eligard leuprorelin acetate composed Leuprorelin acetate ↑ blood circulation time Cancer cells Prostate cancer Chimica FDA (2002) of PLGA (85:15) ↑ tumor uptake (EPR) e Farmaceutica NMP and LA Colloidal suspension without ↑ Solubility Breast Ca. solvent of paclitaxel bound to Abraxane Paclitaxel ↑ blood circulation time Cancer and stroma cells Non-small lung Ca., American FDA (2005) albumin (active substance) in ↑ tumor uptake (EPR) Pancreatic Biosciencem, Inc. the form of a spherical Ca. ↓ severe toxicity nanoparticle ↑ blood circulation time Trastuzumab, covalently ↑ tumor uptake (EPR) HER2+ breast Roche EMA (2013) Kadcyla linked to DM1 via the stable DM1 (or Emtansine) Cancer cells ↑ selectivity Ca. Genentech FDA (2013) thioether linker MCC ↓ toxicity ↑ Solubility Metastatic breast Ca., Paclitaxel formulated as metastatic albumin ↑ blood circulation time Pazenir Paclitaxel Cancer cells adenocarcinoma of the Ratiopharm GmbH EMA (2019) bound nanoparticles. Powder ↑ tumor uptake (EPR) pancreas, non-small cell for dispersion for infusion ↓ severe toxicity lung Ca. Metallic nanoparticles ↑ blood circulation time Nanoparticles of ↑ tumor uptake (EPR) Residual cancer and Glioblastoma, prostate, NanoTherm superparamagnetic iron oxide Fe2 O3 -heat production under Magforce EMA (2013) stroma cells and pancreatic Ca. coated with amino silane stimulation with EMF -teranostic properties Abbreviations: ↑: increase; ↓: decrease; Ca.: cancer; MR: molar ratio; MPEG-DSPE: N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero3-phosphoethanolamine sodium salt; HSPC: fully hydrogenated soy phosphatidylcholine; DGPS: 1,2-Dioleoyl-sn-glycero-3-phospho-L-serine; DSPC: distearoylphosphatidylcholine; POGP: 1-Palmitoyl-2- oleoyl-sn-glycero-3-phosphocholine; CHO: cholesterol; E211: Sodium benzoate; SoyPC: soybean phosphatidylcholine; PC: phosphatidylcholine; DSPC: 1,2-distearoyl-sn-glycero-3- phosphocholine; mPEG: Monomethoxypolyethylene glycol; MPEG-2000-DSPE: methoxy-terminated polyethylene glycol (MW 2000)-distearoylphosphatidyl ethanolamine; DEPG: Distearoylphosphatidylglycero; PG: propylene glycol; SM: sphingomyelin; MSP: sodium dihydrogen phosphate (monohydrate); MS: monosodium salt; Na2HPO4: disodium phosphate; NaCl: sodium chloride; NaOH: sodium hydroxide; PLGA: poly(lactic-co-glycolic acid); NMP: N-Methyl-2-Pyrrolidone; and LA: leuprolide acetate. Biomolecules 2022, 12, 784 11 of 27 5.1. Lipid-Based Approved Nanopharmaceuticals Liposomes were the first drug-delivery systems in the market and are still the most used to date [75]. Their flexibility of composition, biocompatibility, biodegradability, and non-immunogenicity are their main advantages compared to other DDSs [76]. Liposomes are artificially prepared single or multilamellar phospholipid vesicles. They are 50–100 nm in size and have anionic, cationic, or neutral charges with a central aqueous phase or core [76,77]. Liposomes and micelles are both made of phospholipids, but they differ in their morphology. Liposomes are mainly used to encapsulate hydrophilic drugs in their aqueous core, but hydrophobic drugs can also be accommodated in the bilayer or chemically attached to the particles [76]. Micelles, instead, have a hydrophobic core that can encapsulate hydrophobic drugs [77]. They are exploited for delivering and reaching a specific target site, thus minimizing biodistribution toxicity. [76]. Conventional liposomes, named the first generation of liposomes, displayed a relatively short blood circulation time and mainly accumulated in the liver and spleen, via the uptake of the mononuclear phagocyte system (MPS), reducing their tumor tissue-specific targeting capacity [78]. The selection of different lipid natures and their combinations has overcome these drawbacks. The sterically stabilization of nanoliposomes with sphingomyelin/choline (SM/CHO) and the polyethylene glycol (PEG)-coated version (pegylated; Stealth) have provided a long circulation time and the ability to extravasate through the ‘leaky’ tumor vasculature by using the passive targeting. In addition, pegylated liposomes are less extensively taken up by cells of the reticuloendothelial system (RES) and have a reduced tendency to leak drugs in circulation. All of these chemical modifications allow for the accumulation of the encapsulated drug in tumor tissue compared to the first generation of liposomes [79]. To date, there are various approved nanopharmaceuticals using lipid-based nanotech- nology platforms. DoxilTM (Bridgewater, NJ, USA) was the first FDA-approved in 1995 [80]. Like DoxilTM , the liposomal-based nanoformulation CaelyxTM (Kenilworth, NJ, USA) and MyocetTM (Castleford, UK) were also approved by the EMA in 1996 and 2000, respec- tively. The three nanopharmaceuticals, DoxilTM, CaelyxTM (PEGylated), and MyocetTM (non-PEGylated), encapsulate and stably retain the chemotherapeutic doxorubicin [80]. They were formulated to improve the safety profile of Doxorubicin, which is characterized by high cardiotoxicity [80]. Their reduced cardiotoxicity allows for a larger cumulative dose than that accept- able for free doxorubicin [81–83]. Doxorubicin is an anthracycline antibiotic that is gen- erally believed to interact with the DNA by intercalation, inhibiting macromolecular biosynthesis [84]. Doxorubicin stabilizes the topoisomerase II complex after it has bro- ken the DNA chain for replication, preventing the DNA double helix from being resealed and stopping the replication process. Another reported mechanism of doxorubicin is its ability to generate free radicals that induce DNA and cell membrane damage [84]. DoxilTM , CaelyxTM, and MyocetTM exhibit a prolonged circulation time and a reduced volume of dis- tribution, thereby improving tumor uptake through the EPR effect and extending effective tumor therapy [78,79]. DoxilTM and CaelyxTM are indicated for the treatment of ovarian cancer, AIDS- related Kaposi’s sarcoma, and in combination with bortezomib, for the treatment of mul- tiple myeloma. CaelyxTM and MyocetTM are also indicated for patients with metastatic breast cancer [78]. DaunoXomeTM (Craigavon, UK) is another nanoliposomal preparation that encapsu- lates Daunorubicin, an anthracycline antibiotic with strong antineoplastic activity. Like Doxorubicin, daunorubicin activity has been attributed mainly to its intercalation between the base pairs of native DNA. It causes DNA damage such as fragmentation and single- strand breaks. There are two limiting factors in the use of anthracyclines as antitumoral agents: chronic or acute cardiotoxicity and spontaneous or acquired resistance. Daunoru- bicin has a particular affinity for phospholipids, and the development of resistance is linked to some membrane alterations [85]. The nanoformulation helps to protect Daunorubicin from chemical and enzymatic degradation in the systemic circulation, minimizing pro- Biomolecules 2022, 12, 784 12 of 27 tein binding and reducing the uptake by normal (non-reticuloendothelial system) tissues, thus increasing the accumulation in tumors by passive targeting [85]. DaunoXomeTM is indicated as a first line for advanced HIV-associated Kaposi’s sarcoma [86]. MepactTM (Cambridge, MA, USA) is the liposomal muramyl tripeptide phosphatidy- lethanolamine, Mifamurtide, an immunomodulator that activates monocytes and macrophages. MepactTM is indicated in children and young adults for the treatment of high-grade re- sectable non-metastatic osteosarcoma after complete surgical resection [87]. AmeluzTM (Leverkusen, Germany) is a gel formulation containing INN-5-aminolaevulinic acid in a nanoemulsion, enhancing its penetration into the epidermis. The substance is metabolized to protoporphyrin IX and activated by a red light, forming a reactive oxygen species and destroying the targeted cells. It is indicated for the treatment of actinic keratosis of mild to moderate intensity on the face and scalp [88]. MarqiboTM (Henderson, NV, USA) is a sphingomyelin- and cholesterol-based nanopar- ticle formulation of Vincristine. It is an antineoplastic drug with a broad spectrum of activity against hematological malignancies and childhood sarcomas. It induces neurotoxicity and peripheral neuropathy in a dose-dependent manner [89]. The liposomal carrier compo- nent facilitates the loading and retention of Vincristine; extravasation; and the slow drug releasing in the tumor microenvironment, and it improves the safety profile of vincristine, reducing its side effects [90]. It is indicated in adults with advanced, relapsed, and refractory Philadelphia chromosome-negative acute lymphoblastic leukemia [91]. OnivydeTM (Cambridge, MA, USA) is Irinotecan (DNA topoisomerase I inhibitor) is encapsulated in a lipid bilayer vesicle, which prolongs the circulation time and increases the delivery of Irinotecan in tumors with compromised vasculature. It is indicated for the treatment of the metastatic adenocarcinoma of the pancreas in patients who have progressed following Gemcitabine-based therapy. VyxeosTM (Dublin, Ireland) is a liposomal formulation of a fixed combination of Daunorubicin (inhibitor of DNA polymerase activity) and Cytarabine (a cell cycle phase- specific antineoplastic agent). It exhibits a prolonged plasma half-life and accumulates and persists in high concentration in the bone marrow. VyxeosTM is indicated as a monotherapy for the treatment of adults with high-risk acute myeloid leukemia [92]. 5.2. Protein-Based Approved Nanopharmaceuticals Protein-based nanoparticles also offer many advantages, such as biocompatibility and biodegradability. Moreover, their preparation and encapsulation processes do not require the use of toxic chemicals or organic solvents (see the detailed review in [93]). These nanoparticles can be generated using proteins such as fibroins, albumin, gelatin, gliadin, legumin, 30Kc19, lipoprotein, and ferritin proteins, with fibroin and albumin being the most widely used. As DDS, they can carry genetic materials, anticancer drugs, peptide hormones, growth factors, DNA, and RNA. In addition, protein from various sources can be manufactured into nanoparticles using an easy, cost-effective synthesis process. They are also more stable than other DDS. Moreover, the application of protein nanoparticles has shown great potential in the future [94]. Several protein-based nanoparticles have been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of cancer. Figure 2 shows the current protein-based marketed nanoparticles. OncasparTM (Suresnes, France) is the PEGylated formulation of the enzyme asparagi- nase, which breaks and reduces the blood level of the amino acid asparagine, needed for tumor cells to grow and multiply, and so its reduction in the blood causes the cells to die. Normal cells, by contrast, can produce their own asparagine and are less affected by the treatment. This nanoformulation prolongs half-life and can reduce the risk of allergic reac- tions in contrast to conventional formulations. OncasparTM is indicated for the treatment of acute lymphoblastic leukemia in adults and children [95,96]. OntakTM (Suresnes, France) is a diphtheria toxin-based recombinant fusion toxin that obtained FDA approval for clinical application in 1999. It is indicated for the treatment of Biomolecules 2022, 12, 784 13 of 27 human CD25+ cutaneous T cell lymphoma (CTCL). DT mediates its cytotoxic effect through the inhibition of protein synthesis in target cells, and it interacts with the heparin-binding epidermal growth factor receptor (HBEGFR) inducing receptor-mediated endocytosis. In the cytoplasm, the catalytic domain first binds to nicotinamide dinucleotide (NAD) and then transfers an adenosine diphosphate ribosyl (ADPR) moiety to elongation factor 2. Thus, the EF2 is irreversibly inactivated, resulting in the inhibition of protein synthesis and cell death [97,98]. Unfortunately, OntakTM immunotoxin was discontinued in 2014 due to issues related to its production process in Escherichia coli [99]. However, other approaches attempt to improve the production or enhance the potency of OntakTM -derived immunotoxins. Some T-cell malignancies overexpress IL2R, making it an ideal target for immunotoxins [100]. Recently, the development of monovalent and bivalent human IL-2 fusion toxins targeting human CD25+ cells using an advanced, unique diphtheria- toxin-resistant yeast Pichia Pastor-is expression system was reported, showing potent and selective binding affinity to cells expressing high-affinity IL-2R [99]. One of the most promis- ing candidates is E7777, which is currently being tested in Phase II and phase III clinical trials (ClinicalTrials.gov identifiers: NCT02676778 and NCT01871727, respectively) [101]. EligardTM (Milano, Italy) is Leuprorelin, a gonadotrophin-releasing hormone (GnRH) agonist. This nanopharmaceutical has a more enhanced potency and a more prolonged du- ration of action than natural GnRH. Chronic exposure results in the suppression of LH, FSH, and testosterone. EligardTM is indicated for the treatment of advanced hormone-dependent prostate cancer and breast cancer, as well as other pathologies such as endometriosis, uter- ine myoma, uterine fibrosis, and precocious puberty [102]. AbraxaneTM (New York, NY, USA) and PazenirTM (San Francisco, CA, USA) are the albumin-bound particles forms of Paclitaxel (nab-paclitaxel), which gained FDA and EMA approvals in 2005 and 2008, respectively. Paclitaxel, better known as Taxol, is the first member of the taxane family to be used in cancer chemotherapy. These compounds exert their cytotoxic effect by arresting mitosis through microtubule stabilization, resulting in cellular apoptosis. Specifically, Paclitaxel blocks cells in the G2/M phase of the cell cycle, and such cells are unable to form a normal mitotic apparatus. It is a broadly accepted option in a variety of solid tumors. Being hydrophobic, paclitaxel requires solvents (Cremophor EL or polysorbate) to enable parenteral administration. Moreover, it was reported that Cremophor EL entraps paclitaxel into circulating micelles, which reduces its availability and delivery into tumors and results in nonlinear kinetics with an absence of a dose response relationship (increasing the dose increases toxicity), which limits the efficacy [103]. However, significant toxicities, such as myelosuppression, allergic reactions, neurotox- icity, and systemic toxicity, have mainly been due to solvents, limiting the effectiveness of paclitaxel-based treatments. Both the absence of solvents and the receptor-mediated deliv- ery result in decreased toxicity and increased antitumor activity [104,105]. The nanophar- maceutical form, nab-Paclitaxel, takes advantage of the increased delivery of albumin to tumors via a receptor-mediated transport called transcytosis. Nab-Paclitaxel binds to gp60, the albumin receptor on endothelial cells, which in turn activates caveolin-1 and the formation of caveolae. Caveolae transports the albumin–paclitaxel conjugate to the extracellular space, including the tumor stroma. There, SPARC (secreted protein, acidic and rich in cysteine) that is selectively secreted by the tumors binds to albumin-bound paclitaxel with the resulting release of paclitaxel in the vicinity of tumor cells [106]. In addition, the internalized nab-paclitaxel exhibits significant immunostimulatory activities to promote the cancer-immunity cycle through the synergistic effect in T cell activation, reversing the immunosuppressive pattern of the TME) and acting synergistically with cyto- toxic lymphocytes (CTLs) in the clearance of tumor cells [107]. AbraxaneTM and PazenirTM are indicated in metastatic breast cancer, the metastatic adenocarcinoma of the pancreas, and for the treatment of non-small cell lung cancer in patients; they are not candidates for surgery and/or radiation therapy [108,109]. KadcylaTM , (Ulm, Germany) also named T-DM1 or Ado-Trastuzumab emtansine, was the first antibody-drug conjugate (ADC) approved by the FDA and EMA in 2013. It is a Biomolecules 2022, 12, 784 14 of 27 30 nm protein-based nanocompound formed by Transtuzumab, an anti-HER-2 humanized monoclonal antibody that is bound to DM-1 (emtansine, an antimicrotubular agent that blocks cellular division) [110]. KadcylaTM , as a single therapy, is indicated for the adjuvant treatment of adult patients with HER2-positive early breast cancer who have residual invasive disease [111]. It is commonly used in combination with other antineoplastics for the treatment of HER-2-positive breast tumors. Trastuzumab exerts an antitumor activity and per se binds to HER-2 receptors that belong to the family of tyrosine kinase receptors and block the cleavage of the extracellular domain, inhibiting the intracellular signaling cascades (MAPK and PI3K/Akt pathways) and, consequently, suppressing cell proliferation and tumor growth. Furthermore, this binding also promotes HER-2 receptor degradation and activates the antibody-dependent cell-mediated cytotoxicity. It is used in combination with other antineoplastics for the treatment of HER-2-positive breast tumors [111,112]. To date, a total of 11 antibody-drug conjugates apart from Kadcyla™ have been ap- proved by the FDA and EMA. [113]. Table 2 summarizes the antibody-drug conjugate trade name, target, company, approval date, and indications. It includes brentuximab ve- dotin (Adcetris™), inotuzumab ozogami-cin (Besponsa™), gemtuzumab ozogamicin (My- lotarg™), Moxetumomab pasudotox (Lumoxiti™), polatuzumab vedotin-piiq (Polivy™), Enfortumab vedotin (Padcev™), Sacituzumab govitecan (Trodelvy™), Trastuzumab derux- tecan (Enhertu™), belantamab mafodotin-blmf (Blenrep™), lon-castuximab tesirine-lpyl (ZYNLONTA™), and tisotumab vedotin-tftv (Tivdak™) [114–124]. Apart from these nanopharmaceuticals, some nanocompounds are regionally mar- keted. Lipusu™ is a non-pegylated liposome formulation containing paclitaxel. It is approved in China (2006), and it is indicated for the treatment of non-small cell lung cancer, and ovarian and breast cancers [125]. Genexol™ (Seoyoon Cheong, Korea) and Nanoxel™ (Seoyoon Cheong, Korea) were approved by South Korean (2007) and Indian agencies. They are formed by polymeric micelles and paclitaxel. They are indicated for the treatment of non-small cell lung cancer and breast cancer (in the case of Genexol™) and metastatic breast cancer, non-small cell lung, and carcinoma Kaposi’s sarcoma (in the case of Nanoxel™) [126,127]. Bevetex™ is a nanoformulation of polymeric-lipidic nanoparticles and paclitaxel, approved in India. It is indicated for the treatment of ovarian, breast, and bladder cancers, and Kaposi’s Sarcoma [128]. 5.3. Metallic-Based Approved Nanopharmaceuticals To date, NanoThermTM (Berlin, Germany) is the only metallic-based for cancer therapy that has gained FDA and EMA approvals [129]. NanoThermTM formulation is a colloidal suspension of amino silane coated with iron oxide nanoparticles suspended and distributed in 15 nm size particles [129]. Magnetic nanoparticles are introduced either directly into the tumor or into the resection cavity wall. They are subsequently heated by an alternat- ing magnetic field, thus destroying the cancer cells or sensitizing them for concomitant radiotherapy or chemotherapy applications to avoid recurrences. This nanoparticle formu- lation is indicated for the treatment of primary or recurrent glioblastoma multiforme and prostate cancer [130]. Biomolecules 2022, 12, 784 15 of 27 Table 2. The approved antibody drug conjugates for cancer therapy. Drug ProductTM Molecular Target Cell Targeting Company Approval (Year) Indication Myeloid stem cells, myeloblasts, monoblasts, Gemtuzumab ozogamicin Mylotarg CD33 monocytes/macrophages, Pfizer/Wyeth 2017; 2000 Relapsed acute myelogenous leukemia (AML) granulocyte precursors, and mast cells Seattle Genetics, Brentuximab vedotin Adcetris CD30 Lymphoid cells Millennium/ 2011 Relapsed HL and relapsed sALCL Takeda Relapsed or refractory CD22-positive B-cell precursor Inotuzumab ozogamicin Besponsa CD22 B-cells Pfizer/Wyeth 2017 acute lymphoblastic leukemia Moxetumomab pasudotox Lumoxiti CD22 Leukemia cells Astrazeneca 2018 Relapsed or refractory hairy cell leukemia (HCL) Relapsed or refractory (R/R) diffuse large B-cell Polatuzumab vedotin-piiq Polivy CD79 B-cells Genentech, Roche 2019 lymphoma (DLBCL) Locally advanced or metastatic urothelial cancer who Enfortumab vedotin Padcev Nectin-4 Cancer cells Astellas/ 2019 Seattle Genetics have received a PD-1 or PD-L1 inhibitor, and a Paclitaxel-containing therapy Unresectable or metastatic HER2-positive breast cancer Trastuzumab deruxtecan Enhertu HER2 Cancer cells AstraZeneca/ 2019 patients who have received two or more prior Daiichi Sankyo anti-HER2-based regimens Metastatic triple-negative breast cancer (mTNBC) patients who have received at least two prior therapies Sacituzumab govitecan Trodelvy Trop-2 Cancer cells Immunomedics 2020 (for patients with relapsed or refractory metastatic disease) Belantamab mafodotin-blmf Blenrep BCMA B-cells GlaxoSmithKline 2020 Relapsed or refractory multiple myeloma Loncastuximab tesirine-lpyl Zynlonta CD19 B cells and follicular ADC Therapeutics 2021 Large B-cell lymphoma dendritic cells Tisotumab vedotin-tftv Tivdak Tissue factor Cancer and stroma Seagen Inc 2021 Recurrent or metastatic cervical cancer cells of TME Biomolecules 2022, 12, 784 16 of 27 6. Nanopharmaceuticals in Clinical Trials for Cancer Therapy Nanomedicine is constantly expanding. Since the early 2000s, almost 30,000 articles have been published, including original research (source MEDLINE/PubMed) and new nanopharmaceuticals for therapy enter clinical investigation every year. Most of them are anticancer and antimicrobial nanodrugs [131]. Concerning only cancer therapy, as of 2021, 55 clinical trials, including the term “nano”, were listed in phase I/II on ClinicalTrials.gov (accessed on 9 May 2022) [132] (Supplementary Table S1). Most of the nanopharmaceuticals are new versions of previously approved low-weight drugs and nanoparticles that have already been proven to be successful, such as liposomes and polymers [133]. The remainder of the investigational nanodrugs demonstrate a trend toward agents using micelles, as Biomolecules 2022, 12, 784 19 of 30 well as the introduction of formulations using dendrimers; meanwhile, polymer-based nanopharmaceuticals are less prevalent. Although the majority of FDA-approved nan- odrugs relied on passive targeting via the EPR effect, next-generation drugs in clinical can offer trials synergistic employ advantages active targeting in comparison approaches (Figureto 3standard imaging or treatment and Supplementary Table S1) alone. [134]. They cannew Another facilitate trendthe diagnosis is the changeandfromtreatment relativelyofsimple diseases at an early stage, nanoparticles provide to complex andin- teresting information on drug distribution to target sites, and enable the multicomponent drug-delivery platforms [135]. In this regard, modern approaches to monitoring of the response protein to therapy.asThey engineering, wellare the most promising as advances in polymercandidates for their and inorganic application chemistry, in a have also personalized resulted in andisease expansion[138]. of novel nanomaterials. This has allowed the initial goals for nanopharmaceuticals To date, several(improved PK,are theranostics efficacy, and safety) in clinical to evolve trials, and some into system of them aredesigns that expected to allow for morefor be approved complex clinicalfunctions, suchshort use in a very as controlled release and active time (Supplementary Table targeting S1. [135]. Figure3.3.The Figure Thestatus statusof ofclinical clinical trials trials using using nano–based nano–basedformulations formulationsfor forcancer cancertherapy. therapy.The Thenumber number ofthe of the total total and and complete completeclinical clinicaltrials, trials,currently currentlyregistered registeredonon www. clinicaltrials.gov (accessed www.clinicaltrials.gov on (accessed 28 April 2022), undergoing nano-based drugs treatment alone or in combination with other thera- on 28 April 2022), undergoing nano-based drugs treatment alone or in combination with other peutics during the periods 1995–2015 and 2015–2021. The results are expressed as the number of therapeutics during the periods 1995–2015 and 2015–2021. The results are expressed as the number of clinical trials divided by the number of years per period. In the last 10 years, second-generation DDS clinical trials divided using active targetingbyhave the number been theofmostyears per period. widely testedIn the lastin10clinical systems years, second-generation trials. DDS using active targeting have been the most widely tested systems in clinical trials. 7. Future Perspectives of Nanopharmaceuticals Targeting TME On the other hand, inorganic nanoparticles (INPs) have been extensively utilized for Active diagnostic targetingFor purposes. hasexample, become gold the new trend in nanomedicine. nanoparticles (AuNPs) have Itbeenhaswidely reachedstudied a high level of precision and selectivity by exploiting molecules overexpressed just on due to their biocompatibility and the ease of controlling their size distribution and shape. the cancer cell surface, which Furthermore, facilitates the surface the uptake chemistry of nanoparticles of AuNPs in tumor can also be easily cells.through modified In addition, new conjuga- targets tion withhave emerged various in recent polymers, years to antibodies, become promising small-molecule strategies therapeutics, andfor cancer therapy. molecular probes. Combining Another CSC marker prevalent type of targeting INP includes andiron drugs loaded oxide onto nanomaterials nanoparticles can be (IONPs), which effective have been against CSCs, increasing specificity and selectivity. Novel tools that aim to detect, widely used for diagnostic imaging [136]. In this context, another trend is the incorporation charac- terize, of and eliminate theranostics CSCs with under clinical enhanced trials. They areefficacy are ongoing multifunctional [139,140]. A considerable nanocompounds, which are number of different well-designed nanoparticles by combining have and diagnostic beentherapeutic evaluated, from anti-CSC capabilities intoADCs [141], a single to na- biocom- noparticle-based RNAi [142], to nano-based thermotherapy [143]. Furthermore, accumulating evidence shows that the tumor microenvironment can re-program tumor initiation, growth, invasion, metastasis, and responses to therapies. In- vestigation and treatment have switched from a tumor cell model to a TME one, consid- ering the increasing significance of TME in cancer biology. A promising strategy for TME Biomolecules 2022, 12, 784 17 of 27 patible and biodegradable nanoparticle [136,137]. This combination can offer synergistic advantages in comparison to standard imaging or treatment alone. They can facilitate the diagnosis and treatment of diseases at an early stage, provide interesting information on drug distribution to target sites, and enable the monitoring of the response to therapy. They are the most promising candidates for their application in a personalized disease [138]. To date, several theranostics are in clinical trials, and some of them are expected to be approved for clinical use in a very short time (Supplementary Table S1). 7. Future Perspectives of Nanopharmaceuticals Targeting TME Active targeting has become the new trend in nanomedicine. It has reached a high level of precision and selectivity by exploiting molecules overexpressed just on the cancer cell surface, which facilitates the uptake of nanoparticles in tumor cells. In addition, new targets have emerged in recent years to become promising strategies for cancer therapy. Combining CSC marker targeting and drugs loaded onto nanomaterials can be effective against CSCs, increasing specificity and selectivity. Novel tools that aim to detect, characterize, and eliminate CSCs with enhanced efficacy are ongoing [139,140]. A considerable number of different nanoparticles have been evaluated, from anti-CSC ADCs [141], to nanoparticle- based RNAi [142], to nano-based thermotherapy [143]. Furthermore, accumulating evidence shows that the tumor microenvironment can re-program tumor initiation, growth, invasion, metastasis, and responses to therapies. In- vestigation and treatment have switched from a tumor cell model to a TME one, considering the increasing significance of TME in cancer biology. A promising strategy for TME target- ing is the use of TAM-directed radiotracers and iron oxide nanoparticles for monitoring cancer immunotherapies with PET and MRI technologies. TAM-directed imaging probes can be designed to include immune-modulating properties, thereby leading to combined diagnostic and therapeutic (theranostic) effects [144]. 8. Challenges in the Clinical Translation of Nanopharmaceuticals Nanotechnology is very promising in the development of cancer therapies; however, it is important to address several issues for clinical use. 8.1. Costs, Production, and Toxicology Limitations Economic issues are key challenges to guaranteeing the success of nanopharmaceuti- cals. The high costs of the raw materials and the production process make their products very expensive. For example, the manufacturing of drugs such as AbraxaneTM and DoxilTM is far more expensive than the production of their free-drug counterparts (paclitaxel and doxorubicin) [145]. The entire process of commercializing a novel nanodrug is estimated to last for more than 10–15 years and cost around $1 billion [146]. Thus, the clinical benefits of nanomedicines should be clear to justify higher prices compared to conventional thera- peutics [147]. The scalable and controlled manufacturing of nanomedicines under good manufacturing practices (GMP) conditions presents unique challenges since even small variations in the process can significantly affect properties such as size, shape, composition, drug loading and release, biocompatibility, toxicity, and the in vivo outcome [148–150]. Therefore, nanomedicine products should be characterized on a batch-to-batch basis, using multiple methods. Moreover, nanomedicines intended for humans must deal with special issues such as their sterility [151]; thus, finding appropriate sterilization but not compromising the physicochemical properties and stability of the therapeutic molecules is one of the major challenges in nanomedicine development. Nanomedicines based on biological molecules such as proteins require special consideration due to their high susceptibility to degra- dation by sterilization techniques [152]. In this context, special consideration must be taken to the contamination by endotoxin. Endotoxin can lead to serious health issues, and more than 30% of nanoformulations fail in early preclinical development owing to endotoxin contamination [153]. Thus, the endotoxin level of nanomedicines must be care- Biomolecules 2022, 12, 784 18 of 27 fully evaluated using appropriate methods [154]. The characterization of the stability and storage aspects (shelf-life) of nanomedicine products is also challenging [155]. More- over, storage conditions in aqueous solutions or even in a lyophilized form can alter the nanomedicine properties [156]. The toxicological effects of nanomaterials must be evaluated, but some toxic effects are not yet completely known. Some derived toxicological data conflict and are inconsistent, except for a few observations reported so far. It is mandatory to implement guidelines to standardize preclinical nanomedicine research, which could promote reproducibility, quan- titative comparisons, meta-analyses, and modeling, which would increase the applicability, cost, efficacy, and toxicity of nanoformulations and help to translate basic research into clinical practice in a very short time. In addition, regulatory issues are relevant for the de- velopment of technologies to characterize nanopharmaceuticals and monitor their quality. Regulatory decisions on nanomedicine therapeutics are based on the individual assessment of benefits and risks, a process that is time-consuming and may result in regulatory delays for nanomedicine products [157]. These actions should include integrating efforts from international consortia comprising academics, clinicians, pharmaceutical companies, and regulatory authorities to increase the clinical impact and patient performance of these antitumoral nanopharmaceuticals. 8.2. Clinical Translation of Nanopharmaceuticals Numerous new papers evaluating a great variety of nanoformulations have been published lately, ranging from inorganic to organic nanoparticles, of several formulation and fabrication procedures and achieving high versatility, controllable size, and shape. They are functionalized for targeted therapy and are loaded with several chemotherapeutics and active molecules. However, good results in preclinical studies are in contrast with the low rate of clinical translation. In fact, a few nano-based drugs have been currently approved for use in clinics. Van der Meel and colleagues [158] proposed several strategic directions: firstly, the application of smart strategies for patient stratification in cancer nanomedicine, including probes and protocols to assess the tumor microenvironment, and imaging-based tumor accumulation, which may identify individuals suitable for inclusion in clinical trials, leading to refined clinical trials. Secondly, they proposed using smart strategies for modular (pro)drug and drug-delivery system design, as well as library screening, which will help to maximize the chances of formulations developed and tested preclinically, and, finally, they reported that the careful rational design of pharmacological combination regimens will amplify the pharmacokinetic and/or pharmacodynamic benefits. These smart strategies will improve nanomedicine performance, translation, and exploitation. 9. FDA and EMA Regulatory Guidelines The FDA, in collaboration with the National Nanotechnology Institute (NNI) and the Nanotechnology Characterization Laboratory (NCL) in the U.S., has developed programs to coordinate efforts in nanoscale science, engineering, and technology. The FDA programs include draft guidance for the industry and a series of five “Final Guidances” related to nanotechnology products. These documents discuss the use of nanotechnology or nanomaterials in FDA-regulated products [159]. The FDA participates in many activities intended to implement a science-based approach to the regulation of products that involve nanomaterials or applications of nanotechnology, builds regulatory science knowledge, and facilitates collaborations and partnerships with stakeholders. It also facilitates innovation, helps ensure timely and clear communication regarding FDA’s nanotechnology activities, and safeguards the public’s health. Similarly, the EMA, in collaboration with the European Technology Platform on Nanomedicine (ETPN) and the European Nano-characterization Laboratory (EU-NCL), is also working to create regulatory guidelines for the evaluation of nanomedicine products. In 2011, the Committee for Medicinal Products for Human Use (CHMP) commissioned the EMA to develop a series of four reflection papers on current scientific and regulatory thinking for nanomedicines [160]. Both the FDA and Biomolecules 2022, 12, 784 19 of 27 EMA are members of the Innovation Task Force (ITF), which is an international and multidisciplinary group that includes scientific, regulatory, and legal competencies for nanotechnology products [161]. Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/biom12060784/s1, Table S1: the current nanopharmaceuticals for cancer therapy in clinical assays [162–210]. Author Contributions: Conceptualization, J.L.C. and M.V.C.; methodology, F.R., P.C., R.R. (Ramón Rovira) and M.G.; software, F.R., P.C., R.R. (Raúl Ruiz) and J.B.; investigation, F.R., P.C., N.D.l.F., P.E., M.G., C.M.-L. and E.L.; resources, F.R., P.C., C.M.-L. and J.B.; writing—original draft preparation, F.R., R.R. (Raúl Ruiz), N.D.l.F. and R.R. (Ramón Rovira); writing—review and editing, J.L.C., M.V.C., E.L. and R.R. (Ramón Rovira); supervision, J.L.C. and M.V.C.; project administration, J.L.C. and M.V.C.; funding acquisition, J.L.C., E.L. and M.V.C. All authors have read and agreed to the published version of the manuscript. Funding: This work was supported by the Spanish “Ministerio de Ciencia, Innovación y Universi- dades”, and “Instituto de Salud Carlos III” through the projects PI17/00553, PI17/00150, PI20/00770, and PI20/00623 and through RICORS RD21/0012/0001 (co-funded by the European Regional De- velopment Fund, “A way to make Europe”). The authors also acknowledge the support of the Fundación Mutua Madrileña (FMMA) through the project “Targeted therapy for selective elimi- nation of metastatic stem cells CXCR4+ in endometrial cancer” (AP1666942017), from Asociación Española contra el cancer (AECC) through the project “Development of an antitumor protein de- livery system into ovarian cancer cells using the subcellular vault” (IDEAS18038BENI), and from CIBER-BBN through the project “Design of protein nanomedicines for targeted therapies in pancre- atic cancer” (PANCREATOR). The Networking Research Center on Bioengineering, Biomaterials, and Nanomedicine (CIBERBBN) is an initiative funded by the VI National R&D&I Plan 2008–2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Conflicts of Interest: The authors declare no conflict of interest. References 1. Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer Statistics, 2021. CA Cancer J. Clin. 2021, 71, 7–33. [CrossRef] 2. Cooper, G.M. The Cell: A Molecular Approach. In The Development and Causes of Cancer, 2nd ed.; Sinauer Associates: Sunderland, MA, USA, 2000. Available online: https://www.ncbi.nlm.nih.gov/books/NBK9963/ (accessed on 1 January 2020). 3. De Jong, W.H.; Borm, P.J. Drug delivery and nanoparticles:applications and hazards. Int. J. Nanomed. 2008, 3, 133–149. [CrossRef] 4. Misra, R.; Acharya, S.; Sahoo, S.K. Cancer nanotechnology: Application of nanotechnology in cancer therapy. Drug Discov. Today 2010, 19, 842–850. [CrossRef] 5. Martinelli, C.; Pucci, C.; Ciofani, G. Nanostructured carriers as innovative tools for cancer diagnosis and therapy. APL Bioeng. 2019, 3, 011502. [CrossRef] 6. Yingchoncharoen, P.; Kalinowski, D.S.; Richardson, D.R. Lipid-Based Drug Delivery Systems in Cancer Therapy: What Is Available and What Is Yet to Come. Pharmacol. Rev. 2016, 68, 701–787. [CrossRef] 7. Mitchell, M.J.; Billingsley, M.M.; Haley, R.M.; Wechsler, M.E.; Peppas, N.A.; Langer, R. Engineering precision nanoparticles for drug delivery. Nat. Rev. Drug Discov. 2020, 20, 101–124. [CrossRef] 8. Xu, X.; Ho, W.; Zhang, X.; Bertrand, N.; Farokhzad, O. Cancer nanomedicine: From targeted delivery to combination therapy. Trends Mol. Med. 2015, 21, 223–232. [CrossRef] 9. Zhu, Y.; Zhou, Y.; Xie, Y.; Song, P.; Ma, X. Signaling Pathways Associated with Cancer Stem Cells Play a Significant Role in Immunotherapy Resistance. J. Oncol. Res. 2019, 1, 1–10. [CrossRef] 10. Dagogo-Jack, I.; Shaw, A.T. Tumour heterogeneity and resistance to cancer therapies. Nat. Rev. Clin. Oncol. 2018, 15, 81–94. [CrossRef] 11. Roma-Rodrigues, C.; Mendes, R.; Baptista, P.V.; Fernandes, A.R. Targeting Tumor Microenvironment for Cancer Therapy. Int. J. Mol. Sci. 2019, 20, 840. [CrossRef] 12. Pucci, C.; Martinelli, C.; Ciofani, G. Innovative approaches for cancer treatment: Current perspectives and new challenges. Ecancermedicalscience 2019, 13, 961. [CrossRef] [PubMed] 13. Batlle, E.; Clevers, H. Cancer stem cells revisited. Nat. Med. 2017, 23, 1124–1134. [CrossRef] [PubMed] Biomolecules 2022, 12, 784 20 of 27 14. Lytle, N.K.; Barber, A.G.; Reya, T. Stem cell fate in cancer growth, progression and therapy resistance. Nat. Rev. Cancer 2018, 18, 669–680. [CrossRef] [PubMed] 15. Yu, Z.; Pestell, T.G.; Lisanti, M.P.; Pestell, R.G. Cancer stem cells. Int. J. Biochem. Cell Biol. 2012, 44, 2144–2151. [CrossRef] 16. Nguyen, L.V.; Vanner, R.; Dirks, P.; Eaves, C.J. Cancer stem cells: An evolving concept. Nat. Rev. Cancer 2012, 12, 133–143. [CrossRef] 17. Pardal, R.; Clarke, M.F.; Morrison, S.J. Applying the principles of stem-cell biology to cancer. Nat. Rev. Cancer 2003, 3, 895–902. [CrossRef] 18. Dianat-Moghadam, H.; Heidarifard, M.; Jahanban-Esfahlan, R.; Panahi, Y.; Hamishehkar, H.; Pouremamali, F.; Rahbarghazi, R.; Nouri, M. Cancer stem cells-emanated therapy resistance: Implications for liposomal drug delivery systems. J. Control. Release 2018, 288, 62–83. [CrossRef] 19. Valent, P.; Bonnet, D.; De Maria, R.; Lapidot, T.; Copland, M.; Melo, J.V.; Chomienne, C.; Ishikawa, F.; Schuringa, J.J.; Stassi, G.; et al. Cancer stem cell definitions and terminology: The devil is in the details. Nat. Rev. Cancer 2012, 12, 767–775. [CrossRef] [PubMed] 20. Mashima, T. Cancer Stem Cells (CSCs) as a Rational Therapeutic Cancer Target, and Screening for CSC-targeting Drugs. Yakugaku Zasshi 2017, 137, 129–132. [CrossRef] [PubMed] 21. Yang, L.; Shi, P.; Zhao, G.; Xu, J.; Peng, W.; Zhang, J.; Zhang, G.; Wang, X.; Dong, Z.; Chen, F.; et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct. Target. Ther. 2020, 5, 1–35. [CrossRef] 22. Takebe, N.; Harris, P.J.; Warren, R.Q.; Ivy, S.P. Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nat. Rev. Clin. Oncol. 2011, 8, 97–106. [CrossRef] [PubMed] 23. Zhang, D.; Tang, D.G.; Rycaj, K. Cancer stem cells: Regulation programs, immunological properties and immunotherapy. Semin. Cancer Biol. 2018, 52, 94–106. [CrossRef] 24. Visvader, J.E.; Lindeman, G.J. Cancer stem cells in solid tumours: Accumulating evidence and unresolved questions. Nat. Rev. Cancer 2008, 8, 755–768. [CrossRef] [PubMed] 25. Phi, L.T.H.; Sari, I.N.; Yang, Y.G.; Lee, S.H.; Jun, N.; Kim, K.S.; Lee, Y.K.; Kwon, H.Y. Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment. Stem Cells Int. 2018, 2018, 5416923. [CrossRef] [PubMed] 26. Prieto-Vila, M.; Takahashi, R.U.; Usuba, W.; Kohama, I.; Ochiya, T. Drug resistance driven by cancer stem cells and their niche. Int. J. Mol. Sci. 2017, 18, 2574. [CrossRef] 27. Lenos, K.J.; Miedema, D.M.; Lodestijn, S.C.; Nijman, L.E.; van den Bosch, T.; Romero Ros, X.; Lourenço, F.C.; Lecca, M.C.; van der Heijden, M.; van Neerven, S.M.; et al. Stem cell functionality is microenvironmentally defined during tumour expansion and therapy response in colon cancer. Nat. Cell Biol. 2018, 20, 1193–1202. [CrossRef] 28. Giraldo, N.A.; Sanchez-Salas, R.; Peske, J.D.; Vano, Y.; Becht, E.; Petitprez, F.; Validire, P.; Ingels, A.; Cathelineau, X.; Fridman, W.H.; et al. The clinical role of the TME in solid cancer. Br. J. Cancer 2019, 120, 45–53. [CrossRef] 29. Hayat, H.; Hayat, H.; Francis, B.; Gudi, D.M.; Bishop, J.O.; Wang, P. Concise Review: The Role of Stem Cells in Cancer Progression and Therapy. Onco Targets Ther. 2021, 14, 2761–2772. [CrossRef] 30. Medema, J.P. Targeting the Colorectal Cancer Stem Cell. N. Engl. J. Med. 2017, 377, 888–890. [CrossRef] 31. Ayob, A.Z.; Ramasamy, T.S. Cancer stem cells as key drivers of tumour progression. J. Biomed. Sci. 2018, 25, 20. [CrossRef] 32. Zhang, C.L.; Huang, T.; Wu, B.L.; He, W.X.; Liu, D. Stem cells in cancer therapy: Opportunities and challenges. Oncotarget 2017, 8, 75756–75766. [CrossRef] [PubMed] 33. Dzobo, K.; Senthebane, D.A.; Ganz, C.; Thomford, N.E.; Wonkam, A.; Dandara, C. Advances in Therapeutic Targeting of Cancer Stem Cells within the Tumor Microenvironment: An Updated Review. Cells 2020, 9, 1896. [CrossRef] [PubMed] 34. Tabassum, N.; Verma, V.; Kumar, M.; Kumar, A.; Singh, B. Nanomedicine in cancer stem cell therapy: From fringe to forefront. Cell Tissue Res. 2018, 374, 427–438. [CrossRef] 35. Balkwill, F.R.; Capasso, M.; Hagemann, T. The tumor microenvironment at a glance. J. Cell Sci. 2012, 125, 5591–5596. [CrossRef] 36. Wang, J.J.; Lei, K.F.; Han, F. Tumor microenvironment: Recent advances in various cancer treatments. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 3855–3864. [CrossRef] 37. Valkenburg, K.C.; De Groot, A.E.; Pienta, K.J. Targeting the tumour stroma to improve cancer therapy. Nat. Rev. Clin. Oncol. 2018, 15, 366–381. [CrossRef] 38. Bazak, R.; Houri, M.; El Achy, S.; Kamel, S.; Refaat, T. Cancer active targeting by nanoparticles: A comprehensive review of literature. J. Cancer Res. Clin. Oncol. 2015, 141, 769–784. [CrossRef] 39. De Palma, M.; Biziato, D.; Petrova, T.V. Microenvironmental regulation of tumour angiogenesis. Nat. Rev. Cancer 2017, 17, 457–474. [CrossRef] 40. Saman, H.; Raza, S.S.; Uddin, S.; Rasul, K. Inducing Angiogenesis, a Key Step in Cancer Vascularization, and Treatment Approaches. Cancers 2020, 12, 1172. [CrossRef] [PubMed] 41. Senthebane, D.A.; Rowe, A.; Thomford, N.E.; Shipanga, H.; Munro, D.; Mazeedi, M.A.M.A.; Almazyadi, H.A.M.; Kallmeyer, K.; Dandara, C.; Pepper, M.S.; et al. The Role of Tumor Microenvironment in Chemoresistance: To Survive, Keep Your Enemies Closer. Int. J. Mol. Sci. 2017, 18, 1586. [CrossRef] [PubMed] 42. Biswas, S.; Guix, M.; Rinehart, C.; Dugger, T.C.; Chytil, A.; Moses, H.L.; Freeman, M.L.; Arteaga, C.L. Inhibition of TGF-beta with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression. J. Clin. Investig. 2007, 117, 1305–1313. [CrossRef] Biomolecules 2022, 12, 784 21 of 27 43. Domanska, U.M.; Boer, J.C.; Timmer-Bosscha, H.; van Vugt, M.A.; Hoving, H.D.; Kliphuis, N.M.; Rosati, S.; van der Poel, H.G.; de Jong, I.J.; de Vries, E.G.; et al. CXCR4 inhibition enhances radiosensitivity, while inducing cancer cell mobilization in a prostate cancer mouse model. Clin. Exp. Metastasis 2014, 31, 829–839. [CrossRef] 44. Domanska, U.M.; Timmer-Bosscha, H.; Nagengast, W.B.; Oude Munnink, T.H.; Kruizinga, R.C.; Ananias, H.J.; Kliphuis, N.M.; Huls, G.; De Vries, E.G.; de Jong, I.J.; et al. CXCR4 inhibition with AMD3100 sensitizes prostate cancer to docetaxel chemotherapy. Neoplasia 2012, 14, 709–718. [CrossRef] [PubMed] 45. Gozgit, J.M.; Wong, M.J.; Moran, L.; Wardwell, S.; Mohemmad, Q.K.; Narasimhan, N.I.; Shakespeare, W.C.; Wang, F.; Clackson, T.; Rivera, V.M. Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models. Mol. Cancer Ther. 2012, 11, 690–699. [CrossRef] 46. Tayoun, T.; Faugeroux, V.; Oulhen, M.; Aberlenc, A.; Pawlikowska, P.; Farace, F. CTC-Derived Models: A Window into the Seeding Capacity of Circulating Tumor Cells (CTCs). Cells 2019, 8, 1145. [CrossRef] 47. Nassar, D.; Blanpain, C. Cancer Stem Cells: Basic Concepts and Therapeutic Implications. Annu. Rev. Pathol. 2016, 11, 47–76. [CrossRef] [PubMed] 48. Ganesh, K.; Massagué, J. Targeting metastatic cancer. Nat. Med. 2021, 27, 34–44. [CrossRef] [PubMed] 49. Dean, M.; Fojo, T.; Bates, S. Tumour stem cells and drug resistance. Nat. Rev. Cancer 2005, 5, 275–284. [CrossRef] 50. Shi, Y.; Riese, D.J.; Shen, J. The Role of the CXCL12/CXCR4/CXCR7 Chemokine Axis in Cancer. Front. Pharmacol. 2020, 11, 574667. [CrossRef] [PubMed] 51. Yang, P.; Hu, Y.; Zhou, Q. The CXCL12-CXCR4 Signaling Axis Plays a Key Role in Cancer Metastasis and is a Potential Target for Developing Novel Therapeutics against Metastatic Cancer. Curr. Med. Chem. 2020, 27, 5543–5561. [CrossRef] [PubMed] 52. Hermann, P.C.; Huber, S.L.; Herrler, T.; Aicher, A.; Ellwart, J.W.; Guba, M.; Bruns, C.J.; Heeschen, C. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 2007, 1, 313–323. [CrossRef] 53. Céspedes, M.V.; Unzueta, U.; Aviñó, A.; Gallardo, A.; Álamo, P.; Sala, R.; Sánchez-Chardi, A.; Casanova, I.; Mangues, M.A.; Lopez-Pousa, A.; et al. Selective depletion of metastatic stem cells as therapy for human colorectal cancer. EMBO Mol. Med. 2018, 10, e8772. [CrossRef] 54. Gzil, A.; Zar˛ebska, I.; Bursiewicz, W.; Antosik, P.; Grzanka, D.; Szylberg, Ł. Markers of pancreatic cancer stem cells and their clinical and therapeutic implications. Mol. Biol. Rep. 2019, 46, 6629–6645. [CrossRef] [PubMed] 55. Fruehauf, S. Current clinical indications for plerixafor. Transfus. Med. Hemother. 2013, 40, 246–250. [CrossRef] 56. Thomas, O.S.; Weber, W. Overcoming Physiological Barriers to Nanoparticle Delivery-Are We There Yet? Front. Bioeng. Biotechnol. 2019, 7, 415. [CrossRef] [PubMed] 57. Upreti, M.; Jyoti, A.; Sethi, P. Tumor microenvironment and nanotherapeutics. Transl. Cancer Res. 2013, 2, 309. [CrossRef] [PubMed] 58. Barua, S.; Mitragotri, S. Challenges associated with Penetration of Nanoparticles across Cell and Tissue Barriers: A Review of Current Status and Future Prospects. Nano Today 2014, 9, 223. [CrossRef] 59. Xu, S.; Olenyuk, B.Z.; Okamoto, C.T.; Hamm-Alvarez, S.F. Targeting receptor-mediated endocytotic pathways with nanoparticles: Rationale and advances. Adv. Drug Deliv. Rev. 2013, 65, 121–138. [CrossRef] 60. Huang, S.; Kauffman, S. How to escape the cancer attractor: Rationale and limitations of multi-target drugs. Semin. Cancer Biol. 2013, 23, 270–278. [CrossRef] 61. Torchilin, V.P. Drug targeting. Eur. J. Pharm. Sci. 2000, 11 (Suppl. 2), S81–S91. [CrossRef] 62. Pethe, A.M.; Yadav, K.S. Polymers, responsiveness and cancer therapy. Artif. Cells Nanomed. Biotechnol. 2019, 47, 395–405. [CrossRef] [PubMed] 63. Cho, K.; Wang, X.; Nie, S.; Chen, Z.G.; Shin, D.M. Therapeutic nanoparticles for drug delivery in cancer. Clin. Cancer Res. 2008, 14, 1310–1316. [CrossRef] [PubMed] 64. Torchilin, V.P. Passive and active drug targeting: Drug delivery to tumors as an example. Handb. Exp. Pharmacol. 2010, 197, 3–53. [CrossRef] 65. Heshmati, N.; Dabbaghianamiri, M.; Tunnell, J.W.; Betancourt, T. Design of Smart Nanomedicines for Effective Cancer Treatment. Int. J. Pharm. 2022, 621, 121791. [CrossRef] [PubMed] 66. Vácha, R.; Martinez-Veracoechea, F.J.; Frenkel, D. Receptor-mediated endocytosis of nanoparticles of various shapes. Nano Lett. 2011, 11, 5391–5395. [CrossRef] 67. Richards, D.A.; Maruani, A.; Chudasama, V. Antibody fragments as nanoparticle targeting ligands: A step in the right direction. Chem. Sci. 2016, 8, 63–77. [CrossRef] 68. Bouchard, P.R.; Hutabarat, R.M.; Thompson, K.M. Discovery and development of therapeutic aptamers. Annu. Rev. Pharmacol. Toxicol. 2010, 50, 237–257. [CrossRef] 69. Gold, L.; Ayers, D.; Bertino, J.; Bock, C.; Bock, A.; Brody, E.N.; Carter, J.; Dalby, A.B.; Eaton, B.E.; Fitzwater, T.; et al. Aptamer-based multiplexed proteomic technology for biomarker discovery. PLoS ONE 2010, 5, e15004. [CrossRef] 70. Jhaveri, A.; Deshpande, P.; Torchilin, V. Stimuli-sensitive nanopreparations for combination cancer therapy. J. Control. Release 2014, 190, 352–370. [CrossRef] 71. Rahim, M.A.; Jan, N.; Khan, S.; Shah, H.; Madni, A.; Khan, A.; Jabar, A.; Khan, S.; Elhissi, A.; Hussain, Z. Recent Advancements in Stimuli Responsive Drug Delivery Platforms for Active and Passive Cancer Targeting. Cancers 2021, 13, 670. [CrossRef] Biomolecules 2022, 12, 784 22 of 27 72. Torchilin, V. Multifunctional and stimuli-sensitive pharmaceutical nanocarriers. Eur. J. Pharm. Biopharm. 2009, 7, 431–444. [CrossRef] 73. Fomina, N.; McFearin, C.; Sermsakdi, M.; Edigin, O.; Almutairi, A. UV and near-IR triggered release from polymeric nanoparticles. J. Am. Chem. Soc. 2010, 132, 9540–9542. [CrossRef] [PubMed] 74. Ribeiro, T.P.; Moreira, J.A.; Monterio, F.J.; Laranjeira, M.S. Nanomaterials in cancer: Reviewing the combination of hyperthermia and triggered chemotherapy. J. Control. Release 2022, S0168–S3659, 240–241. [CrossRef] 75. Farjadian, F.; Ghasemi, A.; Gohari, O.; Roointan, A.; Karim, M.; Hamblin, M.R. Nanopharmaceuticals and nanomedicines currently on the market: Challenges and opportunities. Nanomedicine 2019, 14, 93–126. [CrossRef] 76. Cattel, L.; Ceruti, M.; Dosio, F. From conventional to stealth liposomes: A new frontier in cancer chemotherapy. J. Chemother. 2004, 16, 94–97. [CrossRef] 77. Immordino, M.L.; Brusa, P.; Arpicco, S.; Stella, B.; Dosio, F.; Cattel, L. Preparation, characterization, cytotoxicity and pharmacoki- netics of liposomes containing docetaxel. J. Control. Release 2003, 91, 417–429. [CrossRef] 78. Jensen, G.M.; Hodgson, D.F. Opportunities and challenges in commercial pharmaceutical liposome applications. Adv. Drug Deliv. Rev. 2020, 154, 2–12. [CrossRef] 79. Tereshkina, Y.A.; Torkhovskaya, T.I.; Tikhonova, E.G.; Kostryukova, L.V.; Sanzhakov, M.A.; Korotkevich, E.I.; Khudoklinova, Y.Y.; Orlova, N.A.; Kolesanova, E.F. Nanoliposomes as drug delivery systems: Safety concerns. J. Drug Target. 2022, 30, 313–325. [CrossRef] [PubMed] 80. DOXIL approved by FDA. AIDS Patient Care 1995, 9, 306. Available online: https://pubmed.ncbi.nlm.nih.gov/11361446/ (accessed on 4 April 2022). 81. Barenholz, Y. Doxil® -the first FDA-approved nano-drug: Lessons learned. J. Control. Release 2012, 160, 117–134. [CrossRef] 82. Makwana, V.; Karanjia, J.; Haselhorst, T.; Anoopkumar-Dukie, S.; Rudrawar, S. Liposomal doxorubicin as targeted delivery platform: Current trends in surface functionalization. Int. J. Pharm. 2021, 593, 120117. [CrossRef] 83. Perez, A.T.; Domenech, G.H.; Frankel, C.; Vogel, C.L. Pegylated liposomal doxorubicin (Doxil) for metastatic breast cancer: The Cancer Research Network, Inc., experience. Cancer Investig. 2002, 20, 22–29. [CrossRef] 84. Rom, J.; Bechstein, S.; Domschke, C.; Golatta, M.; Mayer, C.; Heil, J.; Thum, J.; Smetanay, K.; Windemuth-Kieselbach, C.; Wallwiener, M.; et al. Efficacy and toxicity profile of pegylated liposomal doxorubicin (Caelyx) in patients with advanced breast cancer. Anti-Cancer Drugs 2014, 25, 219–224. [CrossRef] [PubMed] 85. Aubel-Sadron, G.; Londos-Gagliardi, D. Daunorubicin and doxorubicin, anthracycline antibiotics, a physicochemical and biological review. Biochimie 1984, 66, 333–352. [CrossRef] 86. Fassas, A.; Anagnostopoulos, A. The use of liposomal daunorubicin (DaunoXome) in acute myeloid leukemia. Leuk. Lymphoma 2005, 46, 795–802. [CrossRef] [PubMed] 87. Kager, L.; Pötschger, U.; Bielack, S. Review of mifamurtide in the treatment of patients with osteosarcoma. Ther. Clin. Risk Manag. 2010, 6, 279–286. [CrossRef] [PubMed] 88. Tzogani, K.; Straube, M.; Hoppe, U.; Kiely, P.; O’Dea, G.; Enzmann, H.; Salmon, P.; Salmonson, T.; Pignatti, F. The European Medicines Agency approval of 5-aminolaevulinic acid (Ameluz) for the treatment of actinic keratosis of mild to moderate intensity on the face and scalp: Summary of the scientific assessment of the Committee for Medicinal Products for Human Use. J. Dermatolog. Treat. 2014, 25, 371–374. [CrossRef] 89. Legha, S.S. Vincristine neurotoxicity. Pathophysiology and management. Med. Toxicol. 1986, 1, 421–427. [CrossRef] [PubMed] 90. FDA Approves Liposomal Vincristine (Marqibo) for Rare Leukemia. Available online: https://www.cancernetwork.com/view/ fda-approves-liposomal-vincristine-marqibo-rare-leukemia (accessed on 4 April 2022). 91. Silverman, J.A.; Deitcher, S.R. Marqibo® (vincristine sulfate liposome injection) improves the pharmacokinetics and pharmacody- namics of vincristine. Cancer Chemother. Pharmacol. 2013, 71, 555–564. [CrossRef] 92. Frampton, J.E. Liposomal Irinotecan: A Review in Metastatic Pancreatic Adenocarcinoma. Drugs 2020, 80, 1007–1018. [CrossRef] 93. Hong, S.; Choi, D.W.; Kim, H.N.; Park, C.G.; Lee, W.; Park, H.H. Protein-Based Nanoparticles as Drug Delivery Systems. Pharmaceutics 2020, 12, 604. [CrossRef] [PubMed] 94. Zhang, J.T.; Ma, J.; Kankala, R.K.; Yu, Q.; Wang, B.; Chen, A.Z. Recent Advances in Fabrication of Well-Organized Protein-Based Nanostructures. ACS Appl. Bio Mater. 2021, 4, 4039–4048. [CrossRef] 95. Dinndorf, P.A.; Gootenberg, J.; Cohen, M.H.; Keegan, P.; Pazdur, R. FDA drug approval summary: Pegaspargase (oncaspar) for the first-line treatment of children with acute lymphoblastic leukemia (ALL). Oncologist 2007, 12, 991–998. [CrossRef] 96. Heo, Y.A.; Syed, Y.Y.; Keam, S.J. Pegaspargase: A Review in Acute Lymphoblastic Leukaemia. Drugs 2019, 79, 767–777. [CrossRef] [PubMed] 97. Bennett, M.J.; Eisenberg, D. Refined structure of monomeric diphtheria toxin at 2.3 A resolution. Protein. Sci. 1994, 3, 1464–1475. [CrossRef] 98. Collier, R.J. Understanding the mode of action of diphtheria toxin: A perspective on progress during the 20th century. Toxicon 2001, 39, 1793–1803. [CrossRef] 99. Wang, Z.; Zheng, Q.; Zhang, H.; Bronson, R.T.; Madsen, J.C.; Sachs, D.H.; Huang, C.A.; Wang, Z. Ontak-like human IL-2 fusion toxin. J. Immunol. Methods 2017, 448, 51–58. [CrossRef] [PubMed] 100. Yonekura, K. Current treatment strategies and emerging therapies for cutaneous lymphoma. J. Dermatol. 2022, 49, 223–231. [CrossRef] [PubMed] Biomolecules 2022, 12, 784 23 of 27 101. National Library of Medicine [NLM]. Available online: https://clinicaltrials.gov/ (accessed on 3 January 2022). 102. Sartor, O. Eligard: Leuprolide acetate in a novel sustained-release delivery system. Urology 2003, 61, 25–31. [CrossRef] 103. Van Tellingen, O.; Huizing, M.T.; Nannan Panday, V.R.; Schellens, J.H.M.; Nooijen, W.J.; Beijnen, J.H. Cremophor EL causes (pseudo-) non-linear pharmacokinetics of paclitaxel in patients. Br. J. Cancer 1999, 81, 330. [CrossRef] 104. Horwitz, S.B. Taxol (paclitaxel): Mechanisms of action. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 1994, 5, S3–S6. 105. Yardley, D.A. nab-Paclitaxel mechanisms of action and delivery. J. Control. Release 2013, 170, 365–372. [CrossRef] [PubMed] 106. Kundranda, M.N.; Niu, J. Albumin-bound paclitaxel in solid tumors: Clinical development and future directions. Drug Des. Devel. Ther. 2015, 9, 3767–3777. [CrossRef] 107. Chen, Y.; Liu, R.; Li, C.; Song, Y.; Liu, G.; Huang, Q.; Yu, L.; Zhu, D.; Lu, C.; Lu, A.; et al. Nab-paclitaxel promotes the cancer-immunity cycle as a potential immunomodulator. Am. J. Cancer Res. 2021, 11, 3445. 108. Li, C.H.; Karantza, V.; Aktan, G.; Lala, M. Current treatment landscape for patients with locally recurrent inoperable or metastatic triple-negative breast cancer: A systematic literature review. Breast Cancer Res. 2019, 21, 143. [CrossRef] [PubMed] 109. Adamska, A.; Domenichini, A.; Falasca, M. Pancreatic Ductal Adenocarcinoma: Current and Evolving Therapies. Int. J. Mol. Sci. 2017, 18, 1338. [CrossRef] 110. Lambert, J.M.; Chari, R.V.J. Ado-trastuzumab emtansine (T-DM1): An antibody-drug conjugate (ADC) for HER2-positive breast cancer. J. Med. Chem. 2014, 57, 6949–6964. [CrossRef] 111. Fraguas-Sánchez, A.I.; Lozza, I.; Torres-Suárez, A.I. Actively Targeted Nanomedicines in Breast Cancer: From Pre-Clinical Investigation to Clinic. Cancers 2022, 14, 1198. [CrossRef] 112. Keam, S.J. Trastuzumab Deruxtecan: First Approval. Drugs 2020, 80, 501–508. [CrossRef] 113. Singh, A.P.; Sharma, S.; Shah, D.K. Quantitative characterization of in vitro bystander effect of antibody-drug conjugates. J. Pharmacokinet. Pharmacodyn. 2016, 43, 567–582. [CrossRef] 114. Bernstein, I.D. Monoclonal antibodies to the myeloid stem cells: Therapeutic implications of CMA-676, a humanized anti-CD33 antibody calicheamicin conjugate. Leukemia 2000, 14, 474–475. [CrossRef] 115. Francisco, J.A.; Cerveny, C.G.; Meyer, D.L.; Mixan, B.J.; Klussman, K.; Chace, D.F.; Rejniak, S.X.; Gordon, K.A.; DeBlanc, R.; Toki, B.E.; et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood 2003, 102, 1458–1465. [CrossRef] 116. Lewis Phillips, G.D.; Li, G.; Dugger, D.L.; Crocker, L.M.; Parsons, K.L.; Mai, E.; Blättler, W.A.; Lambert, J.M.; Chari, R.V.; Lutz, R.J.; et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008, 68, 9280–9290. [CrossRef] 117. DiJoseph, J.F.; Goad, M.E.; Dougher, M.M.; Boghaert, E.R.; Kunz, A.; Hamann, P.R.; Damle, N.K. Potent and specific antitumor efficacy of CMC-544, a CD22-targeted immunoconjugate of calicheamicin, against systemically disseminated B-cell lymphoma. Clin. Cancer Res. 2004, 10, 8620–8629. [CrossRef] 118. Salvatore, G.; Beers, R.; Margulies, I.; Kreitman, R.J.; Pastan, I. Improved cytotoxic activity toward cell lines and fresh leukemia cells of a mutant anti-CD22 immunotoxin obtained by antibody phage display. Clin. Cancer Res. 2002, 8, 995–1002. 119. Dornan, D.; Bennett, F.; Chen, Y.; Dennis, M.; Eaton, D.; Elkins, K.; French, D.; Go, M.A.; Jack, A.; Junutula, J.R.; et al. Therapeutic potential of an anti-CD79b antibody-drug conjugate, anti-CD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma. Blood 2009, 114, 2721–2729. [CrossRef] 120. Challita-Eid, P.M.; Satpayev, D.; Yang, P.; An, Z.; Morrison, K.; Shostak, Y.; Raitano, A.; Nadell, R.; Liu, W.; Lortie, D.R.; et al. Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models. Cancer Res. 2016, 76, 3003–3013. [CrossRef] 121. Ogitani, Y.; Hagihara, K.; Oitate, M.; Naito, H.; Agatsuma, T. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci. 2016, 107, 1039–1046. [CrossRef] 122. Cardillo, T.M.; Govindan, S.V.; Sharkey, R.M.; Trisal, P.; Arrojo, R.; Liu, D.; Rossi, E.A.; Chang, C.H.; Goldenberg, D.M. Saci- tuzumab Govitecan (IMMU-132), an Anti-Trop-2/SN-38 Antibody-Drug Conjugate: Characterization and Efficacy in Pancreatic, Gastric, and Other Cancers. Bioconjug. Chem. 2015, 26, 919–931. [CrossRef] 123. Yu, B.; Jiang, T.; Liu, D. BCMA-targeted immunotherapy for multiple myeloma. J. Hematol. Oncol. 2020, 13, 125. [CrossRef] 124. Zammarchi, F.; Corbett, S.; Adams, L.; Tyrer, P.C.; Kiakos, K.; Janghra, N.; Marafioti, T.; Britten, C.E.; Havenith, C.E.G.; Chivers, S.; et al. ADCT-402, a PBD dimer–containing antibody drug conjugate targeting CD19-expressing malignancies. Blood 2018, 131, 1094–1105. [CrossRef] 125. Zhao, M.; Li, H.; Fan, L.; Ma, Y.; Gong, H.; Lai, W.; Fang, Q.; Hu, Z. Quantitative proteomic analysis to the first commercialized liposomal paclitaxel nano-platform Lipusu revealed the molecular mechanism of the enhanced anti-tumor effect. Artif. Cells Nanomed. Biotechnol. 2018, 46, S147–S155. [CrossRef] 126. Ahn, H.K.; Jung, M.; Sym, S.J.; Shin, D.B.; Kang, S.M.; Kyung, S.Y.; Park, J.W.; Jeong, S.H.; Cho, E.K. A phase II trial of Cremorphor EL-free paclitaxel (Genexol-PM) and gemcitabine in patients with advanced non-small cell lung cancer. Cancer Chemother. Pharmacol. 2014, 74, 277–282. [CrossRef] [PubMed] 127. Ranade, A.A.; Joshi, D.A.; Phadke, G.K.; Patil, P.P.; Kasbekar, R.B.; Apte, T.G.; Dasare, R.R.; Mengde, S.D.; Parikh, P.M.; Bhattacharyya, G.S.; et al. Clinical and economic implications of the use of nanoparticle paclitaxel (Nanoxel) in India. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2013, 24, v6–v12. [CrossRef] Biomolecules 2022, 12, 784 24 of 27 128. Bernabeu, E.; Cagel, M.; Lagomarsino, E.; Moretton, M.; Chiappetta, D.A. Paclitaxel: What has been done and the challenges remain ahead. Int. J. Pharm. 2017, 526, 474–495. [CrossRef] 129. Mahmoudi, K.; Bouras, A.; Bozec, D.; Ivkov, R.; Hadjipanayis, C. Magnetic hyperthermia therapy for the treatment of glioblastoma: A review of the therapy’s history, efficacy and application in humans. Int. J. Hyperth. 2018, 34, 1316–1328. [CrossRef] [PubMed] 130. Rivera Gil, P.; Hühn, D.; del Mercato, L.L.; Sasse, D.; Parak, W.J. Nanopharmacy: Inorganic nanoscale devices as vectors and active compounds. Pharmacol. Res. 2010, 62, 115–125. [CrossRef] 131. Havel, H.A. Where Are the Nanodrugs? An Industry Perspective on Development of Drug Products Containing Nanomaterials. AAPS J. 2016, 18, 1351–1353. [CrossRef] 132. Ventola, C.L. Progress in Nanomedicine: Approved and Investigational Nanodrugs. Pharm. Ther. 2017, 42, 742. 133. Germain, M.; Caputo, F.; Metcalfe, S.; Tosi, G.; Spring, K.; Åslund, A.K.O.; Pottier, A.; Schiffelers, R.; Ceccaldi, A.; Schmid, R. Delivering the power of nanomedicine to patients today. J. Control. Release 2020, 326, 164–171. [CrossRef] [PubMed] 134. Salvioni, L.; Rizzuto, M.A.; Bertolini, J.A.; Pandolfi, L.; Colombo, M.; Prosperi, D. Thirty Years of Cancer Nanomedicine: Success, Frustration, and Hope. Cancers 2019, 11, 1855. [CrossRef] 135. Bukhari, S.N.A. Emerging Nanotherapeutic Approaches to Overcome Drug Resistance in Cancers with Update on Clinical Trials. Pharmaceutics 2022, 14, 866. [CrossRef] [PubMed] 136. Gobbo, O.L.; Sjaastad, K.; Radomski, M.W.; Volkov, Y.; Prina-Mello, A. Magnetic Nanoparticles in Cancer Theranostics. Theranostics 2015, 5, 1249–1263. [CrossRef] [PubMed] 137. Jokerst, J.V.; Gambhir, S.S. Molecular imaging with theranostic nanoparticles. Acc. Chem. Res. 2011, 44, 1050–1060. [CrossRef] [PubMed] 138. Ho, D.; Quake, S.R.; McCabe, E.R.B.; Chng, W.J.; Chow, E.K.; Ding, X.; Gelb, B.D.; Ginsburg, G.S.; Hassenstab, J.; Ho, C.M.; et al. Enabling Technologies for Personalized and Precision Medicine. Trends Biotechnol. 2020, 38, 497–518. [CrossRef] [PubMed] 139. Duan, H.; Liu, Y.; Gao, Z.; Huang, W. Recent advances in drug delivery systems for targeting cancer stem cells. Acta Pharm. Sin. B 2021, 11, 55–70. [CrossRef] [PubMed] 140. Ertas, Y.N.; Abedi Dorcheh, K.; Akbari, A.; Jabbari, E. Nanoparticles for Targeted Drug Delivery to Cancer Stem Cells: A Review of Recent Advances. Nanomaterials 2021, 11, 1755. [CrossRef] [PubMed] 141. Marcucci, F.; Caserta, C.A.; Romeo, E.; Rumio, C. Antibody-Drug Conjugates (ADC) Against Cancer Stem-Like Cells (CSC)-Is There Still Room for Optimism? Front. Oncol. 2019, 9, 167. [CrossRef] 142. Tang, Y.; Chen, Y.; Zhang, Z.; Tang, B.; Zhou, Z.; Chen, H. Nanoparticle-Based RNAi Therapeutics Targeting Cancer Stem Cells: Update and Prospective. Pharmaceutics 2021, 13, 2116. [CrossRef] 143. Suo, X.; Zhang, J.; Zhang, Y.; Liang, X.J.; Zhang, J.; Liu, D. A nano-based thermotherapy for cancer stem cell-targeted therapy. J. Mater. Chem. B 2020, 8, 3985–4001. [CrossRef] 144. Mukherjee, S.; Sonanin, D.; Maurer, A.; Daldrup-Link, H.E. The yin and yang of imaging tumor associated macrophages with PET and MRI. Theranostics 2019, 9, 7730–7748. [CrossRef] 145. Resnik, D.B.; Tinkle, S.S. Ethics in nanomedicine. Nanomedicine 2007, 2, 345–350. [CrossRef] [PubMed] 146. Bobo, D.; Robinson, K.J.; Islam, J.; Thurecht, K.J.; Corrie, S.R. Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date. Pharm. Res. 2016, 33, 2373–2387. [CrossRef] 147. Allen, T.M.; Cullis, P.R. Liposomal drug delivery systems: From concept to clinical applications. Adv. Drug Deliv. Rev. 2013, 65, 36–48. [CrossRef] 148. Aillon, K.L.; Xie, Y.; El-Gendy, N.; Berkland, C.J.; Forrest, M.L. Effects of nanomaterial physicochemical properties on in vivo toxicity. Adv. Drug Deliv. Rev. 2009, 61, 457–466. [CrossRef] 149. Dobrovolskaia, M.A.; McNeil, S.E. Immunological properties of engineered nanomaterials. Nat. Nanotechnol. 2007, 2, 469–478. [CrossRef] 150. Nel, A.E.; Mädler, L.; Velegol, D.; Xia, T.; Hoek, E.M.; Somasundaran, P.; Klaessig, F.; Castranova, V.; Thompson, M. Understanding biophysicochemical interactions at the nano-bio interface. Nat. Mater. 2009, 8, 543–557. [CrossRef] 151. Fornaguera, C.; García-Celma, M.J. Personalized Nanomedicine: A Revolution at the Nanoscale. J. Pers. Med. 2017, 7, 12. [CrossRef] 152. Nakamura, K.; Kiminami, H.; Yamashita, A.; Abe, Y.; Yoshino, K.; Suzuki, S. Assessment of the effects of sterilization methods on protein drug stability by elucidating decomposition mechanism and material analysis. Int. J. Pharm. 2015, 484, 51–56. [CrossRef] 153. Li, Y.; Boraschi, D. Endotoxin contamination: A key element in the interpretation of nanosafety studies. Nanomedicine 2016, 11, 269–287. [CrossRef] 154. Smulders, S.; Kaiser, J.P.; Zuin, S.; Van Landuyt, K.L.; Golanski, L.; Vanoirbeek, J.; Wick, P.; Hoet, P.H. Contamination of nanoparticles by endotoxin: Evaluation of different test methods. Part. Fibre Toxicol. 2012, 9, 41. [CrossRef] 155. Vasir, J.K.; Labhasetwar, V. Biodegradable nanoparticles for cytosolic delivery of therapeutics. Adv. Drug Deliv. Rev. 2007, 59, 718–728. [CrossRef] 156. Drummond, D.C.; Meyer, O.; Hong, K.; Kirpotin, D.B.; Papahadjopoulos, D. Optimizing liposomes for delivery of chemothera- peutic agents to solid tumors. Pharmacol. Rev. 1999, 51, 691–743. 157. Desai, N. Challenges in development of nanoparticle-based therapeutics. AAPS J. 2012, 14, 282–295. [CrossRef] 158. van der Meel, R.; Sulheim, E.; Shi, Y.; Kiessling, F.; Mulder, W.J.M.; Lammers, T. Smart cancer nanomedicine. Nat. Nanotechnol. 2019, 14, 1007–1017. [CrossRef] Biomolecules 2022, 12, 784 25 of 27 159. FDA U.S. Food and Drug Administration. Available online: https://www.fda.gov/science-research/nanotechnology-programs- fda/nanotechnology-guidance-documents (accessed on 9 May 2022). 160. EMA European Medicine Agency. Available online: https://www.ema.europa.eu/en/human-regulatory/research-development/ scientific-guidelines (accessed on 9 May 2022). 161. Innovation Task Force. Available online: https://www.tsa.gov/itf (accessed on 9 May 2022). 162. Northfelt, D.W.; Dueck, A.C.; Flynn, T.P.; Zander, P.J.; Stella, P.J.; Melnik, M.; Pavey, E.S.; Perez, E.A. Phase II trial combining nab-paclitaxel (NP), gemcitabine (G), and bevacizumab (B) in patients (pts) with metastatic breast cancer (MBC): NCCTG N0735. ASCO Annu. Meet. I 2011, 29 (Suppl. 15), 1126. [CrossRef] 163. Roy, V.; Laplant, B.R.; Gross, G.G.; Bane, C.L.; Palmieri, F.M. Phase II trial of weekly nab (nanoparticle albumin-bound)-paclitaxel (nab-paclitaxel) (Abraxane® ) in combination with gemcitabine in patients with metastatic breast cancer (N0531). Ann. Oncol. 2009, 20, 449. [CrossRef] 164. Yardley, D.; Burris, H.; Peacock, N.; Raefsky, E.; Melnik, M.; Inhorn, R.; Shipley, D.; Hainsworth, J. A pilot study of adjuvant nanoparticle albumin-bound (nab) paclitaxel and cyclophosphamide, with trastuzumab in HER2-positive patients, in the treatment of early-stage breast cancer. Breast Cancer Res. Treat. 2010, 123, 471–475. [CrossRef] 165. Nahleh, Z.A.; Barlow, W.E.; Hayes, D.F.; Schott, A.F.; Gralow, J.R.; Sikov, W.M.; Perez, E.A.; Chennuru, S.; Mirshahidi, H.R.; Corso, S.W.; et al. SWOG S0800 (NCI CDR0000636131): Addition of bevacizumab to neoadjuvant nab-paclitaxel with dose-dense doxorubicin and cyclophosphamide improves pathologic complete response (pCR) rates in inflammatory or locally advanced breast cancer. Breast Cancer Res. Treat. 2016, 158, 485–495. [CrossRef] [PubMed] 166. Herbst, R.S.; Prager, D.; Hermann, R.; Fehrenbacher, L.; Johnson, B.E.; Sandler, A.; Kris, M.G.; Tran, H.T.; Klein, P.; Li, X.; et al. TRIBUTE: A phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J. Clin. Oncol. 2005, 23, 5892–5899. [CrossRef] 167. Bertino, E.M.; Williams, T.M.; Nana-Sinkam, S.P.; Shilo, K.; Chatterjee, M.; Mo, X.; Rahmani, M.; Phillips, G.S.; Villalona-Calero, M.A.; Otterson, G.A. Stromal Caveolin-1 Is Associated With Response and Survival in a Phase II Trial of nab-Paclitaxel With Carboplatin for Advanced NSCLC Patients. Clin. Lung Cancer 2015, 16, 466–474. [CrossRef] [PubMed] 168. Mrózek, E.; Layman, R.; Ramaswamy, B.; Lustberg, M.; Vecchione, A.; Knopp, M.V.; Shapiro, C.L. Phase II trial of neoadjuvant weekly nanoparticle albumin-bound paclitaxel, carboplatin, and biweekly bevacizumab therapy in women with clinical stage II or III HER2-negative breast cancer. Clin. Breast Cancer 2014, 14, 228–234. [CrossRef] [PubMed] 169. Hirsh, V. nab-paclitaxel for the management of patients with advanced non-small-cell lung cancer. Expert Rev. Anticancer Ther. 2014, 14, 129–141. [CrossRef] [PubMed] 170. Hosein, P.J.; de Lima Lopes, G., Jr.; Pastorini, V.H.; Gomez, C.; Macintyre, J.; Zayas, G.; Reis, I.; Montero, A.J.; Merchan, J.R.; Rocha Lima, C.M. A phase II trial of nab-Paclitaxel as second-line therapy in patients with advanced pancreatic cancer. Am. J. Clin. Oncol. 2013, 36, 151–156. [CrossRef] 171. Connolly, R.M.; Leal, J.P.; Goetz, M.P.; Zhang, Z.; Zhou, X.C.; Jacobs, L.K.; Mhlanga, J.; Joo, H.O.; Carpenter, J.; Storniolo, A.M.; et al. TBCRC 008: Early change in 18F-FDG uptake on PET predicts response to preoperative systemic therapy in human epidermal growth factor receptor 2-negative primary operable breast cancer. J. Nucl. Med. 2015, 56, 31–37. [CrossRef] [PubMed] 172. Ip, E.J.; Lee-Ma, A.; Troxell, L.S.; Chan, J. Low-dose filgrastim in patients with breast cancer treated with docetaxel, doxorubicin, and cyclophosphamide. Am. J. Health Syst. Pharm. 2008, 65, 1552–1555. [CrossRef] 173. Hamilton, E.; Kimmick, G.; Hopkins, J.; Marcom, P.K.; Rocha, G.; Welch, R.; Broadwater, G.; Blackwell, K. Nab- paclitaxel/bevacizumab/carboplatin chemotherapy in first-line triple negative metastatic breast cancer. Clin. Breast Cancer 2013, 13, 416–420. [CrossRef] 174. Burke, J.M.; Lamm, D.L.; Meng, M.V.; Nemunaitis, J.J.; Stephenson, J.J.; Arseneau, J.C.; Aimi, J.; Lerner, S.; Yeung, A.W.; Kazarian, T.; et al. A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer. J. Urol. 2012, 88, 2391–2397. [CrossRef] 175. Symonds, L.; Linden, H.; Gadi, V.; Korde, L.; Rodler, E.; Gralow, J.; Redman, M.; Baker, K.; Wu, Q.V.; Jenkins, I.; et al. Combined Targeted Therapies for First-line Treatment of Metastatic Triple Negative Breast Cancer-A Phase II Trial of Weekly Nab-Paclitaxel and Bevacizumab Followed by Maintenance Targeted Therapy With Bevacizumab and Erlotinib. Clin. Breast Cancer 2019, 19, e283–e296. [CrossRef] 176. Teneriello, M.G.; Tseng, P.C.; Crozier, M.; Encarnacion, C.; Hancock, K.; Messing, M.J.; Boehm, K.A.; Williams, A.; Asmar, L. Phase II evaluation of nanoparticle albumin-bound paclitaxel in platinum-sensitive patients with recurrent ovarian, peritoneal, or fallopian tube cancer. J. Clin. Oncol. 2009, 27, 1426–1431. [CrossRef] 177. Quintanilha, J.C.F.; Wang, J.; Sibley, A.B.; Jiang, C.; Etheridge, A.S.; Shen, F.; Jiang, G.; Mulkey, F.; Patel, J.N.; Hertz, D.L.; et al. Bevacizumab-induced hypertension and proteinuria: A genome-wide study of more than 1000 patients. Br. J. Cancer 2021, 126, 265–274. [CrossRef] 178. Conlin, A.K.; Seidman, A.D.; Bach, A.; Lake, D.; Dickler, M.; D’Andrea, G.; Traina, T.; Danso, M.; Brufsky, A.M.; Saleh, M.; et al. Phase II trial of weekly nanoparticle albumin-bound paclitaxel with carboplatin and trastuzumab as first-line therapy for women with HER2-overexpressing metastatic breast cancer. Clin. Breast Cancer 2010, 10, 281–287. [CrossRef] [PubMed] Biomolecules 2022, 12, 784 26 of 27 179. Ho, C.; Davies, A.M.; Sangha, R.S.; Lau, D.; Lara, P., Jr.; Chew, H.K.; Beckett, L.; Mack, P.C.; Riess, J.W.; Gandara, D.R.; et al. Phase I/II trial of pemetrexed plus nab-paclitaxel in advanced solid tumor patients with emphasis on non-small cell lung cancer. Investig. New Drugs 2013, 31, 1587–1591. [CrossRef] 180. Blum, J.L.; Savin, M.A.; Edelman, G.; Pippen, J.E.; Robert, N.J.; Geister, B.V.; Kirby, R.L.; Clawson, A.; O’Shaughnessy, J.A. Phase II study of weekly albumin-bound paclitaxel for patients with metastatic breast cancer heavily pretreated with taxanes. Clin. Breast Cancer 2007, 7, 850–856. [CrossRef] 181. Lammers, P.E.; Lu, B.; Horn, L.; Shyr, Y.; Keedy, V. nab-Paclitaxel in Combination With Weekly Carboplatin With Concurrent Radiotherapy in Stage III Non-Small Cell Lung Cancer. Oncologist 2015, 20, 491–492. [CrossRef] 182. Cohen, A.L.; Ray, A.; Van Brocklin, M.; Burnett, D.M.; Bowen, R.C.; Dyess, D.L.; Butler, T.W.; Dumlao, T.; Khong, H.T. A phase I trial of azacitidine and nanoparticle albumin bound paclitaxel in patients with advanced or metastatic solid tumors. Oncotarget 2016, 8, 52413–52419. [CrossRef] [PubMed] 183. Kaklamani, V.G.; Siziopikou, K.; Scholtens, D.; Lacouture, M.; Gordon, J.; Uthe, R.; Meservey, C.; Hansen, N.; Khan, S.A.; Jeruss, J.S.; et al. Pilot neoadjuvant trial in HER2 positive breast cancer with combination of nab-paclitaxel and lapatinib. Breast Cancer Res. Treat. 2012, 132, 833–842. [CrossRef] [PubMed] 184. Chun, S.G.; Hughes, R.; Sumer, B.D.; Myers, L.L.; Truelson, J.M.; Khan, S.A.; Ma, T.W.; Xie, Y.; Yordy, J.S.; Cooley, S.; et al. A Phase I/II Study of Nab-Paclitaxel, Cisplatin, and Cetuximab With Concurrent Radiation Therapy for Locally Advanced Squamous Cell Cancer of the Head and Neck. Cancer Investig. 2017, 35, 23–31. [CrossRef] 185. Yardley, D.A.; Hart, L.; Bosserman, L.; Salleh, M.N.; Waterhouse, D.M.; Hagan, M.K.; Richards, P.; DeSilvio, M.L.; Mahoney, J.M.; Nagarwala, Y. Phase II study evaluating lapatinib in combination with nab-paclitaxel in HER2-overexpressing metastatic breast cancer patients who have received no more than one prior chemotherapeutic regimen. Breast Cancer Res. Treat. 2013, 137, 457–464. [CrossRef] 186. Fujiwara, Y.; Mukai, H.; Saeki, T.; Ro, J.; Lin, Y.C.; Nagai, S.E.; Lee, K.S.; Watanabe, J.; Ohtani, S.; Kim, S.B.; et al. A multi-national, randomised, open-label, parallel, phase III non-inferiority study comparing NK105 and paclitaxel in metastatic or recurrent breast cancer patients. Br. J. Cancer 2019, 120, 475–480. [CrossRef] 187. Sohal, D.P.S.; Duong, M.; Ahmad, S.A.; Gandhi, N.S.; Beg, M.S.; Wang-Gillam, A.; Wade, J.L.; Chiorean, E.G.; Guthrie, K.A.; Lowy, A.M.; et al. Efficacy of Perioperative Chemotherapy for Resectable Pancreatic Adenocarcinoma: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2021, 7, 421–427. [CrossRef] 188. Kanwal, M.; Smahel, M.; Olsen, M.; Smahelova, J.; Tachezy, R. Aspartate β-hydroxylase as a target for cancer therapy. J. Exp. Clin. Cancer Res. 2020, 39, 163. [CrossRef] 189. Adkins, D.; Ley, J.; Oppelt, P.; Gay, H.A.; Daly, M.; Paniello, R.C.; Jackson, R.; Pipkorn, P.; Rich, J.; Zevallos, J.; et al. Impact on Health-Related Quality of Life of Induction Chemotherapy Compared With Concurrent Cisplatin and Radiation Therapy in Patients With Head and Neck Cancer. Clin. Oncol. R. Coll. Radiol. 2019, 31, e123–e131. [CrossRef] 190. Salazar, L.G.; Lu, H.; Reichow, J.L.; Childs, J.S.; Coveler, A.L.; Higgins, D.M.; Waisman, J.; Allison, K.H.; Dang, Y.; Disis, M.L.; et al. Topical Imiquimod Plus Nab-paclitaxel for Breast Cancer Cutaneous Metastases: A Phase 2 Clinical Trial. JAMA Oncol. 2017, 3, 969–973. [CrossRef] 191. Yardley, D.A.; Coleman, R.; Conte, P.; Cortes, J.; Brufsky, A.; Shtivelband, M.; Young, R.; Bengala, C.; Ali, H.; Eakel, J.; et al. nab-Paclitaxel plus carboplatin or gemcitabine versus gemcitabine plus carboplatin as first-line treatment of patients with triple-negative metastatic breast cancer: Results from the tnAcity trial. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2018, 29, 1763–1770. [CrossRef] 192. Jani, A.; Horowitz, D.P. Radiation Therapy Deviations in Trial of Locally Advanced Pancreatic Cancer. JAMA 2016, 316, 1409. [CrossRef] [PubMed] 193. Cheng, Y.; Zhang, L.; Hu, J.; Wang, D.; Hu, C.; Zhou, J.; Wu, L.; Cao, L.; Liu, J.; Zhang, H.; et al. Pembrolizumab Plus Chemotherapy for Chinese Patients With Metastatic Squamous NSCLC in KEYNOTE-407. JTO Clin. Res. Rep. 2021, 2, 10. [CrossRef] [PubMed] 194. Paz-Ares, L.; Vicente, D.; Tafreshi, A.; Robinson, A.; Soto Parra, H.; Mazières, J.; Hermes, B.; Cicin, I.; Medgyasszay, B.; Rodríguez- Cid, J.; et al. A Randomized, Placebo-Controlled Trial of Pembrolizumab Plus Chemotherapy in Patients With Metastatic Squamous NSCLC: Protocol-Specified Final Analysis of KEYNOTE-407. J. Thorac. Oncol. 2020, 15, 1657–1669. [CrossRef] 195. Germann, U.A.; Furey, B.F.; Markland, W.; Hoover, R.R.; Aronov, A.M.; Roix, J.J.; Hale, M.; Boucher, D.M.; Sorrell, D.A.; Martinez- Botella, G.; et al. Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib). Mol. Cancer Ther. 2017, 16, 2351–2363. [CrossRef] 196. Seiwert, T.Y.; Foster, C.C.; Blair, E.A.; Karrison, T.G.; Agrawal, N.; Melotek, J.M.; Portugal, L.; Brisson, R.J.; Dekker, A.; Kochanny, S.; et al. OPTIMA: A phase II dose and volume de-escalation trial for human papillomavirus-positive oropharyngeal cancer. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2019, 30, 297–302. [CrossRef] [PubMed] 197. Gennari, A.; Sun, Z.; Hasler-Strub, U.; Colleoni, M.; Kennedy, M.J.; Von Moos, R.; Cortés, J.; Vidal, M.J.; Hennessy, B.; Walshe, J.; et al. A randomized phase II study evaluating different maintenance schedules of nab-paclitaxel in the first-line treatment of metastatic breast cancer: Final results of the IBCSG 42-12/BIG 2-12 SNAP trial. Ann. Oncol. 2018, 29, 661–668. [CrossRef] Biomolecules 2022, 12, 784 27 of 27 198. Alberts, D.S.; Blessing, J.A.; Landrum, L.M.; Warshal, D.P.; Martin, L.P.; Rose, S.L.; Bonebrake, A.J.; Ramondetta, L.M. Phase II trial of nab-paclitaxel in the treatment of recurrent or persistent advanced cervix cancer: A gynecologic oncology group study. Gynecol. Oncol. 2012, 127, 451–455. [CrossRef] [PubMed] 199. Green, D.S.; Bodman-Smith, M.D.; Dalgleish, A.G.; Fischer, M.D. Phase I/II study of topical imiquimod and intralesional interleukin-2 in the treatment of accessible metastases in malignant melanoma. Br. J. Dermatol. 2007, 156, 337–345. [CrossRef] [PubMed] 200. Sanoff, H.K.; Moon, D.H.; Moore, D.T.; Boles, J.; Bui, C.; Blackstock, W.; O’Neil, B.H.; Subramaniam, S.; McRee, A.J.; Carlson, C.; et al. Phase I/II trial of nano-camptothecin CRLX101 with capecitabine and radiotherapy as neoadjuvant treat- ment for locally advanced rectal cancer. Nanomedicine 2019, 18, 189–195. [CrossRef] 201. Werner, T.L.; Ray, A.; Lamb, J.G.; VanBrocklin, M.; Hueftle, K.; Cohen, A.L.; Beck, A.C.; Buys, S.S.; Dyess, D.L.; Butler, T.W.; et al. A Phase I Study of Neoadjuvant Chemotherapy With Nab-Paclitaxel, Doxorubicin, and Cyclophosphamide in Patients With Stage II to III Breast Cancer. Clin. Breast Cancer 2017, 17, 503–509. [CrossRef] [PubMed] 202. Kottschade, L.A.; Suman, V.J.; Perez, D.G.; McWilliams, R.R.; Kaur, J.S.; Amatruda, T.T.; Geoffroy, F.J.; Gross, H.M.; Cohen, P.A.; Jaslowski, A.J.; et al. A randomized phase 2 study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma: A North Central Cancer Treatment Group study, N0775. Cancer 2013, 119, 586–592. [CrossRef] 203. Guminski, A.D.; Lee, A.; Lumba, S.; Maher, R. Nab-paclitaxel salvage chemotherapy for metastatic ocular melanoma. J. Clin. Oncol. 2012, 30, e19042. [CrossRef] 204. Kottschade, L.A.; Suman, V.J.; Amatruda, T.; McWilliams, R.R.; Mattar, B.I.; Nikcevich, D.A.; Behrens, R.; Fitch, T.R.; Jaslowski, A.J.; Markovic, S.N. A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma: A North Central Cancer Treatment Group Study, N057E(1). Cancer 2011, 117, 1704–1710. [CrossRef] 205. Tolcher, A.W.; Papadopoulos, K.P.; Patnaik, A.; Rasco, D.W.; Martinez, D.; Wood, D.L.; Fielman, B.; Sharma, M.; Janisch, L.A.; Brown, B.D.; et al. Safety and activity of DCR-MYC, a first-in-class Dicer-substrate small interfering RNA (DsiRNA) targeting MYC, in a phase I study in patients with advanced solid tumors. J. Clin. Oncol. 2015, 33, 11006. [CrossRef] 206. Feliu, J.; Jorge Fernández, M.; Macarulla, T.; Massuti, B.; Albero, A.; González González, J.F.; Quintero-Aldana, G.; Delgado- Mingorance, J.I.; Fernández Montes, A.; García Piernavieja, C.; et al. Phase II clinical trial of nab-paclitaxel plus gemcitabine in elderly patients with previously untreated locally advanced or metastatic pancreatic adenocarcinoma: The BIBABRAX study. Cancer Chemother. Pharmacol. 2021, 87, 543–553. [CrossRef] 207. Spitler, L.E.; Boasberg, P.; O’Day, S.; Hamid, O.; Cruickshank, S.; Mesko, S.; Weber, R.W. Phase II study of nab-paclitaxel and bevacizumab as first-line therapy for patients with unresectable stage III and IV melanoma. Am. J. Clin. Oncol. 2015, 38, 61–67. [CrossRef] [PubMed] 208. Liu, C.; Luo, L.; Zeng, L.; Xing, J.; Xia, Y.; Sun, S.; Zhang, L.; Yu, Z.; Yao, J.; Yu, Z.; et al. Porous Gold Nanoshells on Functional NH2 -MOFs: Facile Synthesis and Designable Platforms for Cancer Multiple Therapy. Small 2018, 14, e1801851. [CrossRef] [PubMed] 209. Clive, S.; Gardiner, J.; Leonard, R.C. Miltefosine as a topical treatment for cutaneous metastases in breast carcinoma. Cancer Chemother. Pharmacol. 1999, 44, S29–S30. [CrossRef] [PubMed] 210. Jazrawi, A.; Pantiora, E.; Abdsaleh, S.; Bacovia, D.V.; Eriksson, S.; Leonhardt, H.; Wärnberg, F.; Karakatsanis, A. Magnetic-Guided Axillary UltraSound (MagUS) Sentinel Lymph Node Biopsy and Mapping in Patients with Early Breast Cancer. A Phase 2, Single-Arm Prospective Clinical Trial. Cancers 2021, 13, 4285. [CrossRef] [PubMed]