Amplification Of Oxidative Stress Research Articles

Chitosan oligosaccharide-functionalized nano-prodrug for cascade chemotherapy through oxidative stress amplification

Redox nanoparticles have been extensively developed for chemotherapy. However, the intracellular oxidative stress induced by constant aberrant glutathione (GSH), reactive oxygen species (ROS) and gamma-glutamyl transpeptidase (GGT) homeostasis remains the primary cause of evading tumor apoptosis. Herein, an oxidative stress-amplification strategy was designed using a pH-GSH-H2O2-GGT sensitive nano-prodrug for precise synergistic chemotherapy. The disulfide bond- conjugated doxorubicin prodrug (DOX-ss) was constructed as a GSH-scavenger. Then, phenylboronic acid (PBA), DOX-ss and poly (γ-glutamic acid) (γ-PGA) were successively conjugated using chitosan oligosaccharide (COS) to obtain the nano-prodrug PBA-COS-ss-DOX/γ-PGA. The PBA-COS-ss-DOX/γ-PGA prodrug could tightly attach to the polymer chain segment by atom transfer radical polymerization. Simultaneously, the drug interacted relatively weakly with the polymer by encapsulating ionic crosslinkers in DOX@PBA-COS/γ-PGA. The disulfide bond of the DOX-ss prodrug as a GSH-scavenger could be activated using overexpressed GSH to release DOX. Particularly, PBA-COS-ss-DOX/γ-PGA could prevent premature drug leakage and facilitate DOX delivery by GGT-targeting and intracellular H2O2-cleavable linker in human hepatocellular carcinoma (HepG2) cells. Concurrently, the nano-prodrug induced strong oxidative stress and tumor cell apoptosis. Collectively, the pH-GSH-H2O2-GGT responsive nano-prodrug shows potential for synergistic tumor therapy.

Closed‐loop of Catalyzed Lactate Oxidization Synergistically Sensitizes Apoptosis and Ferroptosis for Cancer Therapy

AbstractLactate accumulated in Tumor is a key oncometabolite and associated with various oncogenic processes, including proliferation, invasion, angiogenesis, metastasis, immunosuppression and therapeutic resistance. Particularly, lactate contributes to the apoptosis and ferroptosis resistance in cancer cells. Consequently, blockade of lactate provides a promising opportunity for cancer therapy. However, due to abnormal tumor microenvironment (TME) and intracellular glutathione (GSH) mediated ferroptosis resistance, the current approaches for regulating lactate to sensitize cells to apoptosis and ferroptosis are still challenging. Herein, we developed a catalytic lactate oxidizing liposomes (Lip‐LM) incorporated with lactate oxidase (LOX)‐loaded MnO2 nanoparticles. O2 regenerated from H2O2 constitute closed‐loop of lactate oxidation catalyzed by LOX, enhancing the lactate‐consuming efficacy in TME. Besides, glutathione is consumed by MnO2 to amplify the ferroptosis susceptibility of cancer cells. The results showed that Lip‐LM achieved synergistical apoptosis and ferroptosis to enhance the anti‐tumor efficacy of amplified oxidative stress in cancer cells through the strategy of self‐sufficient O2 supplying and GSH consumption. The results of transcriptomics and proteomics analyses also support the synergistical anti‐tumor mechanisms of Lip‐LM. Hence, it is a promising catalytic nanoplatform combined lactate regulation and oxidative stress amplification and have great potential to further enhance therapeutic outcomes based on synergistical apoptosis and ferroptosis.

Tumor-Microenvironment-Responsive Cerium-Enriched Copper Nanozyme with O2 Supply and Oxidative Stress Amplification for In Situ Disulfiram Chemotherapy and Chemodynamic Therapy Intensification.

Traditional chemotherapy has faced tough challenges of systemic toxicity, hypoxia resistance, and inadequacy of monotherapy. Developing the tumor-specific O2-supply-enhanced chemotherapy without toxic drugs while combing other precise treatments can substantially improve therapeutic efficacy. Herein, a CeO2-enriched CuO nanozyme with O2 supply and oxidative stress amplification for tumor-specific disulfiram (DSF) chemotherapy and intensified chemodynamic therapy by synergistic in situ "nontoxicity-toxicity" activation is developed. Notably, CeO2 can not only act as a morphological "regulator," but also serve as a cascaded enzyme-mimetic catalyst via tumor-microenvironment-responsive cascaded-logical programmable valence conversion. Once internalized inside tumor cells, the nanozyme can be degraded by lysosomal acidity to release nontoxic DSF and Cu2+, which can trigger in situ "Cu2+-DSF" chelation, generating a highly toxic Cu(DTC)2 for in situ chemotherapy. Moreover, the enriched CeO2 with catalase-mimetic activity can decompose the endogenous H2O2 into O2, which can relieve the hypoxia to enhance the chemotherapeutic efficacy. Furthermore, the simultaneously generated Ce3+ can exert peroxidase-mimetic activity to catalyze H2O2 into hydroxyl radicals (•OH) for chemodynamic therapy. This Fenton-like chemistry is accompanied by the regeneration of Ce4+, which can deplete the intracellular overproduced GSH to amplify the oxidative stress. Therefore, this nanozyme can provide an alternative to precise cancer treatment.

Covalent organic frameworks-derived carbon nanospheres based nanoplatform for tumor specific synergistic therapy via oxidative stress amplification and calcium overload

Combinational therapy in cancer treatment that integrates the merits of different therapies is an effective approach to improve therapeutic outcomes. Herein, a simple nanoplatform (N-CNS-CaO2-HA/Ce6 NCs) that synergized chemodynamic therapy (CDT), photodynamic therapy (PDT), photothermal therapy (PTT), and Ca2+ interference therapy (CIT) has been developed to combat hypoxic tumors. With high photothermal effect, excellent peroxidase-like activity, and inherent mesoporous structure, N-doped carbon nanospheres (N-CNSs) were prepared via in situ pyrolysis of an established nanoscale covalent organic frameworks (COFs) precursor. These N-CNSs acted as PTT/CDT agents and carriers for the photosensitizer chlorin e6 (Ce6), thereby yielding a minimally invasive PDT/PTT/CDT synergistic therapy. Hyaluronic acid (HA)-modified CaO2 nanoparticles (CaO2-HA NPs) coated on the surface of the nanoplatform endowed the nanoplatform with O2/H2O2 self-supply capability to respond to and modulate the tumor microenvironment (TME), which greatly facilitated the tumor-specific performance of CDT and PDT. Moreover, the reactive oxygen species (ROS) produced during PDT and CDT enhanced the Ca2+ overloading due to CaO2 decomposition, amplifying the intracellular oxidative stress and leading to mitochondrial dysfunction. Notably, the HA molecules not only increased the cancer-targeting efficiency but also prevented CaO2 degradation during blood circulation, providing double insurance of tumor-selective CIT. Such a nanotherapeutic system possessed boosted antitumor efficacy with minimized systemic toxicity and showed great potential for treating hypoxic tumors.

Thiol responsive 6-thioguanine delivery using fluorescent gold nanoconjugate for synergistic oxidative stress amplification and chemotherapy: A combinatorial approach in cancer management

The FDA-approved purine analog 6-thioguanine (6-TG) has shown unsatisfactory therapeutic effects in solid cancers due to poor solubility and bioavailability. In this study, an efficient thiol-based drug delivery platform is developed by conjugating 6-TG to BSA stabilized gold nanocluster (AuNC@BSA-TG) in a facile one-pot synthesis approach by fine-tuning of 6-TG to albumin concentration for maximum drug loading but without compromising the inherent fluorescent properties of gold nanoclusters. AuNC@BSA-TG nanoconjugate has a size of ∼3.3 ± 0.76 nm and exhibits ∼60 % 6-TG conjugation efficiency. The release of 6-TG depends on cellular thiols, with ∼90 % release within 24 h in the presence of 10 mM GSH at pH 7.4, mimicking the cytosol-reducing environment in cancer cells. The nanoconjugate also exhibits synergistic amplification of oxidative stress through GSH depletion and peroxidase mimetic (POD-mimetic) activity. Cytotoxicity analysis reveals an approximately 50 % reduction in IC50 values for AuNC@BSA-TG compared to free 6-TG for HCT116 and A549 cells exhibiting KRAS mutation. Interestingly, KRAS wild-type HEK293T cells showed minimal toxicity to AuNC@BSA-TG under similar conditions. This combinatorial approach subsequently produces overwhelming oxidative stress due to simultaneous intracellular GSH depletion and POD-mimetic activity to generate high ROS levels, which subsequently initiates DNA breakdown and activation of the Caspase 3/7 cascade, leading to apoptotic cell death, thereby potentiating the chemotherapeutic efficacy of 6-TG. Notably, to the best of our knowledge, this is the first attempt to develop a protein-stabilized fluorescent theranostic nanosystem for synergistic oxidative stress amplification and 6-TG-based chemotherapy in treating and managing challenging KRAS-mutated cancers.

CoFeSe2 @DMSA@FA Nanocatalyst for Amplification of Oxidative Stress to Achieve Multimodal Tumor Therapy.

Nanomedicine has significantly advanced precise tumor therapy, providing essential technical blessing for active drug accumulation, targeted consignment, and mitigation of noxious side effects. To enhance anti-tumor efficacy, the integration of multiple therapeutic modalities has garnered significant attention. Here, we designed an innovative CoFeSe2 @DMSA@FA nanocatalyst with Se vacancies (abbreviated as CFSDF), which exhibits synergistic chemodynamic therapy (CDT) and photothermal therapy (PTT), leading to amplified tumor oxidative stress and enhanced photothermal effects. The multifunctional CFSDF nanocatalyst exhibits the remarkable ability to catalyze the Fenton reaction within the acidic tumor microenvironment, efficiently converting hydrogen peroxide (H2 O2 ) into highly harmful hydroxyl radicals (⋅OH). Moreover, the nanocatalyst effectively diminishes GSH levels and ameliorates intracellular oxidative stress. The incorporation of FA modification enables CFSDF to evade immune detection and selectively target tumor tissues. Numerous in vitro and in vivo investigations have consistently demonstrated that CFSDF optimizes its individual advantages and significantly enhances therapeutic efficiency through synergistic effects of multiple therapeutic modalities, offering a valuable and effective approach to cancer treatment.

Multifunctional Nanoparticles for Enhanced Chemodynamic/Photodynamic Therapy through a Photothermal, H2O2-Elevation, and GSH-Consumption Strategy.

Chemodynamic therapy (CDT) has witnessed significant advancements in recent years due to its specific properties. Its association with photodynamic therapy (PDT) has also garnered increased attention due to its mutually reinforcing effects. However, achieving further enhancement of the CDT/PDT efficacy remains a major challenge. In this study, we have developed an integrated nanosystem comprising a Fenton catalyst and multifunctional photosensitizers to achieve triply enhanced CDT/PDT through photothermal effects, H2O2 elevation, and GSH consumption. We prepared nano-ZIF-8 vesicles as carriers to encapsulate ferrocene-(phenylboronic acid pinacol ester) conjugates (Fc-BE) and photosensitizers IR825. Subsequently, cinnamaldehyde-modified hyaluronic acid (HA-CA) was coated onto ZIF-8 through metal coordination interactions, resulting in the formation of active targeting nanoparticles (NPs@Fc-BE&IR825). Upon cellular internalization mediated by CD44 receptors, HA-CA elevated H2O2 levels, while released Fc-BE consumed GSH and catalyzed H2O2 to generate highly cytotoxic hydroxyl radicals (·OH). Furthermore, NIR irradiation led to increased ·OH production and the generation of singlet oxygen (1O2), accompanied by a greater GSH consumption. This accelerated and strengthened amplification of oxidative stress can be harnessed to develop highly effective CDT/PDT nanoagents.

Tumour‐microenvironment‐responsive Na2S2O8 nanocrystals encapsulated in hollow organosilica–metal–phenolic networks for cycling persistent tumour‐dynamic therapy

AbstractTraditional tumour‐dynamic therapy still inevitably faces the critical challenge of limited reactive oxygen species (ROS)‐generating efficiency due to tumour hypoxia, extreme pH condition for Fenton reaction, and unsustainable mono‐catalytic reaction. To fight against these issues, we skilfully develop a tumour‐microenvironment‐driven yolk‐shell nanoreactor to realize the high‐efficiency persistent dynamic therapy via cascade‐responsive dual cycling amplification of •SO4−/•OH radicals. The nanoreactor with an ultrahigh payload of free radical initiator is designed by encapsulating the Na2S2O8 nanocrystals into hollow tetra‐sulphide‐introduced mesoporous silica (HTSMS) and afterward enclosed by epigallocatechin gallate (EG)‐Fe(II) cross‐linking. Within the tumour microenvironment, the intracellular glutathione (GSH) can trigger the tetra‐sulphide cleavage of nanoreactors to explosively release Na+/S2O82−/Fe2+ and EG. Then a sequence of cascade reactions will be activated to efficiently generate •SO4− (Fe2+‐catalyzed S2O82− oxidation), proton (•SO4−‐catalyzed H2O decomposition), and •OH (proton‐intensified Fenton oxidation). Synchronously, the oxidation‐generated Fe3+ will be in turn recovered into Fe2+ by excessive EG to circularly amplify •SO4−/•OH radicals. The nanoreactors can also disrupt the intracellular osmolarity homeostasis by Na+ overload and weaken the ROS‐scavenging systems by GSH exhaustion to further amplify oxidative stress. Our yolk–shell nanoreactors can efficiently eradicate tumours via multiple oxidative stress amplification, which will provide a perspective to explore dynamic therapy.

A metal-phenolic network-assembled nanotrigger evokes lethal ferroptosis via self-supply loop-based cytotoxic reactions

The therapeutic efficacy of photodynamic therapy (PDT) is compromised by the hypoxic tumor microenvironment, while the ferroptosis therapy suffers from a lack of selectivity. Herein, the photosensitizer chlorin e6 (Ce6)-loaded hemoglobin (Hb) is assembled with the metal–phenolic network (MPN) formed by ferric ions (Fe3+) and tannic acid (TA), to construct a nanotrigger Hb–Ce6–Fe3+–TA (HCFT) for the combination of oxygen self-supply PDT and light-triggered ferroptosis therapy. Benefiting from the oxygen-carrying ability of Hb, the nanotrigger can relieve the tumor hypoxia and induce enhanced photodynamic reaction, resulting in the increase of intracellular reactive oxygen species (including H2O2) level. Furthermore, the elevated H2O2 level facilitates the continuation of the MPN-mediated Fe2+ self-supply Fenton reaction and thereby causes excessive cellular lipid peroxidation, which ultimately leads to lethal ferroptosis in tumor cells. Under laser irradiation, HCFT shows satisfactory antitumor effect due to the synergistic amplification of oxidative stress induced by photodynamic reaction and enhanced Fenton reaction. By comparison, without light illumination, the HCFT nanotrigger exhibits negligible cytotoxicity, indicating its light-controlled lethality. This study may have implications for the future development of efficacious oxidative stress-based synergistic therapeutic strategies that may possibly lead to successful clinical translation.

PH-Activated Scallop-Type Nanoenzymes for Oxidative Stress Amplification and Photothermal Enhancement of Antibacterial and Antibiofilm Effect.

Ferric phosphate (FePOs) nanoenzymes can express peroxidase (POD) activity under the dual stimulation of an acidic environment and high H2O2 concentrations. In living organisms, this generates reactive oxygen species (ROS) in sites of lesion infection, and thus FePOs nanoenzymes can act as antimicrobial agents. Here, CeO2 and ZnO2 were immobilized in a scallop-type FePOs nanoenzyme material loaded with a photosensitizer, indocyanine green, to synthesize a multifunctional cascade nanoparticle system (FePOs-CeO2-ZnO2-ICG, FCZI NPs). H2O2 concentrations could be adjusted through the ZnO2 self-activation response to the slightly acidic environment in biofilms, further promoting the release of ROS from the POD-like reaction of FePOs, achieving amplification of oxidative stress, DNA and cell membrane damage, and exploiting the photodynamic/photothermal effects of indocyanine green to enhance the antibiofilm effects. CeO2 can remove redundant ROS by switching from Ce4+ to Ce3+ valence, enhancing its ability to fight chronic inflammation and oxidative stress and thus promoting the regeneration of tissues around infection. By maintaining the redox balance of normal cells, increasing ROS at the infection site, eliminating redundant ROS, and protecting normal tissues from damage, the synthesized system maximizes the elimination of biofilms and treatment at the infection site. Therefore, this work may pave the way for the application of biocompatible nanoenzymes.

A mitochondria-targeted multifunctional nanoplatform combining carbon monoxide delivery with O2-independent free radical burst under 1064nm light irradiation for efficient hypoxic tumor therapy.

In situ mitochondrial oxidative stress amplification is an effective strategy to improve efficacy of cancer treatment. In this work, a tumor and mitochondria dual-targeted multifunctional nanoplatform CMS@AIPH@PDA@COTPP@FA (CAPCTF) was prepared, in which a thermally decomposable radical initiator AIPH was loaded inside the mesoporores of CuxMoySz (CMS) nanoparticles with polydopamine (PDA) covered films that were further covalently functionalized by a mitochondria-targeted CO donor (COTPP) and a directing group of folic acid (FA). The prepared CAPCTF nanoplatform selectively accumulated in cancer cells and further targeted the mitochondrial organelle where carbon monoxide (CO) and O2-independent free radicals (•OH/•R) were in situ generated upon 1064nm laser irradiation. Furthermore, the CMS nanocarrier was capable of depleting the GSH overexpressed in the tumor microenvironment (TME), thus preventing free radical scavenging. As a result, the CAPCTF nanoplatform exhibited outstanding in vitro and in vivo antitumor efficacy under hypoxic conditions. This provides an innovative strategy that combines O2-independent free radicals (•OH/•R) generation, CO delivery and GSH consumption to amplify intracellular oxidative stresses and induce mitochondrial dysfunction, thus leading to cancer cells eradication, which may have significant implications for personalized hypoxic tumor treatment.

Glutathione/pH-responsive copper-based nanoplatform for amplified chemodynamic therapy through synergistic cycling regeneration of reactive oxygen species and dual glutathione depletion

The rapid scavenging of reactive oxygen species (ROS) by glutathione (GSH) and insufficient endogenous hydrogen peroxide (H2O2) in tumor cells are the major factors greatly restricting the efficacy of chemodynamic therapy (CDT). Herein, we developed a tumor microenvironment (TME)-responsive Cu-based metal-mesoporous organosilica nanoplatform integrating vitamin k3 (VK3), which could deplete GSH and specifically regenerate H2O2 for amplified CDT of cancer. Once the CuO@MON-PEG/VK3 nanoparticles entered into the tumor cells through enhanced permeability and retention (EPR) effect, the organosilicon shell and CuO core would be successively degraded upon the triggering of GSH and endo/lysosomal acidity. Subsequently, the enriched tetrasulfide bridges and released Cu2+ could consume GSH substantially, thus triggering Fenton-like reaction for CDT. Furthermore, the released VK3 could be catalyzed by the highly expressed quinone oxidoreductase-1 (NQO1) inside tumor cells to generate sufficient H2O2 through a “reversible” redox cycle, which in turn promoted Cu+-mediated Fenton-like reaction. Both in vitro and in vivo studies demonstrated that this nanoplatform could achieve synergistic CDT against tumor through synergistic cycling regeneration of ROS and dual GSH exhaustion with excellent biosafety. Our finding highlight the promising potential of CuO@MON-PEG/VK3 nanoplatform with multiple oxidative stress amplification for highly efficient tumor therapy.

Cascade Amplification of Pyroptosis and Apoptosis for Cancer Therapy through a Black Phosphorous-Doped Thermosensitive Hydrogel.

Cell pyroptosis has a reciprocal relationship with various cancer treatment modalities such as chemotherapy. However, the tumor microenvironment, characterized by hypoxia, substantially restricts the development and application of tumor therapies that integrate cell pyroptosis. Therefore, the cascade amplification of oxidative stress by interfering with redox homeostasis in tumors may be a promising approach. In this study, black phosphorus (BP) nanosheets and a glutathione peroxidase 4 inhibitor (RSL3) were coloaded into a thermosensitive PDLLA-PEG-PDLLA (PLEL) hydrogel (RSL3/BP@PLEL). Owing to the photothermal property of BP nanosheets, the RSL3/BP@PLEL hydrogel may trigger the release of loaded drugs in a more controllable and on-demand manner. Investigation of the antitumor effect in a mouse liver tumor model demonstrated that local injection of the hydrogel formulation in combination with near infrared laser irradiation could efficiently suppress tumor growth by interfering with the redox balance in tumors. Mechanistic study indicated that the combined treatment of photothermal therapy and glutathione depletion based on this hydrogel efficiently induced cell pyroptosis through both caspase-1/GSDMD and caspase-3/GSDME pathways, thereby triggering the repolarization of tumor-associated macrophages from M2 to M1. Overall, we developed a biocompatible and biodegradable hydrogel formulation for application in combination cancer treatment, providing a new platform for enhancing the efficacy of cancer therapy by amplifying cell pyroptosis and apoptosis.

Self‐Immolative Amphiphilic Poly(ferrocenes) for Synergistic Amplification of Oxidative Stress in Tumor Therapy

AbstractAmphiphilic self‐immolative polymers (SIPs) can achieve complete degradation solely through one triggerable event, which potentially optimize the blood clearance and uncontrollable/inert degradability for therapeutic nanoparticles. Herein, we report self‐immolative amphiphilic poly(ferrocenes), BPnbs‐Fc, composed by self‐immolative backbone and aminoferrocene (AFc) side chains as well as end‐capping poly(ethylene glycol) monomethyl ether. Upon triggering by tumor acidic milieu, the BPnbs‐Fc nanoparticles readily degrade to release azaquinone methide (AQM) moieties, which can rapidly deplete intracellular glutathione (GSH) to cascade release AFc. Furthermore, both AFc and its product Fe2+ can catalyze intracellular hydrogen peroxide (H2O2) into highly reactive hydroxyl radicals (⋅OH), thus amplifying the oxidative stress of tumor cells. Rational synergy of GSH depletion and ⋅OH burst can efficiently inhibit tumor growth by the SIPs in vitro and in vivo. This work provides an elegant design to adopt innate tumor milieu‐triggerable SIPs degradation to boost cellular oxidative stress, which is a promising candidate for precision medicine.

Self-Immolative Amphiphilic Poly(ferrocenes) for Synergistic Amplification of Oxidative Stress in Tumor Therapy.

Amphiphilic self-immolative polymers (SIPs) can achieve complete degradation solely through one triggerable event, which potentially optimize the blood clearance and uncontrollable/inert degradability for therapeutic nanoparticles. Herein, we report self-immolative amphiphilic poly(ferrocenes), BPnbs-Fc, composed by self-immolative backbone and aminoferrocene (AFc) side chains as well as end-capping poly(ethylene glycol) monomethyl ether. Upon triggering by tumor acidic milieu, the BPnbs-Fc nanoparticles readily degrade to release azaquinone methide (AQM) moieties, which can rapidly deplete intracellular glutathione (GSH) to cascade release AFc. Furthermore, both AFc and its product Fe2+ can catalyze intracellular hydrogen peroxide (H2O2) into highly reactive hydroxyl radicals (·OH), thus amplifying the oxidative stress of tumor cells. Rational synergy of GSH depletion and ·OH burst can efficiently inhibit tumor growth by the SIPs in vitro and in vivo. This work provides an elegant design to adopt innate tumor milieu-triggerable SIPs degradation to boost cellular oxidative stress, which is a promising candidate for precision medicine.

Ultrasound-driven nanoreactor with USP39 ShRNAi-intensified ferroptosis for synergistic sono-chemodynamic therapy

The promotion of cellular ferroptosis through ultrasound (US)-assisted Fenton chemistry has emerged as a promising strategy for tumor therapy. To enhance the therapeutic effect, we designed a GSH-responsive ultrasound-driven nanoreactor for RNA interference (RNAi)-intensified ferroptosis in synergistic sono-chemodynamic therapy. Our nanoreactor comprises Fe3+/tetrasulfide bond (-s-s-s-s-) enriched dendritic organosilica encapsulating USP39 shRNA, along with co-loading of sinophoryrin sodium (DVDMS) and sulfasalazine (SAS). Hyaluronic acid surface functionalization ensures high tumor accumulation for active targeting of tumor cells. Upon internalization into tumor cells, the nanoreactor degrades upon the triggering of intracellular overproduced GSH. Ultrasound-triggered release of DVDMS generates large amounts of ROS, synergizing with Fe-catalyzed Fenton chemistry. The simultaneous depletion of glutathione peroxidase 4 and GSH by SAS and Fe3+ weakens the ROS-scavenging system, leading to tumoral redox dyshomeostasis via oxidative stress amplification. This results in the accumulation of lipid peroxide in tumor cells, efficiently inducing ferroptosis. Additionally, USP39 shRNA effectively silences the expression of the USP39 gene in cells, inhibiting tumor cell proliferation, while promoting ATG5 gene expression to intensify ferroptosis. Our work provides a promising nanoreactor for high-efficiency synergistic tumor therapy via RNAi-intensified ferroptosis, highlighting the potential of sono-chemodynamic therapy in cancer treatment.

A hybrid nanopharmaceutical for specific-amplifying oxidative stress to initiate a cascade of catalytic therapy for pancreatic cancer

BackgroundOxidative stress (OS) induced by an imbalance of oxidants and antioxidants is an important aspect in anticancer therapy, however, as an adaptive response, excessive glutathione (GSH) in the tumor microenvironment (TME) acts as an antioxidant against high reactive oxygen species (ROS) levels and prevents OS damage to maintain redox homoeostasis, suppressing the clinical efficacy of OS-induced anticancer therapies.ResultsA naturally occurring ROS-activating drug, galangin (GAL), is introduced into a Fenton-like catalyst (SiO2@MnO2) to form a TME stimulus-responsive hybrid nanopharmaceutical (SiO2-GAL@MnO2, denoted SG@M) for enhancing oxidative stress. Once exposed to TME, as MnO2 responds and consumes GSH, the released Mn2+ converts endogenous hydrogen peroxide (H2O2) into hydroxyl radicals (·OH), which together with the subsequent release of GAL from SiO2 increases ROS. The “overwhelming” ROS cause OS-mediated mitochondrial malfunction with a decrease in mitochondrial membrane potential (MMP), which releases cytochrome c from mitochondria, activates the Caspase 9/Caspase 3 apoptotic cascade pathway. Downregulation of JAK2 and STAT3 phosphorylation levels blocks the JAK2/STAT3 cell proliferation pathway, whereas downregulation of Cyclin B1 protein levels arrest the cell cycle in the G2/M phase. During 18 days of in vivo treatment observation, tumor growth inhibition was found to be 62.7%, inhibiting the progression of pancreatic cancer. Additionally, the O2 and Mn2+ released during this cascade catalytic effect improve ultrasound imaging (USI) and magnetic resonance imaging (MRI), respectively.ConclusionThis hybrid nanopharmaceutical based on oxidative stress amplification provides a strategy for multifunctional integrated therapy of malignant tumors and image-visualized pharmaceutical delivery.Graphical

Self-driven nanoprodrug platform with enhanced ferroptosis for synergistic photothermal-IDO immunotherapy

Insufficient immune stimulation and stubborn immune resistance are the critical factors limiting tumor immunotherapy. Here, we report a multifunctional nanoprodrug platform with self-driven indoximod (IND) release and oxidative stress amplification. The aim is to awaken immune responses and block the indoleamine 2,3-dioxygenase (IDO) pathway through a combination of ferroptosis, photothermal therapy, and immunotherapy. This nanosystem improved the delivery efficiency of IND due to click chemistry linked ROS responsive prodrug and self-driven drug release. Meanwhile, the tactic of simultaneously increasing ROS and eliminating GSH amplified oxidative stress and strengthened ferroptosis, which further enhanced immunogenicity along with polydopamine-based photothermal therapy. IDO immunization combined with ferroptosis as well as photothermal therapy not only stimulated immune response, but also reversed immune suppression with enhanced immune memory. Therefore, primary tumor, distant tumor, and cancer metastasis were inhibited. This study provides a perspective on immunotherapeutics for cancer treatment.

Injectable thermo-sensitive hydrogel loaded hollow copper sulfide nanoparticles for ROS burst in TME and effective tumor treatment.

Introduction: Lung cancer the most prevalent cause of cancer-related deaths, and current therapies lack sufficient specificity and efficacy. This study developed an injectable thermosensitive hydrogel harboring hollow copper sulfide nanoparticles and β-lapachone (Lap) (CLH) for lung tumor treatment. Methods: The hydrogel-encapsulated CLH system can remotely control the release of copper ions (Cu2+) and drugs using photothermal effects for non-invasive controlled-release drug delivery in tumor therapy. The released Cu2+ consumes the overexpressed GSH in TME and the generated Cu+ further exploits the TME characteristics to initiate nanocatalytic reactions for generating highly toxic hydroxyl radicals. In addition, in cancer cells overexpressing Nicotinamide adenine dinucleotide (phosphate): quinone oxidoreductase 1 (NQO1), Lap can catalyze the generation of hydrogen peroxide (H2O2) through futile redox cycles. H2O2 is further converted into highly toxic hydroxyl radicals via the Fenton-like reaction, leading to a burst of reactive oxygen species in TME, which further enhances the therapeutic effect of chemokines. Results: Analysis of the antitumor efficacy in a subcutaneous A549 lung tumor model mice showed a significant delay in tumor growth and no systemic toxicity was detected. Discussion: In conclusion, we have established a CLH nanodrug platform that enables efficient lung tumor therapy through combined photothermal/chemodynamic therapy (CDT) treatment and self-supplying H2O2 to achieve cascade catalysis, leading to explosive amplification of oxidative stress.

Biomimetic nanoplatform with H2O2 homeostasis disruption and oxidative stress amplification for enhanced chemodynamic therapy.

Chemodynamic therapy (CDT) is a powerful cancer treatment strategy by producing excessive amount of reactive oxygen species (ROS) to kill cancer cells. However, the inadequate hydrogen peroxide (H2O2) supply and antioxidant defense systems in tumor tissue significantly impair the therapeutic effect of CDT, hindering its further applications. Herein, we present an intelligent nanoplatform with H2O2 homeostasis disruption and oxidative stress amplification properties for enhanced CDT. This nanoplatform is obtained by encapsulating glucose oxidase (GOx) in a pH- and glutathione (GSH)-responsive degradable copper doped-zeolitic imidazolate framework (Cu-ZIF8), followed by loading of 3-amino-1,2,4-triazole (3AT) and modification of hyaluronic acid (HA) for tumor targeting delivery. The GOx@Cu-ZIF8-3AT@HA not only reduces energy supply and increases H2O2 level by exhausting intratumoral glucose, but also disturbs tumor antioxidant defense systems by inhibiting the activity of catalase (CAT) and depleting intracellular GSH, resulting in disrupted H2O2 homeostasis in tumor. Moreover, the elevated H2O2 will transform into highly toxic hydroxyl radical (·OH) by Cu+ that generated from redox reaction between Cu2+ and GSH, amplifying the oxidative stress to enhance the CDT efficacy. Consequently, GOx@Cu-ZIF8-3AT@HA has significantly inhibited the 4T1 xenograft tumor growth without discernible side effects, which provides a promising strategy for cancer management. STATEMENT OF SIGNIFICANCE: The inadequate H2O2 level and antioxidant defense system in tumor tissues significantly impair the therapeutic effect of CDT. Herein, we developed an intelligent nanoplatform with H2O2 homeostasis disruption and oxidative stress amplification properties for enhanced CDT. In this nanoplatform, GOx could exhaust intratumoral glucose to reduce energy supply accompanied with production of H2O2, while the suppression of CAT activity by 3AT and depletion of GSH by Cu2+ would weaken the antioxidant defense system of tumors. Ultimately, the raised H2O2 level would convert to highly toxic •OH by Fenton-like reaction, amplifying the CDT efficacy. This work provides a promising strategy for cancer management.