Combination Of Chemodynamic Therapy Research Articles

Redox homeostasis disruptors enhanced cuproptosis effect for synergistic photothermal/chemodynamic therapy

The combination of chemodynamic therapy (CDT) with photothermal therapy (PTT) is a promising approach to enhance antitumor efficacy of chemotherapeutics. In this paper, we developed novel copper-chelated polydopamine (PDA) nanoparticles (NPs) functionalized with hyaluronic acid (HA) (Cu-PDA-HA NPs) to induce apoptosis and cuproptosis-induced cell death, synergistically combining PTT and CDT. Experimental results revealed that Cu-PDA-HA NPs can respond to excessive glutathione (GSH) and hydrogen peroxide (H2O2) in the tumor microenvironment (TME), which will enable their specific degradation, thereby leading to efficient accumulation of Cu2+ within tumor cells. The released Cu2+ ions were reduced by GSH to generate Cu+, which catalyzed in situ Fenton-like reactions to produce cytotoxic hydroxyl radicals (·OH), disrupting cellular redox homeostasis and promoting apoptosis-related CDT. Meanwhile, the photothermal effect of the Cu-PDA-HA NPs could enhance oxidative stress within the tumor by elevating the temperature and subsequent ·OH production. The enhanced oxidative stress made tumor cells more vulnerable to cuproptosis-induced toxicity. Furthermore, in vivo experiments demonstrated that Cu-PDA-HA NPs can still undergo a temperature increase of 18.9°C following 808 nm near-infrared irradiation (1.0 W/cm2, 5 min). Meanwhile, Cu-PDA-HA NPs were able to induce oligomerization of dihydrolipoamide S-acetyltransferase (DLAT) and down-regulate Fe-S cluster proteins such as ferredoxin (FDX1), thereby activating cuproptosis. Therefore, this study provides a novel approach for designing multifunctional nanoparticles with on-demand Cu2+ release and offers a fresh perspective for exploring synergistic therapeutic strategies involving CDT/PTT/apoptosis/cuproptosis.

Tumor-targeted delivery of hyaluronic acid/polydopamine-coated Fe2+-doped nano-scaled metal–organic frameworks with doxorubicin payload for glutathione depletion-amplified chemodynamic-chemo cancer therapy

Chemodynamic therapy (CDT), an emerging cancer treatment modality, uses multivalent metal elements to convert endogenous hydrogen peroxide (H2O2) to toxic hydroxyl radicals (•OH) via a Fenton or Fenton-like reaction, thus eliciting oxidative damage of cancer cells. However, the antitumor potency of CDT is largely limited by the high glutathione (GSH) concentration and low catalytic efficiency in the tumor sites. The combination of CDT with chemotherapy provides a promising strategy to overcome these limitations. In this work, to enhance antitumor potency by tumor-targeted and GSH depletion-amplified chemodynamic-chemo therapy, the hyaluronic acid (HA)/polydopamine (PDA)-decorated Fe2+-doped ZIF-8 nano-scaled metal–organic frameworks (FZ NMs) were fabricated and utilized to load doxorubicin (DOX), a chemotherapy drug, via hydrophobic, π-π stacking and charge interactions. The attained HA/PDA-covered DOX-carrying FZ NMs (HPDFZ NMs) promoted DOX and Fe2+ release in weakly acidic and GSH-rich milieu and exhibited acidity-activated •OH generation. Through efficient CD44-mediated endocytosis, the HPDFZ NMs internalized by CT26 cells not only prominently enhanced •OH accumulation by consuming GSH via PDA-mediated Michael addition combined with Fe2+/Fe3+ redox couple to cause mitochondria damage and lipid peroxidation, but also achieved intracellular DOX release, thus eliciting apoptosis and ferroptosis. Importantly, the HPDFZ NMs potently inhibited CT26 tumor growth in vivo at a low DOX dose and had good biosafety, thereby showing promising potential in tumor-specific treatment.

Self-Reinforced Bimetallic Mito-Jammer for Ca2+ Overload-Mediated Cascade Mitochondrial Damage for Cancer Cuproptosis Sensitization.

Overproduction of reactive oxygen species (ROS), metal ion accumulation, and tricarboxylic acid cycle collapse are crucial factors in mitochondria-mediated cell death. However, the highly adaptive nature and damage-repair capabilities of malignant tumors strongly limit the efficacy of treatments based on a single treatment mode. To address this challenge, a self-reinforced bimetallic Mito-Jammer is developed by incorporating doxorubicin (DOX) and calcium peroxide (CaO2) into hyaluronic acid (HA) -modified metal-organic frameworks (MOF). After cellular, Mito-Jammer dissociates into CaO2 and Cu2+ in the tumor microenvironment. The exposed CaO2 further yields hydrogen peroxide (H2O2) and Ca2+ in a weakly acidic environment to strengthen the Cu2+-based Fenton-like reaction. Furthermore, the combination of chemodynamic therapy and Ca2+ overload exacerbates ROS storms and mitochondrial damage, resulting in the downregulation of intracellular adenosine triphosphate (ATP) levels and blocking of Cu-ATPase to sensitize cuproptosis. This multilevel interaction strategy also activates robust immunogenic cell death and suppresses tumor metastasis simultaneously. This study presents a multivariate model for revolutionizing mitochondria damage, relying on the continuous retention of bimetallic ions to boost cuproptosis/immunotherapy in cancer.

Dual chemodynamic/photothermal therapeutic nanoplatform based on DNA-functionalized prussian blue

The combination of chemodynamic therapy and photothermal therapy has a promising application owing to its impressive anti-cancer effects. However, the degradability of the material and the lack of targeting severely limit its further clinical application. Herein, DNAs containing nucleolin aptamer (AS1411) and different bases sequences were used to functionalize PB NPs for the targeted treatment. Compared to prussian blue, DNA-functionalized prussian blue does not reduce the photothermal properties of prussian blue. Moreover, DNA confers DNA-functionalized prussian blue targeting and higher enzymatic activity, thereby achieving a more effective combination of chemodynamic and photothermal treatment. The therapeutic efficacy of this nanoplatform was evaluated in vivo and in vitro experiments, exhibiting that DNA-functionalized prussian blue nanozyme can maximize the precise control of the therapeutic effect, reduce the toxic and side effects caused by non-specific accumulation on other normal cells, and effectively achieve targeted killing of cancer cells. This work demonstrates that DNA-functionalized prussian blue can improve the efficiency of combined tumor treatment and enhance the application value of prussian blue in tumor treatment, which is expected to provide theoretical support for clinical application.

Ultrasmall Bi/Cu Coordination Polymer Combined with Glucose Oxidase for Tumor Enhanced Chemodynamic Therapy by Starvation and Photothermal Treatment.

Multi-modal combination therapy for tumor is expected to have superior therapeutic effect compared with monotherapy. In this study, a super-small bismuth/copper-gallic acid coordination polymer nanoparticle (BCN) protected by polyvinylpyrrolidone is designed, which is co-encapsulated with glucose oxidase (GOX) by phospholipid to obtain nanoprobe BCGN@L. It shows that BCN has an average size of 1.8 ± 0.7nm, and photothermal conversion of BCGN@L is 31.35% for photothermal imaging and photothermal therapy (PTT). During the treatment process of 4T1 tumor-bearing nude mice, GOX catalyzes glucose in the tumor to generate gluconic acid and hydrogen peroxide (H2 O2 ), which reacts with copper ions (Cu2+ ) to produce toxic hydroxyl radicals (•OH) for chemodynamic therapy (CDT) and new fresh oxygen (O2 ) to supply to GOX for further catalysis, preventing tumor hypoxia. These reactions increase glucose depletion for starvation therapy , decrease heat shock protein expression, and enhance tumor sensitivity to low-temperature PTT. The in vitro and in vivo results demonstrate that the combination of CDT with other treatments produces excellent tumor growth inhibition. Blood biochemistry and histology analysis suggests that the nanoprobe has negligible toxicity. All the positive results reveal that the nanoprobe can be a promising approach for incorporation into multi-modal anticancer therapy.

Photothermal and Acid-Responsive Fucoidan-CuS Bubble Pump Microneedles for Combined CDT/PTT/CT Treatment of Melanoma.

Transdermal cancer therapy faces great challenges in clinical practice due to the low drug transdermal efficiency and the unsatisfactory effect of monotherapy. Herein, we develop a novel bubble pump microneedle system (BPMN-CuS/DOX) by embedding sodium bicarbonate (NaHCO3) into hyaluronic acid microneedles (MNs) loaded with fucoidan-based copper sulfide nanoparticles (Fuc-CuS NPs) and doxorubicin (DOX). BPMN-CuS/DOX can generate CO2 bubbles triggered by an acidic tumor microenvironment for deep and rapid intradermal drug delivery. Fuc-CuS NPs exhibit excellent photothermal effect and Fenton-like catalytic activity, producing more reactive oxygen species (ROS) by photothermal therapy (PTT) and chemodynamic therapy (CDT), which enhances the antitumor efficacy of DOX and reduces the dosage of its chemotherapy (CT). Simultaneously, DOX increases intracellular hydrogen peroxide (H2O2) supplementation and promotes the sustained production of ROS. BPMN-CuS/DOX significantly inhibits melanoma both in vitro and in vivo by the combination of CDT, PTT, and CT. In short, our study significantly enhances the effectiveness of transdermal drug delivery by constructing BPMNs and provides a promising novel strategy for transdermal cancer treatment with multiple therapies.

High aspect ratio plasmonic Au/Ag nanorods-mediated NIR-II photothermally enhanced nanozyme catalytic cancer therapy

Chemodynamic therapy (CDT) is based on the endogenous generation of cytotoxic hydroxyl free radicals (·OH) with high specificity and selectivity between cancer and normal cells. However, its efficacy is often limited by the relatively deficient catalytic activity of nanozymes in the tumor microenvironment (TME). Therefore, the combination of CDT with other strategy to realize synergistic therapy is necessary. Herein, a versatile plasmonic Au/Ag nanorods (abbreviated as Au/Ag NRs) via anisotropic Ag overgrowth on Au nanobipyramids was rationally devised to achieve synergistic nanozyme catalytic therapy and near infrared II (NIR-II) light induced photothermal therapy (PTT) with the guidance of computed tomography (CT) imaging. As TME contains high concentrations of H+ and H2O2, Au/Ag NRs exhibited peroxidase (POD) activity to catalyze H2O2 to produce ·OH, inducing cancer cell death. Meanwhile, Au/Ag NRs showed a preeminent NIR-II photothermal effect. More importantly, the enhanced ·OH generation by in-situ heating up resulting from PTT could conversely inhibit the expression of heat shock proteins (HSPs) to abate their resistance to PTT, realizing self-augmented synergistic effect. The NIR-II photothermally enhanced nanozyme catalytic cancer therapy validly inhibited the cancer proliferation, as demonstrated via both cell and animal assays. Moreover, ideal high-contrast CT imaging was realized, owing to the X-ray attenuation capability of elemental Au. The multifunctional Au/Ag NRs hold potential in oncotherapy with imaging capability, high efficiency and low side effects.

Dual-targeting nanozyme for tumor activatable photo-chemodynamic theranostics

Tumor phototheranostics holds a great promise on account of its high spatiotemporal resolution, tumor-specificity, and noninvasiveness. However, physical limitation of light penetration and “always on” properties of conventional photothermal-conversion agents usually cause difficulty in accurate diagnosis and completely elimination of tumor. Meanwhile, nanozymes mediated Fenton reactions can well utilize the tumor microenvironment (TME) to generate hydroxyl radicals for chemodynamic therapy (CDT), but limited by the concentration of H2O2 in TME and the delivery efficiency of nanozymes. To overcome these problems, a dual-targeting nanozyme (FTRNPs) is developed for tumor-specific in situ theranostics, based upon the assembling of ultrasmall Fe3O4 nanoparticles, 3,3’,5,5’-tetrameth-ylbenzidine (TMB) and the RGD peptide. The FTRNPs after H2O2 treatment exhibits superior photothermal stability and high photothermal conversion efficiency (η = 50.9%). FTRNPs shows extraordinary accumulation and retention in the tumor site by biological/physical dual-targeting, which is 3.54-fold higher than that without active targeting. Cascade-dual-response to TME for nanozymes mediated Fenton reactions and TMB oxidation further improves the accuracy of both photoacoustic imaging and photothermal therapy (PTT). The tumor inhibition rate of photo-chemodynamic therapy is ~ 97.76%, which is ~ 4-fold higher than that of PTT or CDT only. Thus, the combination of CDT and PTT to construct “turn on” nanoplatform is of great significance to overcome their respective limitations. Considering its optimized “all-in-one” performance, this new nanoplatform is expected to provide an advanced theranostic strategy for the future treatment of cancers.Graphical abstract

Boosting Doxorubicin-Induced Mitochondria Apoptosis for the Monodrug-Mediated Combination of Chemotherapy and Chemodynamic Therapy.

Doxorubicin (Dox)-mediated generation of reactive oxygen radicals (ROS) for mitochondrial apoptosis is identified as a new cytotoxic mechanism in addition to the well-established one via nuclear DNA replication interference. However, this mechanism contributes far less than the latter to Dox therapy. This newly identified pathway to make Dox therapy function like the combination of chemodynamic therapy (CDT) and chemotherapy-mediated by Dox alone would be amplified. One-pot nanoconstruction (HEBD) is fabricated based on the chemical reactions driven assemblies among epigallocatechin gallate (EGCG), buthionine sulfoximine (BSO) and formaldehyde in aqueous mediums followed by Dox adsorption. Acid tumor microenvironments allow the liberation of EGCG, BSO, and Dox due to the breakage of Schiff base bonds. EGCG component in HEBD is responsible for targeting mitochondria and disrupting mitochondrial electron transport chain (mETC) to compel electrons leakage in favor of their capture by Dox to produce more ROS. EGCG-induced mETC disruption results in mitochondrial respiration inhibition with alleviated hypoxia in tumor cells while BSO inhibits glutathione biosynthesis to protect ROS from redox depletion, further boosting Dox-induced CDT. This strategy of amplifying CDT pathway for the Dox-mediated combined therapy could largely improve antitumor effect, extend lifespan of tumor-bearing mice, reduce risks of cardiotoxicity and metastasis.

PH-responsive Mannose-modified ferrocene Metal-Organic frameworks with rare earth for Tumor-targeted synchronous Chemo/Chemodynamic therapy

The combination of chemodynamic therapy (CDT) and chemotherapy is a promising strategy to achieve enhanced anticancer effects. Metal-organic frameworks (MOFs), as multifunctional drug delivery vehicles, have received extensive attention in the biomedical field. Carbohydrate has excellent biocompatibility and targeting ability, which can be used as a targeting ligand due to a specific recognition with glycoprotein receptors that overexpress on cancer cell membranes. Herein, the pH-responsive mannose-modified ferrocene MOFs with rare earth metal were synthesized via coordination-driven self-assembly of 1,1′-Ferrocenedicarboxylic acid and ytterbium chloride. Subsequently, DOX@Fc-MOFs-Mann nanoparticles (NPs) were obtained by loading doxorubicin (DOX) and modifying mannose (Mann), where DOX@Fc-MOFs-Mann NPs were able to precisely target HepG2 cells via mannose receptor and slowly decompose in the acidic environment of tumor to release ferrocene, DOX, and Yb3+. Fe2+ in ferrocene effectively activated Fenton reaction to produce high levels of reactive oxygen species (ROS) for irreversible induction of cell apoptosis or necroptosis. Combined with the chemotherapy (CT) ability of DOX, Yb3+ further induced cell death through its own toxicity to successfully achieved the rare earth metal synergistic CDT and CT combination therapy. This synergistic CDT and CT strategy not only opens up new horizons for rare earth metals in biomedical applications but also provides new inspiration into the construction of glycosyl-modified MOFs.

Single-site bimetallic nanosheet for imaging guided mutually-reinforced photothermal-chemodynamic therapy

The combination of chemodynamic therapy (CDT) and photothermal therapy (PTT) is a promising strategy against malignant tumor. However, its clinical application is significantly restricted by the suboptimal Fenton reaction rate, hyperthermia-induced heat shock response, and available agents with superior performance in both CDT and PTT. Herein, we reported an ultrathin single-site bimetallic (copper hexacyanocobaltate) nanosheet (CuCo NS) possessing superior Fenton-like activities and high photothermal conversion efficiency (PCE) (22.62%) for mutually-reinforced PTT-CDT. Within tumor microenvironment, the CuCo NS can not only deplete tumor-overexpressed glutathione (GSH), but also could exert Fenton-like activity to produce OH for CDT. More importantly, the GSH-depletion and OH-generation can be further enhanced by its photothermal effect, resulting in a large intracellular accumulation of OH and lipid peroxides (LPO), which, in turn, could disrupt the heat shock proteins to attenuate the thermoresistance of tumor cells, thus leading to a mutually-reinforced PTT-CDT. Additionally, the high PCE and the presence of high-spin Cu/Co species allow CuCo NS as a photoacoustic/magnetic resonance imaging contrast agent to real-time monitor the agents’ bio-distribution and treatment progress. Both in vitro and in vivo experiments consistently confirmed that the mutually-reinforced PTT-CDT can significantly inhibit the tumor growth via a synergistic ferroptosis-apoptosis pathway. Therefore, this work pioneers a credible paradigm to integrate photothermal and Fenton-like activities into one nanoplatform through single-site dual-metal coordination strategy and provides an ideal candidate for achieving mutually-reinforced PTT-CDT.

PH-programmed responsive nanoplatform for synergistic cancer therapy based on single atom catalysts

The development of stimuli-responsive nanoplatform provides powerful tool for simultaneously enhancing the efficiency and accuracy of cancer therapies. Herein, we develop a pH-programmed responsive and synergistically theranostic nanoplatform based on CaCO3 mineralized single atom iron nanoparticles (SAF NPs). Basically, the highly active site on SAF NPs nanoagent can trigger in-situ produce toxic •OH in tumor microenvironment (TME) that kill cancer cells for Fenton-reaction-based chemodynamic therapy (CDT). The porous structure of SAF NPs can serve as delivery platforms to package and programmed release chemotherapeutic drug doxorubicin (DOX) to enhance chemotherapy (CT) efficiency. The nanoplatform was simultaneously in-situ mineralized with CaCO3 and A549 cell membrane (CM) which could avoid DOX leakage during transport in bloodstream and target homologous cancer cells. In addition, overload Ca2+ decomposed from CaCO3 triggers mitochondrial dysfunction, induces cytoskeleton collapse and oxidative stress to formulate calcium ions interference therapy (CIT). With the combination of CDT, CT and CIT, the designed multi-synergetic nanoplatform exhibits excellent biocompatibility, specificity and tunable drug release behavior, which has a broad application prospect in tumor therapy.

A core-shell liquid metal-Cu nanoparticle with glutathione consumption via an in situ replacement strategy for tumor combination treatment of chemodynamic, microwave dynamic and microwave thermal therapy.

The presence of high content glutathione (GSH) provides an effective "protective shield" for tumor cells, which undoubtedly is a huge impediment to reactive oxygen species (ROS)-based treatment. Fortunately, divalent copper (Cu2+) can not only consume GSH, destroying the protection mechanism of GSH, but also can be reduced to Cu+ with excellent Fenton-like reaction activity. Hence, capitalizing on the properties of liquid metals, we introduced Cu with three different valances via an in situ replacement reaction. A stable core-shell liquid-metal based "Cu storage pool" was obtained. It can effectively deplete GSH within the cells, and simultaneously produce ·OH through a Fenton-like reaction, further improving the effect of chemodynamic therapy (CDT). Under microwave irradiation, it is also capable of producing a large amount of ROS to promote tumor treatment. In addition, the loading of ionic liquid endows LZC@IL nanoparticles with certain microwave heating performance, which is able to augment microwave thermal therapy (MWTT). With the combination of CDT, microwave dynamic therapy (MDT) and MWTT, LZC@IL has an excellent effect on tumor elimination. This work offers a new idea for the application of liquid metals and the combined treatment of tumors, which has potential application value.

A novel iron oxychloride nanosheets-based multifunctional nanocomposites for synergistic cancer treatment

Glucose oxidase (GOx) has been employed as a noninvasive critical agent for cancer therapy, which mediates the generation of hydrogen peroxide (H2O2) in physiological metabolism progress ·H2O2 showed a huge benefit in enhancing synergistic cancer therapy, such as the combination of chemodynamic therapy (CDT) and starving-like therapy. Moreover, the photothermal therapy (PTT) approach induced by laser irradiation with growing attention, can be a highly effective method in minimally invasive cancer therapy. In this work, we constructed iron oxychloride nanosheet-based nanocomposites (FeOCl@AMP@GOx@PEI@PGA@Au NCs) with multiple functions, such as mediating synergistic starving-like therapy, CDT, and PTT. The functional pathways can be concluded as follows: (1) GOx participates and fosters intratumoral glycometabolism process to enhance energy consumption, and produces toxic product H2O2; (2) catalase-like activity of FeOCl foster H2O2 further decompose into oxygen (O2) and reactive oxygen species (ROS), which can enhance the efficacy of cancer starving-like therapy and CDT; (3) adenosine 5′-monophosphate (AMP) as part of horseradish peroxidase (HRP) can improve the activity of FeOCl NSs in producing activated H2O2; (4) poly (γ-glutamic acid) (γ-PGA) as a targeted polymer can enhance tumor accumulation; (5) the loading of gold nanoparticles (AuNPs) on the surface of NCs induce the photothermal effect. Taken together, we concluded that iron-based nanomaterial FeOCl@AMP@GOx@PEI@PGA@Au NCs could excite novel aspects in nanotheranostics applications for tumor therapy.

Hierarchical Two-Dimensional Layered Double Hydroxide Coated Polydopamine Nanocarriers for Combined Chemodynamic and Photothermal Tumor Therapy

The combination of chemodynamic therapy (CDT) and photothermal therapy (PTT) has proven to be successful in combating the challenges associated with cancer therapy. A combination of these therapies can maximize the benefits of each therapeutic modality through endogenous reduction-oxidation (redox) reaction and external laser power induction. In the current work, we have designed a copper-aluminum layered double hydroxide (CuAl-LDH) loaded doxorubicin (DOX) by a co-precipitation method; the surface was coated with polydopamine (PDA). The synthesized CuAl-LDH@DOX@PDA nanocarrier (NC) served as a Fenton-like catalyst with photothermal properties. It is well known that metal ion incorporated NCs can induce intracellular depletion of reduced glutathione (GSH) levels along with the reduction of Cu2+ to Cu+. The Cu+ ions in turn react with DOX leading to the generation of intracellular hydrogen peroxide (H2O2) molecules to produce the highly toxic hydroxyl radicals (•OH) through a Fenton-like reaction. The enhanced absorption of CuAl@DOX@PDA at 810 nm, greatly improved the photothermal efficiency in comparison with bare CuAl-LDH and CuAl-LDH@DOX. In vitro studies revealed the tremendous CDT/PTT efficacy of CuAl@DOX@PDA in suppressing A549 cancer cells. Furthermore, reactive oxygen species (ROS) assays and intracellular levels of various ROS cascade biomolecules support our findings in the efficient destruction of cancer cells through synergistic CDT/PTT therapy.

Construction of a Single-Atom Nanozyme for Enhanced Chemodynamic Therapy and Chemotherapy.

To fulfill the demand of precision and personalized medicine, single-atom catalysts (SACs) have emerged as a frontier in biomedical fields due to enzyme-mimic catalysis. Herein, we present a biocompatible and versatile nanoagent consisting of single-atom iron-containing nanoparticles (SAF NPs), DOX and A549 cell membrane (CM). The designed porous iron-based SACs originally served as a drug-carrying nanoplatform to release DOX selectively in a tumor microenvironment (TME) for chemotherapy (CT) due to their high loading capacity (155 %) for DOX; this signifies that SACs are promising candidates for universal cargo delivery. Besides, the designed single-atom nanoagent can perform like peroxidase, which effectively triggers an in situ tumor-specific Fenton reaction to generate abundant toxic hydroxyl radicals (⋅OH) selectively in the acidic TME for chemodynamic therapy (CDT). With the combination of CDT and CT, the constructed SAF NPs@DOX@CM nanoagent demonstrates better in vivo therapeutic performance than single-pathway therapy. In the meantime, after modification with CM, SAF NPs@DOX@CM can achieve homologous binding to target tumor tissues and avoid early clearance. This study presents a type of multifunctional SACs for enhanced cancer treatment via the capacity of a drug carrier combined with the enzymatic therapies of single-atom catalytic sites.

Nanotechnology-enabled Chemodynamic Therapy and Immunotherapy.

High-level reactive oxygen species (ROS) have been reported to exert a robust anti-tumor effect by inducing cell apoptosis or necroptosis. Based on the Fenton reaction or Fenton-like reaction, a therapeutic strategy (i.e., chemodynamic therapy (CDT)) is proposed, where hydroxyl radicals (·OH) are one of the ROS that can be produced to kill tumors via the spontaneous activation by an endogenous stimulus. Moreover, high-level ROS can also facilitate tumor-associated antigen exposure, which benefits phagocytosis of corpses and debris by antigen-presenting cells (e.g., dendritic cells (DCs)) and further activates systematic immune responses. Great efforts have been made, wherein the development in the field of nanotechnology has been witnessed by the interdisciplinary communities. For providing a comprehensive understanding of CDT, state-of-theart strategies on nanotechnology-enabled CDT have been discussed in detail in this study. In particular, the combination of CDT with its augmented immunotherapy against tumors has been highlighted for overcoming the poor outcome of the mono-CDT. Moreover, the potential challenges have also been discussed.

Enhanced Antitumor Efficacy by a Cascade of Reactive Oxygen Species Generation and Drug Release

AbstractReactive oxygen species (ROS) can be used not only as a therapeutic agent for chemodynamic therapy (CDT), but also as a stimulus to activate release of antitumor drugs, achieving enhanced efficacy through the combination of CDT and chemotherapy. Here we report a pH/ROS dual‐responsive nanomedicine consisting of β‐lapachone (Lap), a pH‐responsive polymer, and a ROS‐responsive polyprodrug. In the intracellular acidic environment, the nanomedicine can realize pH‐triggered disassembly. The released Lap can efficiently generate hydrogen peroxide, which will be further converted into highly toxic hydroxyl radicals via the Fenton reaction. Subsequently, through ROS‐induced cleavage of thioketal linker, doxorubicin is released from the polyprodrug. In vivo results indicate that the cascade of ROS generation and antitumor‐drug release can effectively inhibit tumor growth. This design of nanomedicine with cascade reactions offers a promising strategy to enhance antitumor efficacy.

Enhanced Antitumor Efficacy by a Cascade of Reactive Oxygen Species Generation and Drug Release.

Reactive oxygen species (ROS) can be used not only as a therapeutic agent for chemodynamic therapy (CDT), but also as a stimulus to activate release of antitumor drugs, achieving enhanced efficacy through the combination of CDT and chemotherapy. Here we report a pH/ROS dual-responsive nanomedicine consisting of β-lapachone (Lap), a pH-responsive polymer, and a ROS-responsive polyprodrug. In the intracellular acidic environment, the nanomedicine can realize pH-triggered disassembly. The released Lap can efficiently generate hydrogen peroxide, which will be further converted into highly toxic hydroxyl radicals via the Fenton reaction. Subsequently, through ROS-induced cleavage of thioketal linker, doxorubicin is released from the polyprodrug. In vivo results indicate that the cascade of ROS generation and antitumor-drug release can effectively inhibit tumor growth. This design of nanomedicine with cascade reactions offers a promising strategy to enhance antitumor efficacy.