Photoactivatable Prodrug-Backboned Polymeric Nanoparticles for Efficient Light-Controlled Gene Delivery and Synergistic Treatment of Platinum-Resistant Ovarian Cancer.

Combination of chemotherapy and gene therapy provides an effective strategy for cancer treatment. However, the lack of suitable codelivery systems with efficient endo/lysosomal escape and controllable drug release/gene unpacking is the major bottleneck for maximizing the combinational therapeutic efficacy. In this work, we developed a photoactivatable Pt(IV) prodrug-backboned polymeric nanoparticle system (CNPPtCP/si(c-fos)) for light-controlled si(c-fos) delivery and synergistic photoactivated chemotherapy (PACT) and RNA interference (RNAi) on platinum-resistant ovarian cancer (PROC). Upon blue-light irradiation (430 nm), CNPPtCP/si(c-fos) generates oxygen-independent N3• with mild oxidation energy for efficient endo/lysosomal escape through N3•-assisted photochemical internalization with less gene deactivation. Thereafter, along with Pt(IV) prodrug activation, CNPPtCP/si(c-fos) dissociates to release active Pt(II) and unpack si(c-fos) simultaneously. Both in vitro and in vivo results demonstrated that CNPPtCP/si(c-fos) displayed excellent synergistic therapeutic efficacy on PROC with low toxicity. This PACT prodrug-backboned polymeric nanoplatform may provide a promising gene/drug codelivery tactic for treatment of various hard-to-tackle cancers.

Single-Stimulus Dual-Drug Sensitive Nanoplatform for Enhanced Photoactivated Therapy.

Photoactivated therapy has become a complementary and attractive modality for traditional cancer treatment. Herein, we demonstrated a novel single-stimulus dual-drug sensitive nanoplatform, Cur-loaded Dex-Pt(N3) nanoparticles (Cur@DPNs) for enhanced photoactivated therapy. The developed Cur@DPNs could be photoactivated by UVA light to simultaneously generate instant reactive oxygen species from Cur for fast photodynamic therapy and release lasting Pt(II) from Pt(N3) for long-acting photochemotherapy. Compared with small free drugs and individual photoactivated therapy, Cur@DPNs exhibited enhanced photoactivated cytotoxicity and in vivo antitumor efficacy with low systemic toxicity accompanied. Therefore, the single-stimulus dual-drug sensitive nanoplatform is convinced to be a promising strategy for multidrug delivery, site-selective and combinational photoactivated therapy in the near future.

Biomimetic Tertiary Lymphoid Structures with Microporous Annealed Particle Scaffolds for Cancer Postoperative Therapy.

Immunotherapy plays a vital role in cancer postoperative treatment. Strategies to increase the variety of immune cells and their sustainable supply are essential to improve the therapeutic effect of immune cell-based immunotherapy. Here, inspired by tertiary lymphoid structures (TLSs), we present a microfluidic-assisted microporous annealed particle (MAP) scaffold for the persistent recruitment of diverse immune cells for cancer postoperative therapy. Based on the thermochemical responsivity of gelatin methacryloyl (GelMA), the MAP scaffold was fabricated by physical cross-linking and sequential photo-cross-linking of GelMA droplets, which were prepared by microfluidic electrospraying. Due to the encapsulation of liquid nitrogen-inactivated tumor cells and immunostimulant, the generated MAP scaffold could recruit a large number of immune cells, involving T cells, macrophages, dendritic cells, B cells, and natural killer cells, thereby forming the biomimetic TLSs in vivo. In addition, by combination of immune checkpoint inhibitors, a synergistic anticancer immune response was provoked to inhibit tumor recurrence and metastasis. These properties make the proposed MAP scaffold-based artificial TLSs of great value for efficient cancer postoperative therapy.

Pt(IV) prodrug initiated microparticles from microfluidics for tumor chemo-, photothermal and photodynamic combination therapy.

Multimodal treatment modalities hold great potential for cancer therapy, thus current efforts are focusing on the development of more effective and practical synergistic therapeutic platforms. Herein, we present a novel trans, trans,trans-[Pt(N3)2(OH)2(py)2] (Pt(IV)) prodrug-initiated hydrogel microparticles (MICG-Pt) with indocyanine green (ICG) encapsulation by microfluidics for efficiently synergistic chemo-, photothermal (PTT) and photodynamic therapy (PDT). The employed Pt(IV) could not only serves as an initiator to generate azidyl radical (N3 •) for photo-polymerization of methacrylate gelatin (GelMA) matrix, but also be reduced to high cytotoxic platinum(II) (Pt(II)) species for tumor chemotherapy. The laden ICG with highly photothermal heating ability and intrinsic reactive oxygen species (ROS) productivity endows the MICG-Pt with effective PTT/PDT performances upon near-infrared (NIR) light irradiation. In addition, benefiting from the production of oxygen during the photo-activation process of Pt(IV), the PDT efficacy of ICG-laden MICG-Pt could be further enhanced. Based on these advantages, we have demonstrated that the MICG-Pt could significantly eliminate cancer cells in vitro, and remarkably suppressed the tumor growth in vivo via synergistic chemotherapy, PTT, and PDT. These results indicate that such Pt(IV)-initiated hydrogel microparticles are ideal candidates of multimodal treatment platforms, holding great prospects for cancer therapy.

Stimuli-Responsive Gene Delivery Nanocarriers for Cancer Therapy.

Gene therapy provides a promising approach in treating cancers with high efficacy and selectivity and few adverse effects. Currently, the development of functional vectors with safety and effectiveness is the intense focus for improving the delivery of nucleic acid drugs for gene therapy. For this purpose, stimuli-responsive nanocarriers displayed strong potential in improving the overall efficiencies of gene therapy and reducing adverse effects via effective protection, prolonged blood circulation, specific tumor accumulation, and controlled release profile of nucleic acid drugs. Besides, synergistic therapy could be achieved when combined with other therapeutic regimens. This review summarizes recent advances in various stimuli-responsive nanocarriers for gene delivery. Particularly, the nanocarriers responding to endogenous stimuli including pH, reactive oxygen species, glutathione, and enzyme, etc., and exogenous stimuli including light, thermo, ultrasound, magnetic field, etc., are introduced. Finally, the future challenges and prospects of stimuli-responsive gene delivery nanocarriers toward potential clinical translation are well discussed. The major objective of this review is to present the biomedical potential of stimuli-responsive gene delivery nanocarriers for cancer therapy and provide guidance for developing novel nanoplatforms that are clinically applicable.

Cryo-shocked cancer cell microgels for tumor postoperative combination immunotherapy and tissue regeneration.

Prevention of recurrence/metastasis and tissue regeneration are critical for post-surgery treatment of malignant tumors. Here, to address these needs, a novel type of microgel co-loading cryo-shocked cancer cells, immunoadjuvant, and immune checkpoint inhibitor is presented by microfluidic electrospray technology and liquid nitrogen treatment. Owing to the encapsulation of cryo-shocked cancer cells and immunoadjuvant, the microgels can recruit dendritic cells and activate them in situ, and evoke a robust immune response. Moreover, with the combination of the immune checkpoint inhibitor, the antitumor immune response is further enhanced by inhibiting the interaction of PD1 and PDL1. With this, the excellent anti-recurrence and anti-metastasis efficacy of the microgels are demonstrated in an orthotopic breast cancer mouse model. Besides, because of the excellent biocompatibility and appropriate degradation performance, the microgels can provide support for normal cell adhesion and growth, which is beneficial to tissue reconstruction. These properties indicate the great value of the cryo-shocked cancer cell microgels for efficient tumor postoperative combination immunotherapy and tissue regeneration.

Multi-Bioinspired MOF Delivery Systems from Microfluidics for Tumor Multimodal Therapy.

Metal-organic framework (MOF)-based drug delivery systems have demonstrated values in oncotherapy. Current research endeavors are centralized on the functionality enrichment of featured MOF materials with designed versatility for synergistic multimodal treatments. Here, inspired by the multifarious biological functions including ferroptosis pattern, porphyrins, and cancer cell membrane (CCM) camouflage technique, novel multi-biomimetic MOF nanocarriers from microfluidics are prepared. The Fe3+ , meso-tetra(4-carboxyphenyl)porphine and oxaliplatin prodrug are incorporated into one MOF nano-system (named FeTPt), which is further cloaked by CCM to obtain a "Trojan Horse"-like vehicle (FeTPt@CCM). Owing to the functionalization with CCM, FeTPt@CCM can target and accumulate at the tumor site via homologous binding. After being internalized by cancer cells, FeTPt@CCM can be activated by a Fenton-like reaction as well as a redox reaction between Fe3+ and glutathione and hydrogen peroxide to generate hydroxyl radical and oxygen. Thus, the nano-platform effectively initiates ferroptosis and improves photodynamic therapy performance. Along with the Pt-drug chemotherapy, the nano-platform exhibits synergistic multimodal actions for inhibiting cancer cell proliferation in vitro and suppressing tumor growth in vivo. These features indicate that such a versatile biomimetic MOF delivery system from microfluidics has great potential for synergistic cancer treatment.

Designing Bioorthogonal Reactions for Biomedical Applications.

Bioorthogonal reactions are a class of chemical reactions that can be carried out in living organisms without interfering with other reactions, possessing high yield, high selectivity, and high efficiency. Since the first proposal of the conception by Professor Carolyn Bertozzi in 2003, bioorthogonal chemistry has attracted great attention and has been quickly developed. As an important chemical biology tool, bioorthogonal reactions have been applied broadly in biomedicine, including bio-labeling, nucleic acid functionalization, drug discovery, drug activation, synthesis of antibody-drug conjugates, and proteolysis-targeting chimeras. Given this, we summarized the basic knowledge, development history, research status, and prospects of bioorthogonal reactions and their biomedical applications. The main purpose of this paper is to furnish an overview of the intriguing bioorthogonal reactions in a variety of biomedical applications and to provide guidance for the design of novel reactions to enrich bioorthogonal chemistry toolkits.

Photopolymerized 3D Printing Scaffolds with Pt(IV) Prodrug Initiator for Postsurgical Tumor Treatment.

Biomedical scaffolds have shown great success in postsurgical tumor treatment; their current efforts are focusing on eradicating residual tumor cells and circulating tumor cells and simultaneously repairing postoperative tissue defects. Herein, we report a novel photopolymerized 3D scaffold with Pt(IV) prodrug initiator to achieve the desired features for tumor comprehensive therapy. The Pt-GelMA scaffold was fabricated from the microfluidic 3D printing of methacrylate gelatin (GelMA) bioinks through a Pt(IV)-induced photocrosslinked process without any other additional photoinitiator and chemotherapeutic drug. Thus, the resultant scaffold displayed efficient cell killing ability against breast cancer cells in vitro and significantly inhibited the local tumor growth and distant metastases on an orthotopic postoperative breast cancer model in vivo. Besides, benefiting from their ordered porous structures and favorable biocompatibility, the scaffolds supported the cell attachment, spreading, and proliferation of normal cells in vitro; could facilitate the nutrient transportation; and induced new tissue ingrowth for repairing tissue defects caused by surgery. These properties indicate that such 3D printing scaffold is a promising candidate for efficient postoperative tumor treatment in the practical application.

Hierarchical Microparticles Delivering Oxaliplatin and NLG919 Nanoprodrugs for Local Chemo-immunotherapy.

Chemo-immunotherapy shows promising antitumor therapeutic outcomes for many primary cancers. Research in this area has been focusing on developing an ideal formula that enables the potent efficacy of chemo-immunotherapy in combating various cancers with reduced systemic toxicity. Herein, we present novel hierarchical hydrogel microparticles (MDDP) delivering oxaliplatin and NLG919 nanoprodrugs for local chemo-immunotherapy with desired features. The oxaliplatin prodrug and NLG919 were efficiently loaded in the dual-drug polymeric nanoparticles (DDP NPs), which were further encapsulated into a MDDP by using microfluidic technology. When delivered to the tumor site, the DDP NPs will be sustainedly released from the MDDP and retained locally to reduce systemic toxicity. After being endocytosed by cancer cells, the cytotoxic oxaliplatin and NLG919 could be successfully triggered to release from DDP NPs in a chain-shattering manner, leading to the immunogenic cell death (ICD) of tumor cells and the suppression of intratumoral immunosuppressive Tregs, respectively. With the assistance of an immune modulator, the chemotherapeutics-induced ICD could trigger robust systemic antitumor immune responses, presenting superior synergistic antitumor efficacies. Thus, the hierarchical microparticles could substantially inhibit the growth of mouse subcutaneous colorectal tumors, breast tumors, and colorectal tumors with large initial sizes via synergized chemo-immunotherapy, showing great potential in the practical clinical application of oncotherapy.

Near-Infrared Light-Triggered Polyprodrug/siRNA Loaded Upconversion Nanoparticles for Multi-Modality Imaging and Synergistic Cancer Therapy.

Stimuli-responsive nanosystems have been widely applied as effective modalities for drug/gene co-delivery in cancer treatment. However, precise spatiotemporal manipulations of drug/gene co-delivery, as well as multi-modality imaging-guided cancer therapy, still remain a daunting challenge. Here, multifunctional polyprodrug/siRNA loaded upconversion nanoparticles (UCNPs) are reported that combine computed tomography (CT), magnetic resonance (MR), and upconversion luminescence (UCL) tri-modality imaging and near-infrared (NIR) light-activated drug/gene on-demand delivery. The photoactivatable platinum(IV) (Pt(IV))-backbone polymers (PPt) and the siRNA targeting polo-like kinase 1 (Plk1) are loaded on the surface of polyethyleneimine (PEI)-coated UCNPs (PUCNP) to obtain the multifunctional polyprodrug/siRNA loaded UCNPs (PUCNP@Pt@siPlk1). The PUCNP@Pt@siPlk1 can be served as a "nanotransducer" to convert NIR light (980 nm) into local ultraviolet (UV) to visible light for the cleavage of photosensitive PPt, resulting in the simultaneous on-demand release of high toxic platinum(II) (Pt(II)) and siPlk1. Meanwhile, the PUCNP@Pt@siPlk1 has CT, T1 -weighted MR, and UCL tri-modality imaging abilities. Based on these merits, PUCNP@Pt@siPlk1 displayed excellent synergistic therapeutic efficacy via image-guided and NIR light-activated platinum-based chemotherapy and RNA interfering in vitro and in vivo. Thus, this developed nanosystem with NIR light-controlled drug/gene delivery and multi-modality imaging abilities, will display great potential in combining chemotherapy and gene therapy.

Continuing Cetuximab vs Bevacizumab plus chemotherapy after first progression in wild-type KRAS, NRAS and BRAF V600E metastatic colorectal cancer: a randomized phase II trial.

To evaluate the clinical efficacy of continuing cetuximab vs bevacizumab plus chemotherapy crossover after first progression to cetuximab regimen in wild-type KRAS, NRAS and BRAF V600E mCRC, we conducted this prospective, open-label and randomized phase 2 trial in three cancer centers from Oct 1, 2016 to July 1, 2020. Eligibility criteria included documented progressive disease during or after first-line treatment with cetuximab regimen; second biopsy confirmed as KRAS, NRAS and BRAF V600E wild-type mCRC. Patients were randomized to arm A (cetuximab+chemo) or arm B (bevacizumab+chemo) with second-line chemotherapy crossover. The primary end point was progression free survival (PFS). Secondary end points included objective response rate (ORR), overall survival (OS) and toxicity. Tissue VEGFA, ERBB2 and MET mRNA were examined by real time RT-PCR. A total of 104 patients (53 in arm A and 51 in arm B) were enrolled. Median PFS was 7.7 months (95% CI: 6.5-8.9) for arm A and 6.3 months (95% CI: 4.5-8.1) for arm B (p=0.931). Median OS was 18.2 months (95% CI: 14.5-21.9) for arm A and 16.4 months (95% CI: 14.2-18.6) for arm B (p=0.339). The ORR was 28.3% and 19.6% in arm A and arm B (p=0.31), respectively. MET mRNA was highly expressed in the cetuximab-progressed tumors, but treatment responsiveness to cetuximab or bevacizumab in each arm was not correlated with the MET expression level. The results showed no significant difference in PFS, OS and ORR between the two arms, but a trend in favor of the cetuximab continuation plus chemotherapy crossover was examined in all end points. High expression of MET in cetuximab-progressed tumors may indicate an existence of MET-dependent tumor cell population.

Curcumin-loaded PEGylated mesoporous silica nanoparticles for effective photodynamic therapy.

Curcumin (Cur) can be used as a photosensitizer in the photodynamic therapy (PDT) of cancer, but its low bioavailability limits further clinical application. A mesoporous silica-based drug delivery system (PEGylated mesoporous silica nanoparticles, MSN-PEG@Cur) was designed to solve the problem. The successful preparation of MSN-PEG@Cur was characterized by several physico-chemistry techniques. The endocytosis, ROS generation and in vitro anti-cancer efficacy of MSN-PEG@Cur were evaluated in detail step by step. The results indicated that MSN-PEG@Cur could be effectively endocytosed into cells and release Cur, which can promptly generate ROS upon irradiation, achieving effective PDT in cancer treatment. This MSNs-based drug delivery system provides an alternative strategy for Cur loading and PDT of cancer.

Photoactivated polyprodrug nanoparticles for effective light-controlled Pt(iv) and siRNA codelivery to achieve synergistic cancer therapy.

Endo/lysosomal escape and the subsequent controllable/precise release of drugs and genes are key challenges for efficient synergistic cancer therapy. Herein, we report a photoactivated polyprodrug nanoparticle system (PPNPsiRNA) centered on effective light-controlled codelivery of Pt(iv) prodrug and siRNA for synergistic cancer therapy. Under green-light irradiation, PPNPsiRNA can sustainedly generate oxygen-independent azidyl radicals to facilitate endo/lysosomal escape through the photochemical internalization (PCI) mechanism. Besides, concurrent Pt(ii) release and siRNA unpacking could occur in a controllable manner after the decomposition of Pt(iv), main chain shattering of photoactivated polyprodrug and the PPNPsiRNA disassociation. Based on these innovative features, excellent synergistic therapeutic efficacy of chemo- and RNAi therapies of PPNPsiBcl-2 could be achieved on ovarian cancer cells under light irradiation. The facile synthesized and prepared photoactivatable polyprodrug nanoparticle system provides a new strategy for effective gene/drug codelivery, where controllable endo/lysosomal escape and the subsequent drug/gene release/unpacking play vital roles, which could be adopted as a versatile codelivery nanoplatform for the treatment of various cancers.

Morphology tunable and acid-sensitive dextran-doxorubicin conjugate assemblies for targeted cancer therapy.

Stimuli-responsive and targetable nanomedicine systems have been widely applied as effective modalities for drug delivery and tumor therapeutics. Particle shape is also important for the biodistribution and cellular uptake in drug delivery applications. Here, morphology tunable and acid-responsive dextran-doxorubicin conjugate assemblies of DD-M and DDF-V for targeted doxorubicin (DOX) delivery were constructed, which contain the following favorable advantages: (1) one-pot synthesis of the drug loaded system with a Schiff base reaction is a green chemistry method which is better than the conventional drug conjugation/encapsulation methods. (2) The morphology of the nanoparticles could be regulated from a micelle (DD-M) to vesicle (DDF-V) structure by either introducing folic acid (FA) or not. (3) The abundant hydroxyl groups and electronegativity give DD-M and DDF-V superior stability in the physiological environment. (4) Besides, the multifunctional DDF-V with its important merits including tumor-targeting ability and acid-responsiveness is specific for DOX delivery in cancer therapy. (5) Compared to free DOX and DD-M, DDF-V displayed enhanced anti-tumor efficacy both in vitro and in vivo without obvious systematic toxicity. The morphology tunable, acid-sensitive and targetable nanosystem could be a promising strategy for site-specific drug delivery and potential cancer therapy in the future.

Light-activatable dual prodrug polymer nanoparticle for precise synergistic chemotherapy guided by drug-mediated computed tomography imaging.

The synergistic efficacy and clinical application of light-responsive polymeric co-delivery systems are severely restricted by uncontrollable/imprecise drug loading, release, and adverse effects caused by the introduction of additional light-responsive molecules or contrast agents when diagnostic imaging is applied to guide therapy. Here, we report the design of a light-activatable dual prodrug polymer nanoparticle (DPP NP) for precise synergistic chemotherapy guided by drug-mediated computed tomography (DMCT) imaging without the introduction of any additional diagnostic imaging agent. DPP NP enables visible light-triggered prodrug polymer backbone cleavage and bioactive Pt(II) release in cancer cell/tumor site; the light-cleaved polymer fragments are further hydrolyzed to produce demethyl cantharidin (DMC). Notably, the drug loading ratio of Pt(IV) and DMC in DPP NP was fixed at an optimal value to achieve maximum synergistic cancer cell killing, which was kept even after cellular uptake, thereby resulting in enhanced synergistic antitumor efficacy both in vitro and in vivo. Because of the high content of the heavy metal Pt in the polymer chain, the spatial/temporal dynamic biodistribution as well as metabolism of DPP NP in vivo can be monitored by Pt DMCT imaging to guide the light irradiation parameters for optimized light-activatable synergistic chemotherapy. Guided by Pt DMCT imaging, DPP NP was able to achieve an improved light-activatable antitumor efficacy, with 75% tumors fully cured and low toxicity. The light-activatable DDP NP system exhibits tremendous potential as precise theranostic nanomedicine. STATEMENT OF SIGNIFICANCE: The synergistic efficacy and clinical application of light-responsive polymeric co-delivery systems are severely restricted by uncontrollable/imprecise drug loading, delivery, and release, as well as adverse effects caused by the introduction of additional light-responsive molecules or contrast agents when diagnostic imaging is applied to guide therapy. Herein, we report the design of a light-activatable dual prodrug polymer nanoparticle (DPP NP) for precise synergistic chemotherapy guided by drug-mediated computed tomography imaging without the introduction of any additional diagnostic imaging agents. Notably, the drug loading ratio of Pt(II) and DMC in DPP NP was fixed at an optimal value to achieve maximum synergistic cancer cell killing, which was kept even after cellular uptake, thereby resulting in enhanced synergistic antitumor efficacy both in vitro and in vivo. The light-activatable DDP NP system exhibits tremendous potential as precise theranostic nanomedicine.

Sandwich-Like Fibers/Sponge Composite Combining Chemotherapy and Hemostasis for Efficient Postoperative Prevention of Tumor Recurrence and Metastasis.

Intraoperative bleeding is an essential factor leading to the earliest recurrence and tumor metastasis frequently seen after resection of solid tumors. Local drug delivery implants show the unique advantages on postoperative cancer therapy. Herein, a sandwich-like cisplatin-loaded fibers/sponge composite (CFSC) combining chemotherapy and hemostasis is constructed. The obtained implantable CFSC is able to simultaneously stop bleeding and absorb disseminated tumor cells after tumor resection. More importantly, sustained released cisplatin can kill local residual tumor cells as well as those concentrated in the CFSC, which significantly inhibits local tumor recurrence and distant tumor metastasis on the subcutaneous postoperative recurrence model and metastasis models. This dual functional implant strategy with low toxicity to healthy organs may inspire new aspects for efficient postoperative cancer therapy.

Biphasic drug release from electrospun polyblend nanofibers for optimized local cancer treatment.

The application of the biphasic release profile furnished by electrospun polyblend nanofibers for local cancer treatment was investigated. By adjusting the weight ratio of the hydrophilic polymer (poly(ethylene oxide), PEO) and hydrophobic polymer (poly(l-lactide), PLA), PEO10-PLA90 fibers with typical biphasic release kinetics were successfully prepared. Due to their unique release profile, PEO10-PLA90 fibers can quickly access the tumor site in vivo at a high drug content within 1 h and keep at a high level for longer than two weeks. In vivo antitumor and safety studies demonstrated that PEO10-PLA90 fibers can achieve optimized local cancer treatment efficacy and avoid undesired adverse reactions. The biphasic drug release profile provided by the polyblend electrospun technology was proven to be a new conception for local chemotherapy.

Pt(iv) prodrug-backboned micelle and DCA loaded nanofibers for enhanced local cancer treatment.

Drug-loaded nanocarriers, especially polymeric micelles, have attracted much attention in recent years, but their application is still limited due to their systemic toxicity and unsatisfactory tumor delivery efficiency through intravenous administration. In this study, we demonstrated an implantable prodrug micelle/small drug molecule co-loaded nanofiber strategy for enhanced local cancer treatment. A reduction-responsive Pt(iv) prodrug-backboned micelle, as a prodrug of bioactive Pt(ii), and DCA were co-electrospun into poly(vinyl alcohol) (PVA) nanofibers. The prepared Pt(iv) prodrug-backboned micelle/DCA fibers exerted a synergistic effect on cancer cells. In contrast to systemic administration of chemotherapeutic agents, this implantable device exhibited enhanced anti-cancer efficacy with lower systemic toxicity against advanced cervical cancer in vivo. This work provides a facile, efficient and safe prospect of using a prodrug micelle and small molecular drug co-loaded electrospun device for localized and advanced cancer therapy.