Emerging Chemodynamic Nanotherapeutics for Cancer Treatment.

Chemodynamic therapy (CDT) has emerged as a transformative paradigm in the realm of reactive oxygen species -mediated cancer therapies, exhibiting its potential as a sophisticated strategy for precise and effective tumor treatment. CDT primarily relies on metal ions and hydrogen peroxide to initiate Fenton or Fenton-like reactions, generating cytotoxic hydroxyl radicals. Its notable advantages in cancer treatment are demonstrated, including tumor specificity, autonomy from external triggers, and a favorable side-effect profile. Recent advancements in nanomedicine are devoted to enhancing CDT, promising a comprehensive optimization of CDT efficacy. This review systematically elucidates cutting-edge achievements in chemodynamic nanotherapeutics, exploring strategies for enhanced Fenton or Fenton-like reactions, improved tumor microenvironment modulation, and precise regulation in energy metabolism. Moreover, a detailed analysis of diverse CDT-mediated combination therapies is provided. Finally, the review concludes with a comprehensive discussion of the prospects and intrinsic challenges to the application of chemodynamic nanotherapeutics in the domain of cancer treatment.

Precisely Self-Cooperative Nanoassembly Enables Photothermal/Ferroptosis Synergistic Tumor Eradication.

Ferroptosis is identified as a potential target for anticancer therapy. However, most conventional ferroptosis inducers not only fail to trigger intracellular lipid peroxidation storm, but are also prone to cause ferroptosis-related toxicity through off-target destruction of intracellular antioxidant defense systems. Therefore, a potent and highly tumor-specific ferroptosis induction modality is desired. Herein, a self-cooperative nanomedicine for imaging-guided photothermal ferrotherapy, which is fabricated based on molecular nanoassembly (NA) of DiR (a photothermal probe) and ferrocene (Fc, a reactant of the Fenton reaction), is elaborately exploited. DiR-elicited hyperthermia induces both photothermal therapy (PTT) and a significant acceleration of the kinetics of the Fc-involved Fenton reaction, collaboratively causing a lipid peroxidation storm in tumor cells. In turn, plenty of lipid peroxides boost PTT through the downregulation of heat shock protein 90. As expected, such a self-cooperative NA demonstrates synergetic tumor eradication in the 4T1 breast tumor-bearing mice xenograft model. This study offers a novel nanotherapeutic paradigm for precise multimodal cancer therapy.

Small molecule-engineered nanoassembly for lipid peroxidation-amplified photodynamic therapy.

Photodynamic therapy (PDT), extensively explored as a non-invasive and spatio-temporal therapeutic modality for cancer treatment, encounters challenges related to the brief half-life and limited diffusion range of singlet oxygen. Lipid peroxides, formed through the oxidation of polyunsaturated fatty acids by singlet oxygen, exhibit prolonged half-life and potent cytotoxicity. Herein, we employed small molecule co-assembly technology to create nanoassemblies of pyropheophorbide a (PPa) and docosahexaenoic acid (DHA) to bolster PDT. DHA, an essential polyunsaturated fatty acid, co-assembled with PPa to generate nanoparticles (PPa@DHA NPs) without the need for additional excipients. To enhance the stability of these nanoassemblies, we introduced 20% DSPE-PEG2k as a stabilizing agent, leading to the formation of PPa@DHA PEG2k NPs. Upon laser irradiation, PPa-produced singlet oxygen swiftly oxidized DHA, resulting in the generation of cytotoxic lipid peroxides. This process significantly augmented the therapeutic efficiency of PDT. Consequently, tumor growth was markedly suppressed, attributed to the sensitizing and amplifying impact of DHA on PDT in a 4T1 tumor-bearing mouse model. In summary, this molecule-engineered nanoassembly introduces an innovative co-delivery approach to enhance PDT with polyunsaturated fatty acids.

Self-engineered binary nanoassembly enabling closed-loop glutathione depletion-amplified tumor ferroptosis.

Ferroptosis has emerged as a promising target for anticancer treatment, comprising iron-dependent lipid peroxidation and excessive accumulation of reactive oxygen species. Given that glutathione (GSH) overproduced in tumor cells antagonizes the cellular oxidation system, the reduction of GSH production has been extensively explored to induce ferroptosis. However, reducing GSH production alone is insufficient to trigger an intense lipid peroxidation storm. It is highly desirable to achieve systemic GSH depletion through simultaneous production and consumption intervention. Herein, we propose a bidirectional blockage strategy for closed-loop GSH depletion-amplified tumor ferroptosis. Sorafenib (Sor) and gambogic acid (GA) were elaborately fabricated as a self-engineered carrier-free nanoassembly without any nanocarrier materials. The PEGylated dual-drug nanoassembly enables favorable co-delivery and tumor-specific release of Sor and GA. Notably, a closed-loop GSH depletion is observed as a result of a Sor-induced decrease in GSH production and GA-accelerated GSH consumption in vitro and in vivo. As expected, this uniquely engineered dual-drug nanoassembly demonstrates vigorous antitumor activity in 4T1 breast tumor-bearing mice. This study presents a novel nanotherapeutic modality for ferroptosis-driven cancer treatment.

Nitric oxide-driven nanotherapeutics for cancer treatment.

Nitric oxide (NO) is a gaseous molecule endowed with diverse biological functions, offering vast potential in the realm of cancer treatment. Considerable efforts have been dedicated to NO-based cancer therapy owing to its good biosafety and high antitumor activity, as well as its efficient synergistic therapy with other antitumor modalities. However, delivering this gaseous molecule effectively into tumor tissues poses a significant challenge. To this end, nano drug delivery systems (nano-DDSs) have emerged as promising platforms for in vivo efficient NO delivery, with remarkable achievements in recent years. This review aims to provide a summary of the emerging NO-driven antitumor nanotherapeutics. Firstly, the antitumor mechanism and related clinical trials of NO therapy are detailed. Secondly, the latest research developments in the stimulation of endogenous NO synthesis are presented, including the regulation of nitric oxide synthases (NOS) and activation of endogenous NO precursors. Moreover, the emerging nanotherapeutics that rely on tumor-specific delivery of NO donors are outlined. Additionally, NO-driven combined nanotherapeutics for multimodal cancer theranostics are discussed. Finally, the future directions, application prospects, and challenges of NO-driven nanotherapeutics in clinical translation are highlighted.

Self-adaptive nanoassembly enabling turn-on hypoxia illumination and periphery/center closed-loop tumor eradication.

Solid tumors are regarded as complex evolving systems rather than simple diseases. Self-adaptive synthetic therapeutics are required to cope with the challenges of entire tumors; however, limitations in accurate positioning and destruction of hypoxic niches seriously hinder complete tumor eradication. In this study, we engineer a molecular nanoassembly of sorafenib and a hypoxia-sensitive cyanine probe (CNO) to facilitate periphery/center synergistic cancer therapies. The self-adaptive nanoassembly with cascade drug release features not only effectively kills the peripheral tumor cells in normoxic rims but precisely illuminates hypoxic niches following the reduction of CNO by nitroreductase. More important, CNO is found to synergistically induce tumor ferroptosis with sorafenib via nicotinamide adenine dinucleotide phosphate (NADPH) depletion in hypoxic niches. As expected, the engineered nanoassembly demonstrates self-adaptive hypoxic illumination and periphery/center synergetic tumor eradication in colon and breast cancer BALB/c mouse xenograft models. This study advances turn-on hypoxia illumination and chemo-ferroptosis toward clinical applicability.

Reduction-Hypersensitive Podophyllotoxin Prodrug Self-Assembled Nanoparticles for Cancer Treatment.

Podophyllotoxin (PPT) has shown strong antitumor effects on various types of cancers. However, the non-specific toxicity and poor solubility severely limits its clinical transformation. In order to overcome the adverse properties of PPT and explore its clinical potential, three novel PTT-fluorene methanol prodrugs linked by different lengths of disulfide bonds were designed and synthesized. Interestingly, the lengths of the disulfide bond affected the drug release, cytotoxicity, pharmacokinetic characteristics, in vivo biodistribution and antitumor efficacy of prodrug NPs. To be more specific, all three PPT prodrugs could self-assemble into uniform nanoparticles (NPs) with high drug loading (>40%) via the one-step nano precipitation method, which not only avoids the use of surfactants and cosurfactants, but also reduces the systemic toxicity of PPT and increases the tolerated dose. Among the three prodrug NPs, FAP NPs containing α-disulfide bond showed the most sensitive tumor-specific response and fastest drug release rate, thus demonstrating the strongest in vitro cytotoxicity. In addition, three prodrug NPs showed prolonged blood circulation and higher tumor accumulation. Finally, FAP NPs demonstrated the strongest in vivo antitumor activity. Our work will advance the pace of podophyllotoxin towards clinical cancer treatment.

Molecularly self-fueled nano-penetrator for nonpharmaceutical treatment of thrombosis and ischemic stroke.

Thrombotic cerebro-cardiovascular diseases are the leading causes of disability and death worldwide. However, current drug therapeutics are compromised by narrow therapeutic windows, unsatisfactory thrombolysis effects, severe bleeding events, and high recurrence rates. In this study, we exploit a self-propelling nano-penetrator with high fuel loading and controllable motion features, which is molecularly co-assembled using a photothermal photosensitizer (DiR) and a photothermal-activable NO donor (BNN6). The precisely engineered nano-penetrator of the BNN6-DiR fuel pair shows distinct advantages in terms of NO productivity and autonomous motion under laser irradiation. In animal models of artery/vein thrombosis and acute ischemic stroke, the self-fueled nano-penetrator enables self-navigated thrombus-homing accumulation, self-propelled clot deep penetration, fluorescence image-guided photothermal/mechanical thrombolysis, and NO-mediated prevention of thrombosis recurrence and acute ischemic stroke salvage. As expected, the molecularly self-fueled nano-penetrator displayed favorable therapeutic outcomes without bleeding risk compared to the clinically available thrombolytic drug. This study offers a facile, safe, and effective nonpharmaceutical modality towards the clinical treatment of thrombosis and ischemic stroke.

Molecularly engineering a dual-drug nanoassembly for self-sensitized photodynamic therapy via thioredoxin impairment and glutathione depletion.

Photodynamic therapy (PDT) has been extensively investigated as a spatiotemporally noninvasive and controllable modality for cancer treatment. However, the intracellular antioxidant systems mainly consisting of thioredoxin (Trx) and glutathione (GSH) significantly counteract and prevent reactive oxygen species (ROS) accumulation, resulting in a serious loss of PDT efficiency. To address this challenge, we propose that PDT can be improved by precisely blocking antioxidant systems. After molecular engineering and synergistic cytotoxic optimization, a DSPE-PEG2K-modified dual-drug nanoassembly (PPa@GA/DSPE-PEG2K NPs) of pyropheophorbide a (PPa) and gambogic acid (GA) is successfully constructed. Interestingly, GA can effectively destroy intracellular antioxidant systems by simultaneously inhibiting Trx and GSH. Under laser irradiation, the cell-killing effects of PPa is significantly enhanced by GA-induced inhibition of the antioxidant systems. As expected, PPa@GA/DSPE-PEG2K nanoparticles demonstrate potent antitumor activity in a 4T1 breast tumor-bearing BALB/c mouse xenograft model. Such a carrier-free self-sensitized nanotherapeutic offers a novel co-delivery strategy for effective PDT.

Lymph node-targeting nanovaccines for cancer immunotherapy.

Cancer immunotherapies such as tumor vaccines, chimeric antigen receptor T cells and immune checkpoint blockades, have attracted tremendous attention. Among them, tumor vaccines prime immune response by delivering antigens and adjuvants to the antigen presenting cells (APCs), thus enhancing antitumor immunotherapy. Despite tumor vaccines have made considerable achievements in tumor immunotherapy, it remains challenging to efficiently deliver tumor vaccines to activate the dendritic cells (DCs) in lymph nodes (LNs). Rational design of nanovaccines on the basis of biomedical nanotechnology has emerged as one of the most promising strategies for boosting the outcomes of cancer immunotherapy. In recent years, great efforts have been made in exploiting various nanocarrier-based LNs-targeting tumor nanovaccines. In view of the rapid advances in this field, we here aim to summarize the latest progression in LNs-targeting nanovaccines for cancer immunotherapy, with special attention to various nano-vehicles developed for LNs-targeting delivery of tumor vaccines, including lipid-based nanoparticles, polymeric nanocarriers, inorganic nanocarriers and biomimetic nanosystems. Moreover, the recent trends in nanovaccines-based combination cancer immunotherapy are provided. Finally, the rationality, advantages and challenges of LNs-targeting nanovaccines for clinical translation and application are spotlighted.

Molecularly Self-Engineered Nanoamplifier for Boosting Photodynamic Therapy via Cascade Oxygen Elevation and Lipid ROS Accumulation.

Photodynamic therapy (PDT) has been extensively explored as a noninvasive cancer treatment modality. However, the dilemma of tumor hypoxia and short half-life of singlet oxygen (1O2) severely restrict the therapeutic efficacy of PDT. Herein, we develop a facile three-in-one PDT nanoamplifier (AA@PPa/Hemin NPs) assembled by pyropheophorbide a (PPa), hemin, and arachidonic acid (AA). Interestingly, AA not only acts as an enabler to facilitate the assembly of PPa and hemin in the construction of ternary hybrid nanoassemblies but also acts as a lipid reactive oxygen species (ROS) amplifier for robust PDT. In tumor cells, hemin plays the role of a catalase-like catalyst that accelerates the production of oxygen (O2) from hydrogen peroxide (H2O2), significantly alleviating tumor hypoxia. Under laser irradiation, vast amounts of 1O2 generated by PPa trigger the peroxidation of AA to produce large amounts of cytotoxic lipid ROS, immensely amplifying the efficiency of PDT by promptly eliciting cellular oxidative stress. As expected, AA@PPa/Hemin NPs exert potent antitumor activity in a 4T1 breast-tumor-bearing BALB/c mice xenograft model. Such a cascade nanohybrid amplifier provides a novel codelivery platform for accurate and effective PDT of cancer.

Elaborately engineering of a dual-drug co-assembled nanomedicine for boosting immunogenic cell death and enhancing triple negative breast cancer treatment.

Pure drug-assembled nanosystem provides a facile and promising solution for simple manufacturing of nanodrugs, whereas a lack of understanding of the underlying assembly mechanism and the inefficient and uncontrollable drug release still limits the development and application of this technology. Here, a simple and practical nanoassembly of DOX and DiR is constructed on basis of their co-assembly characteristics. Multiple interaction forces are found to drive the co-assembly process. Moreover, DOX release from the nanoassembly can be well controlled by the acidic tumor microenvironment and laser irradiation, resulting in favorable delivery efficiency of DiR and DOX in vitro and in vivo. As expected, the nanoassembly with high therapeutic safety completely eradicated the mice triple negative breast cancer cells (4T1) on BALB/c mice, owing to synergistic chemo-photothermal therapy. More interestingly, DiR and DOX synergistically induce immunogenic cell death (ICD) of tumor cells after treatment, enabling the mice to acquire immune memory against tumor growth and recurrence. Such a facile nanoassembly technique provides a novel multimodal cancer treatment platform of chemotherapy/phototherapy/immunotherapy.

Emerging photodynamic nanotherapeutics for inducing immunogenic cell death and potentiating cancer immunotherapy.

Immunotherapy has emerged as a promising cancer treatment modality. Despite the rapid progress in cancer immunotherapy, the therapeutic efficiency and clinical translation of immunotherapy are not as satisfactory as expected, especially for the patients with immune-cold tumors. Immunogenic cell death (ICD) represents a particular form of tumor cell death accompanied by the production of tumor-specific antigens, which facilitates the infiltration of effector T cells and potentiates immune response in solid tumors. Thus, ICD contributes to stimulating immune-cold tumors to immune-hot ones. Increasing evidence shows that photodynamic therapy (PDT) is able to effectively induce ICD. Recently, a variety of photodynamic nanotherapeutics have been developed to induce ICD and to potentiate cancer immunotherapy. Herein, this review outlines the recent advances in the field at the intersection of PDT, nanotechnology and ICD, including PDT-induced ICD, PDT-based synergistic induction of ICD, and multimodal immunotherapy in basis of PDT-induced ICD. Finally, the prospects and challenges of these photodynamic nanotherapeutics in ICD induction-based cancer immunotherapy are discussed.

Pure photosensitizer-driven nanoassembly with core-matched PEGylation for imaging-guided photodynamic therapy.

Pure drug-assembled nanomedicines (PDANs) are currently under intensive investigation as promising nanoplatforms for cancer therapy. However, poor colloidal stability and less tumor-homing ability remain critical unresolved problems that impede their clinical translation. Herein, we report a core-matched nanoassembly of pyropheophorbide a (PPa) for photodynamic therapy (PDT). Pure PPa molecules are found to self-assemble into nanoparticles (NPs), and an amphiphilic PEG polymer (PPa-PEG2K) is utilized to achieve core-matched PEGylating modification via the π‒π stacking effect and hydrophobic interaction between the PPa core and the PPa-PEG2K shell. Compared to PCL-PEG2K with similar molecular weight, PPa-PEG2K significantly increases the stability, prolongs the systemic circulation and improves the tumor-homing ability and ROS generation efficiency of PPa-nanoassembly. As a result, PPa/PPa-PEG2K NPs exert potent antitumor activity in a 4T1 breast tumor-bearing BALB/c mouse xenograft model. Together, such a core-matched nanoassembly of pure photosensitizer provides a new strategy for the development of imaging-guided theragnostic nanomedicines.

Investigating the crucial roles of aliphatic tails in disulfide bond-linked docetaxel prodrug nanoassemblies.

Disulfide bond-bridging strategy has been extensively utilized to construct tumor specificity-responsive aliphatic prodrug nanoparticles (PNPs) for precise cancer therapy. Yet, there is no research shedding light on the impacts of the saturation and cis-trans configuration of aliphatic tails on the self-assembly capacity of disulfide bond-linked prodrugs and the in vivo delivery fate of PNPs. Herein, five disulfide bond-linked docetaxel-fatty acid prodrugs are designed and synthesized by using stearic acid, elaidic acid, oleic acid, linoleic acid and linolenic acid as the aliphatic tails, respectively. Interestingly, the cis-trans configuration of aliphatic tails significantly influences the self-assembly features of prodrugs, and elaidic acid-linked prodrug with a trans double bond show poor self-assembly capacity. Although the aliphatic tails have almost no effect on the redox-sensitive drug release and cytotoxicity, different aliphatic tails significantly influence the chemical stability of prodrugs and the colloidal stability of PNPs, thus affecting the in vivo pharmacokinetics, biodistribution and antitumor efficacy of PNPs. Our findings illustrate how aliphatic tails affect the assembly characteristic of disulfide bond-linked aliphatic prodrugs and the in vivo delivery fate of PNPs, and thus provide theoretical basis for future development of disulfide bond-bridged aliphatic prodrugs.

Molecularly engineered carrier-free co-delivery nanoassembly for self-sensitized photothermal cancer therapy.

BACKGROUND: Photothermal therapy (PTT) has been extensively investigated as a tumor-localizing therapeutic modality for neoplastic disorders. However, the hyperthermia effect of PTT is greatly restricted by the thermoresistance of tumor cells. Particularly, the compensatory expression of heat shock protein 90 (HSP90) has been found to significantly accelerate the thermal tolerance of tumor cells. Thus, a combination of HSP90 inhibitor and photothermal photosensitizer is expected to significantly enhance antitumor efficacy of PTT through hyperthermia sensitization. However, it remains challenging to precisely co-deliver two or more drugs into tumors. METHODS: A carrier-free co-delivery nanoassembly of gambogic acid (GA, a HSP90 inhibitor) and DiR is ingeniously fabricated based on a facile and precise molecular co-assembly technique. The assembly mechanisms, photothermal conversion efficiency, laser-triggered drug release, cellular uptake, synergistic cytotoxicity of the nanoassembly are investigated in vitro. Furthermore, the pharmacokinetics, biodistribution and self-enhanced PTT efficacy were explored in vivo. RESULTS: The nanoassembly presents multiple advantages throughout the whole drug delivery process, including carrier-free fabrication with good reproducibility, high drug co-loading efficiency with convenient dose adjustment, synchronous co-delivery of DiR and GA with long systemic circulation, as well as self-tracing tumor accumulation with efficient photothermal conversion. As expected, HSP90 inhibition-augmented PTT is observed in a 4T1 tumor BALB/c mice xenograft model. CONCLUSION: Our study provides a novel and facile dual-drug co-assembly strategy for self-sensitized cancer therapy.

Photosensitizer-driven nanoassemblies of homodimeric prodrug for self-enhancing activation and synergistic chemo-photodynamic therapy.

Carrier-free prodrug-nanoassemblies have emerged as promising nanomedicines. In particular, the self-assembled nanoparticles (NPs) composed of homodimeric prodrugs with ultrahigh drug loading have attracted broad attention. However, most homodimeric prodrugs show poor self-assembly ability due to their symmetric structures. Herein, we developed photosensitizer-driven nanoassemblies of homodimeric prodrug for self-enhancing activation and chemo-photodynamic synergistic therapy. Methods: In this work, a pyropheophorbide a (PPa)-driven nanoassemblies of an oxidation-responsive cabazitaxel homodimer (CTX-S-CTX) was fabricated (pCTX-S-CTX/PPa NPs). The assembly mechanisms, aggregation-caused quenching (ACQ) effect alleviation, singlet oxygen generation, self-enhancing prodrug activation, cellular uptake, intracellular reactive oxygen species (ROS) generation and synergistic cytotoxicity of pCTX-S-CTX/PPa NPs were investigated in vitro. Moreover, the pharmacokinetics, ex vivo biodistribution and in vivo therapeutic efficacy of pCTX-S-CTX/PPa NPs were studied in mice bearing 4T1 tumor. Results: Interestingly, PPa was found to drive the assembly of CTX-S-CTX, which cannot self-assemble into stable NPs alone. Multiple intermolecular forces were found to be involved in the assembly process. Notably, the nanostructure was destroyed in the presence of endogenous ROS, significantly relieving the ACQ effect of PPa. In turn, ROS generated by PPa under laser irradiation together with the endogenous ROS synergistically promoted prodrug activation. As expected, the nanoassemblies demonstrated potent antitumor activity in a 4T1 breast cancer BALB/c mice xenograft model. Conclusion: Our findings offer a simple strategy to facilitate the assembly of homodimeric prodrugs and provide an efficient nanoplatform for chemo-photodynamic therapy.

Erythrocyte membrane-camouflaged carrier-free nanoassembly of FRET photosensitizer pairs with high therapeutic efficiency and high security for programmed cancer synergistic phototherapy.

Phototherapy has been intensively investigated as a non-invasive cancer treatment option. However, its clinical translation is still impeded by unsatisfactory therapeutic efficacy and severe phototoxicity. To achieve high therapeutic efficiency and high security, a nanoassembly of Forster Resonance Energy Transfer (FRET) photosensitizer pairs is developed on basis of dual-mode photosensitizer co-loading and photocaging strategy. For proof-of-concept, an erythrocyte-camouflaged FRET pair co-assembly of chlorine e6 (Ce6, FRET donor) and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR, FRET acceptor) is investigated for breast cancer treatment. Notably, Ce6 in the nanoassemby is quenched by DiR and could be unlocked for photodynamic therapy (PDT) only when DiR is photobleached by 808-nm laser. As a result, Ce6-caused phototoxicity could be well controlled. Under cascaded laser irradiation (808-660 nm), tumor-localizing temperature rise following laser irradiation on DiR not only induces tumor cell apoptosis but also facilitates the tumor penetration of NPs, relieves tumor hypoxia, and promotes the PDT efficacy of Ce6. Such FRET pair-based nanoassembly provides a new strategy for developing multimodal phototherapy nanomedicines with high efficiency and good security.

Oxidation-strengthened disulfide-bridged prodrug nanoplatforms with cascade facilitated drug release for synergetic photochemotherapy.

One of the major barriers in utilizing prodrug nanocarriers for cancer therapy is the slow release of parent drug in tumors. Tumor cells generally display the higher oxidative level than normal cells, and also displayed the heterogeneity in terms of redox homeostasis level. We previously found that the disulfide bond-linkage demonstrates surprising oxidation-sensitivity to form the hydrophilic sulfoxide and sulphone groups. Herein, we develop oxidation-strengthened prodrug nanosystem loaded with pyropheophorbide a (PPa) to achieve light-activatable cascade drug release and enhance therapeutic efficacy. The disulfide bond-driven prodrug nanosystems not only respond to the redox-heterogeneity in tumor, but also respond to the exogenous oxidant (singlet oxygen) elicited by photosensitizers. Once the prodrug nanoparticles (NPs) are activated under irradiation, they would undergo an oxidative self-strengthened process, resulting in a facilitated drug cascade release. The IC50 value of the PPa@PTX-S-S NPs without irradiation was 2-fold higher than those of NPs plus irradiation. In vivo, the PPa@PTX prodrug NPs display prolonged systemic circulation and increased accumulation in tumor site. The PPa@PTX-S-S NPs showed much higher efficiency than free PTX or the PPa@PTX-C-C NPs to suppress the growth of 4T1 tumors. Therefore, this novel oxidation-strengthened disulfide-bridged prodrug-nanosystem has a great potential in the enhanced efficacy of cancer synergetic photochemotherapy.

Emerging carrier-free nanosystems based on molecular self-assembly of pure drugs for cancer therapy.

The potential toxicity of nanocarrier excipients and complicated preparation technologies have impeded the clinical application of nanomedicine. Recently, pure drug-assembled nanosystems (PDANS) have been widely investigated, due to the unique self-assembly characteristics of pure drug molecules. PDANS provides a facile nanoplatform for developing carrier-free nanomedicine. Herein, the recent trends in PDANS for cancer therapy are outlined. First, the emerging strategies to develop single pure drug-based nanoassemblies are discussed. Second, co-assembly of two or more pure drugs for efficient combination therapy is overviewed. Then, the functional self-assembly of non-cytotoxic agents in tumor sites is presented. Finally, the rational design and self-assembly mechanisms of these unique nanoplatforms are highlighted.