Intratumoral Glucose Research Articles

Cascade-reaction-triggered engineering nanocatalytic theranostics reconstructing tumor microenvironment through synergistic oxidative damage and aerobic glycolysis inhibition against colon cancer

Intratumoral glucose consumption-induced cancer starvation provides an emerging strategy for anticancer therapy, but encounters significant challenges as nonspecificity, adaptive development of parallel energy supplies and so on. Herein, the intelligent nanocatalytic theranostics (denoted as GOx/Fe3O4/RA NP) featured reactive oxygen species (ROS)-cleavable linker and pH-sensitive segment was designed, realizing the on-demand cargo releasing, and integration of glucose oxidase (GOx), Fe3O4 and cyclopeptide RA-V with highly orchestrated cooperation. On one hand, as an efficient enzyme catalyst, GOx not only starved the tumor cells for achieving starvation therapy (ST), but also supplied gluconic acid for irritating drug release, simultaneously supplied H2O2 for subsequent Fenton-like reaction mediated by Fe3O4. The generated hydroxyl radicals (•OH) catalyzed by Fe3O4 effectively further accelerated decomposition of GOx/Fe3O4/RA NP, in addition to inducing tumor cells apoptosis and death for realizing the enhanced chemodynamic therapy (CDT). On the other hand, RA-V as a chemotherapeutic lead compound was also found to inhibit pivotal proteins involving in aerobic glycolysis pathway. The synergy between the GOx and RA-V exhibited a dual destruction in abnormal glucose metabolism through cutting off energy-supplying in cancer cell. As a result, the nano-platform (GOx/Fe3O4/RA NP) consisted of GOx-mediated ST, Fe3O4-elicited CDT, and RA-V-induced chemotherapy, demonstrated remarkable anticancer activity in vitro and in vivo, which provides the potential to develop mutual promotion strategy.

Injectable alginate hydrogels for synergistic tumor combination therapy through repolarization of tumor-associated macrophages

Locally administered drug delivery systems are promising as they allow to circumvent the side effects associated with systematic administration. In this study, we constructed multifunctional hydrogels by simply mixing commercial alginate (ALG) sols with glucose oxidase (GOx)-conjugated polyacrylic acid-stabilized iron oxide nanoparticles (GPI NPs) and Toll-like receptor 7/8 agonist resiquimod (R848). The injectable sols were able to transform into hydrogels (GPI/R848@ALG) by the ionic cross-linking between ALG and physiological Ca2+ to trap the therapeutic components within the hydrogel framework. Upon intratumoral injection, the hydrogels were employed for starvation therapy, promoted chemodynamic therapy and tumor-associated macrophages (TAMs) repolarization. The energy supply was blocked by consuming the intratumoral glucose via the GOx-catalyzed conversion of glucose into gluconic acid and hydrogen peroxide (H2O2).In vitro results showed that the generated H2O2 could be further converted into highly cytotoxic hydroxyl radicals (·HO) by the Fenton reaction to induce enhanced chemodynamic therapy. The TAMs repolarization studies in vitro exhibited that the GPI/R848@ALG hydrogels up-regulated the expression of CD86 by 63% and down-regulated the proportion of CD206 by 14% with a synergistic effect of the presence of Fe3O4 and R848, suggesting that the multifunctional hydrogels exert functions to direct the remodeling of TAMs from the tumor supportive M2-like phenotype to the tumor destructive M1-like phenotype to further contribute to the antitumor effect. Moreover, both in vitro and in vivo experiments demonstrate that the multifunctional hydrogels exhibit admirable antitumor performance towards 4T1 tumors. This work thereby provides a promising multifunctional nanoplatform for synergistic cancer starvation therapy, chemodynamic therapy and TAMs repolarization.

Near-Infrared-II Plasmonic Trienzyme-Integrated Metal-Organic Frameworks with High-Efficiency Enzyme Cascades for Synergistic Trimodal Oncotherapy.

Natural enzyme-based catalytic cascades hold great promise for cancer therapy, but their clinical utility is greatly hindered by the loss of their functions during in vivo delivery. Herein, a plasmonic trienzyme-integrated metal-organic framework (plasEnMOF) nanoplatform with high-efficiency enzyme cascades is reported for synergistic starvation, chemodynamic, and plasmonic hyperthermia trimodal therapy of hypoxic tumors. These plasEnMOFs are created with encapsulation of near-infrared-II (NIR-II) plasmonic Au nanorods and natural enzymes-catalase (CAT), glucose oxidase (GOx), and horseradish peroxidase (HRP) within zeolitic imidazolate framework-8 (ZIF-8) MOFs. As a trienzyme cascade system, the plasEnMOFs effectively deplete intratumoral glucose and generate toxic reactive oxygen species (ROS) for starvation therapy and chemodynamic therapy (CDT) combined with the plasmonic hyperthermia therapy (PHT). The enhanced glucose consumption and ROS generation by the NIR-II plasmonic photothermal effect are also demonstrated. The improved chemo- and thermotolerance of the encapsulated natural enzymes within the protective ZIF-8 MOFs are evidenced. With the integrated enzyme cascades and NIR-II photothermal effects, these plasEnMOFs are demonstrated with exceptional therapeutic effects on 4T1 xenograft tumors through the combined starvation/CDT/PHT therapy. This work highlights the superiority of natural enzyme cascade systems integrated in plasmonic MOFs for high-efficiency enzymatic cancer therapy.

Boosting nutrient starvation-dominated cancer therapy through curcumin-augmented mitochondrial Ca2+ overload and obatoclax-mediated autophagy inhibition as supported by a novel nano-modulator GO-Alg@CaP/CO

BackgroundBy hindering energy supply pathway for cancer cells, an alternative therapeutic strategy modality is put forward: tumor starvation therapy. And yet only in this blockade of glucose supply which is far from enough to result in sheer apoptosis of cancer cells.ResultsIn an effort to boost nutrient starvation-dominated cancer therapy, here a novel mitochondrial Ca2+ modulator Alg@CaP were tailor-made for the immobilization of Glucose oxidase for depriving the intra-tumoral glucose, followed by the loading of Curcumin to augment mitochondrial Ca2+ overload to maximize the therapeutic efficiency of cancer starvation therapy via mitochondrial dysfunctions. Also, autophagy inhibitors Obatoclax were synchronously incorporated in this nano-modulator to highlight autophagy inhibition.ConclusionHere, a promising complementary modality for the trebling additive efficacy of starvation therapy was described for cutting off the existing energy sources in starvation therapy through Curcumin-augmented mitochondrial Ca2+ overload and Obatoclax-mediated autophagy inhibition.Graphical

A platinum nanourchin-based multi-enzymatic platform to disrupt mitochondrial function assisted by modulating the intracellular H2O2 homeostasis

Endogenous H2O2 sacrifices for diversified therapeutic reactions against tumor. However, the treatment outcome is not always satisfactory owing to the unsustainable H2O2 supply from tumor microenvironment (TME). Herein, a platinum (Pt) nanourchin-based multi-enzymatic platform (referred to PGMA) is established by surface conjugation of glucose oxidase (GOx) capped with manganese carbonyl (MnCO) and loading 3-amino-1,2,4-triazole (3-AT). The mild acidic and H2O2-rich TME can render the degradation of MnCO, followed by triggering the release of CO gas, 3-AT and Mn2+/3+. The resultant GOx exposure initiates intratumoral glucose depletion, which is promoted by the O2 replenishment through Pt-catalyzed decomposition of H2O2. Meanwhile, intracellular reactive oxygen species (ROS) level is elevated through Mn2+/3+ couple-mediated Fenton-like reaction. Hence, CO release-initiated gas therapy, glucose exhaustion-induced tumor starvation and ROS-triggered chemodynamic therapy are committed to realizing a combinatorial disruption effect on mitochondrial function. Importantly, the released 3-AT can inhibit the activity of endogenous catalase, which effectively elevates the intracellular H2O2 level to compensate its consumption and provides incremental reactant for cascade utilizations. Taken together, this study aims to emphasize the importance of intracellular H2O2 balance during H2O2-depleted therapeutic process, and affords a prime paradigm of applying this strategy for tumor treatment via mitochondrial dysfunction.

Tumor microenvironment responsive polypeptide-based supramolecular nanoprodrugs for combination therapy

Tumor microenvironment responsive nanomedicine has drawn considerable attention for combination therapy, but still remains a significant challenge for less side effects and enhanced anti-tumor efficiency. Herein, we develop a pH/ROS dual-responsive supramolecular polypeptide nanoprodrug (PFW-DOX/GOD) by using pillar[5]arene-based host-guest strategy for combined glucose degradation, chemodynamic therapy (CDT), and chemotherapy (CT). The PFW-DOX/GOD consists of a pH-responsive ferrocene/pillar[5]arene-containing polypeptide, a ROS-responsive polyprodrug, and encapsulated glucose oxidase (GOD). Upon into intracellular acidic environment, PFW-DOX/GOD exhibits rapid pH-triggered disassembly behavior. Simultaneously, the released GOD can catalyze intratumoral glucose into massive H2O2, which are further converted into highly toxic hydroxyl radicals (•OH) by the catalysis of ferrocene via the Fenton reaction. Thereafter, induced by the ROS-responsive cleavage of thioketal linkage, the conjugated DOX prodrug was released and activated. The combined glucose degradation, chemodynamic therapy (CDT), and chemotherapy (CT) of PFW-DOX/GOD present anti-tumor effect with 96% of tumor inhibitory rate (TIR). Therefore, such tumor microenvironment-responsive supramolecular polypeptide nanoprodrugs represent a potential candidate for combination therapy with minimal side effects. Statement of significanceIn this work, a tumor microenvironment-responsive supramolecular polypeptide nanoprodrug (PFW-DOX/GOD) was prepared via pillar[5]arene-based host-guest interactions, and presented low side effects and high tumor accumulation owing to the diameters of about 200 nm and surface PEG segment. After pH-responsive release of GOD in the intracellular acidic environment, the cascade catalytic reactions including GOD-catalyzed degradation of intratumoral glucose and Fenton reaction, effectively happened to generate •OH for chemodynamic therapy (CDT), which subsequently induced the cleavage of thioketal linkage to activate free DOX for chemotherapy (CT). Collectively, this supramolecular polypeptide nanoprodrugs provide a promising strategy for combination therapy with synergetic anti-tumor effect.

Tumor microenvironment self-regulation: Bimetallic metal nanozyme-derived multifunctional nanodrug for optimizable cascade catalytic reaction-synergetic anti-tumor theranostics

The tumor microenvironment (TME) responsive multimodal theranostic nanoplatforms have attracted great attentions for precision medicine. To design well-defined cascade catalytic therapy and achieve the synergistic effect of different components in a nanoplatform, herein a spindle-shaped nanodrug termed as FeCu-GOx PNzyme-MTO was constructed by in-situ growth of bimetallic metal nanozyme (FeCu PNzyme), and simultaneous encapsulation of glucose oxidase (GOx) as well as fluorescent and chemotherapeutic mitoxanthrone (MTO). Interestingly, the obtained FeCu-GOx PNzyme is able to efficiently upregulate endogenous H2O2 level and down-regulate acidity via inducing the catalytic decomposition of intratumoral glucose to gluconic acid and H2O2 in TME, which is benefit to the cascade catalytic reactions for chemodynamic therapy (CDT). After efficient loading of MTO, such intelligent nanozyme triggers reactive oxygen species (ROS) generation in situ with tumor stimuli, self-augment ROS level upon intrinsic photothermal-conversion efficiency (53.05%) and glutathione (GSH) depletion, and specifically TME-responsive release of MTO to achieve high chemotherapeutic efficacy and biosafety. Both in vitro cellular assays and in vivo tumor-xenograft experiments proved that the tumor-specific cytotoxicity, biodegradability and potent antitumor efficiency of nanodrug, with co-contributions from highly cytotoxic ROS generated and precise drug delivery within tumors. This work thus presents the friendly construction of biocompatible FeCu-GOx PNzyme-MTO as effective nanodrug to provided a promising strategy for a new perspective on effective tumor therapy.

Starvation therapy enabled “switch-on” NIR-II photothermal nanoagent for synergistic in situ photothermal immunotherapy

Tumor photonic hyperthermia in the second near-infrared biowindow (NIR-II) represents the distinct therapeutic modality owing to the high tissue penetration and excellent spatiotemporal controllability. However, the non-specific “always on” nature of conventional NIR-II photothermal agents and the photothermal therapy (PTT)-associated tumor metastasis have restricted the progress of photonic hyperthermia. In this study, a cascade nanoreactor (denoted as LGT) based on clinically transformable liposomal nanoparticles is rationally engineered by encapsulating a pro-photothermal agent, 3,3′,5,5′-tetramethylbenzidine (TMB), and a tumor starvation mediator, glucose oxidase (GOD), for starvation therapy activated in-situ photothermal immunotherapy in inhibiting primary and metastasized tumors. Accompany with GOD-mediated intratumoral glucose depletion and hydrogen peroxide generation, the pro-photothermal agent is in-situ converted into the NIR-II absorbing charge transfer complex (CTC) in tumor microenvironment (TME). Collaboratively, glucose deprivation not only cuts the energy supply to tumor cells but also makes LGT sensitive to photothermal ablation. Upon NIR-II laser irradiation, LGT-mediated in-situ PTT ablates primary tumors, and further elicits the exposure of tumor-associated antigens. Importantly, the combination of starvation therapy enabled in situ PTT with anti-CTLA-4 checkpoint blockade therapy effectively inhibits distant tumor growth and tumor metastasis. Therefore, the present work provides a representative paradigm for tumor starvation therapy activated “switch-on” photothermal immunotherapy of cancer.

Bimetallic PdPt-based nanocatalysts for Photothermal-Augmented tumor starvation and sonodynamic therapy in NIR-II biowindow assisted by an oxygen Self-Supply strategy

Tumor starvation by depleting intratumoral glucose has been validated as a promising therapeutic strategy to combat cancer. However, inadequate oxygenation in hypoxic tumorous tissue significantly compromises the treatment efficacy. Herein, PdPt bimetallic nanocatalyst conjugated with glucose oxidase (GOx) and sonosensitizer IR780 is developed for photothermal-augmented tumor starvation and sonodynamic therapy (SDT) in near-infrared (NIR)-II biowindow, assisted by an oxygen self-supply strategy. As a catalase-mimicking nanozyme, PdPt@GOx/IR780 (PGI) can facilitate the alleviation of tumor hypoxia through catalyzing H2O2 decomposition into O2. Furthermore, GOx-mediated intratumoral glucose consumption may block the essential energy and nutrient supply to achieve tumor starvation. The resultant H2O2 production enables a continuous supply of local O2, which subsequently aggravates glucose depletion. Meanwhile, the hypoxia alleviation also promotes the production of 1O2 for a more efficacious SDT with the aid of sonosensitizer IR780. In another aspect, hyperthermia generation by PGI under NIR-II laser irradiation leads to the thermal ablation of tumor cells, which effectively incorporates with tumor starvation and SDT for a complete tumor eradication. More importantly, the combination therapy can trigger strong immunogenic cell death (ICD), which favors the overcoming of immune suppression and the enhancement of antitumor immunity. The admirable tumor suppression effect by PGI is demonstrated on tumor-bearing mice with minimal adverse effect. Taken together, this paradigm provides a useful strategy for PdPt functionalization in the pursuit of effective tumor therapy with high clinical relevance.

Anti-VEGFR2-labeled enzyme-immobilized metal-organic frameworks for tumor vasculature targeted catalytic therapy

Tumor vasculature-targeting therapy either using angiogenesis inhibitors or vascular disrupting agents offers an important new avenue for cancer therapy. In this work, a tumor-specific catalytic nanomedicine for enhanced tumor ablation accompanied with tumor vasculature disruption and angiogenesis inhibition was developed through a cascade reaction with enzyme glucose oxidase (GOD) modified on Fe-based metal organic framework (Fe-MOF) coupled with anti-VEGFR2.The GOD enzyme could catalyze the intratumoral glucose decomposition to trigger tumor starvation and yet provide abundant hydrogen peroxide as the substrate for Fenton-like reaction catalyzed by Fe-MOF to produce sufficient highly toxic hydroxyl radicals for enhanced chemodynamic therapy and instantly attacked tumor vascular endothelial cells to destroy the existing vasculature, while the anti-VEGFR2 antibody guided the nanohybrids to target blood vessels and block the VEGF-VEGFR2 connection to prevent angiogenesis. Both in vitro and in vivo results demonstrated the smart nanohybrids could cause the tumor cell apoptosis and vasculature disruption, and exhibited enhanced tumor regression in A549 xenograft tumor-bearing mice model. This study suggested that synergistic targeting tumor growth and its vasculature network would be more promising for curing solid tumors. Statement of significanceCooperative destruction of tumor cells and tumor vasculature offers a potential avenue for cancer therapy. Under this premise, a tumor-specific catalytic nanomedicine for enhanced tumor ablation accompanied with tumor vasculature disruption and new angiogenesis inhibition was developed through a cascade reaction with glucose oxidase modified on the surface of iron-based metal organic framework coupled with VEGFR2 antibody. The resulting data demonstrated that a therapeutic regimen targeting tumor growth as well as its vasculature with both existing vasculature disruption and neovasculature inhibition would be more potential for complete eradication of tumors.

Surface functionalized biomimetic bioreactors enable the targeted starvation-chemotherapy to glioma

Altering the glucose supply and the metabolic pathways would be an intriguing strategy in starvation therapy toward cancers. Nevertheless, starvation therapy alone could be inadequate to eliminate tumor cells completely. Herein, a multifunctional bioreactor was fabricated for synergistic starvation-chemotherapy through embedding glucose oxidase (GOx) and doxorubicin (DOX) in the tumor targeting ligands (RGD) modified red blood cell membrane camouflaged metal-organic framework (MOF) nanoparticle (denoted as RGD-mGZD). Owing to the remarkable biointerfacing property, the designed RGD-mGZD could not only possess enhanced blood retention time inherited from red blood cells, but also preferentially target the tumor site after the modification with RGD peptide. Once the bioreactor reached the desired region, GOx promptly consumed the intratumoral glucose and oxygen to starve cancer cells for robust starvation therapy. More importantly, the aggravated acidic microenvironment at the tumor region was found to induce the decomposition of the MOF structure, thus triggering the release of DOX for reinforced chemotherapy. This bioreactor would further prompt the development of synergistic patterns toward cancer treatment in a spatiotemporally controlled manner.

Self-Assembly of Multifunctional DNA Nanohydrogels with Tumor Microenvironment-Responsive Cascade Reactions for Cooperative Cancer Therapy.

A DNA structure-based nanoreactor has emerged as a promising biomaterial for antitumor therapy with its intrinsic biodegradability, biocompatibility, and tunable multifunctionality. Herein, the intelligent DNA nanohydrogel was reported to target cancer cells, control the size, be pH-responsive, and be loaded with glucose oxidase (GOx). Two kinds of X-shaped DNA monomers and DNA linkers were assembled to form a DNA nanohydrogel by hybridization. GOx was successfully encapsulated in the DNA nanohydrogel. The DNA linker was designed with i-motif sequences and modified with ferrocene (Fc). The i-motif-like quadruplex structures were formed in acidic tumor microenvironments, resulting in the disassembly of the DNA nanohydrogel to release GOx. The GOx could oxidize the intratumoral glucose to produce gluconic acid and H2O2. The generated H2O2 was catalyzed by Fc to induce toxic hydroxyl radicals (•OH), which could effectively kill cancer cells. Both the in vitro and the in vivo results demonstrated that the multifunctional DNA nanohydrogel had high-efficiency tumor suppression through combined chemodynamic and starvation cancer therapies.

Phosphate-Degradable Nanoparticles Based on Metal-Organic Frameworks for Chemo-Starvation-Chemodynamic Synergistic Antitumor Therapy.

Chemodynamic therapy (CDT) was regarded as a promising approach for tumor treatment. However, owing to the insufficient amount of endogenous hydrogen peroxide (H2O2) in tumor cells, the efficacy of CDT was limited. In this study, we designed phosphate-responsive nanoparticles (denoted as MGDFT NPs) based on metal-organic frameworks, which were simultaneously loaded with drug doxorubicin (DOX) and glucose oxidases (GOx). The decorated GOx could act as a catalytic nanomedicine for the response to the abundant glucose in the tumor microenvironment, generating a great deal of H2O2, which would enhance the Fenton reaction and produce toxic hydroxyl radicals (·OH). Meanwhile, the growth of tumors would also be inhibited by overconsuming the intratumoral glucose, which was the "fuel" for cell proliferation. When the nanoparticles entered into tumor cells, a high concentration of phosphate induced structure collapse, releasing the loaded DOX for chemotherapy. Furthermore, the decoration of target agents endowed the nanoparticles with favorable target ability to specific tumor cells and mitochondria. Consequently, the designed MGDFT NPs displayed desirable synergistic therapeutic effects via combining chemotherapy, starvation therapy, and enhanced Fenton reaction, facilitating the development of multimodal precise antitumor therapy.

Cell-Intrinsic Programs Partition Nutrients in Tumor Microenvironment.

Myeloid cells in the tumor microenvironment exhibited the highest uptake of intratumoral glucose.

Cell-programmed nutrient partitioning in the tumour microenvironment.

Cancer cells characteristically consume glucose through Warburg metabolism1, a process that forms the basis of tumour imaging by positron emission tomography (PET). Tumour-infiltrating immune cells also rely on glucose, and impaired immune cell metabolism in the tumour microenvironment (TME) contributes to immune evasion by tumour cells2-4. However, whether the metabolism of immune cells is dysregulated in the TME by cell-intrinsic programs or by competition with cancer cells for limited nutrients remains unclear. Here we used PET tracers to measure the access to and uptake of glucose and glutamine by specific cell subsets in the TME. Notably, myeloid cells had the greatest capacity to take up intratumoral glucose, followed by T cells and cancer cells, across a range of cancer models. By contrast, cancer cells showed the highest uptake of glutamine. This distinct nutrient partitioning was programmed in a cell-intrinsic manner through mTORC1 signalling and the expression of genes related to the metabolism of glucose and glutamine. Inhibiting glutamine uptake enhanced glucose uptake across tumour-resident cell types, showing that glutamine metabolism suppresses glucose uptake without glucose being a limiting factor in the TME. Thus, cell-intrinsic programs drive the preferential acquisition of glucose and glutamine by immune and cancer cells, respectively. Cell-selective partitioning of these nutrients could be exploited to develop therapies and imaging strategies to enhance or monitor the metabolic programs and activities of specific cell populations in the TME.

One-pot synthesis of a self-reinforcing cascade bioreactor for combined photodynamic/chemodynamic/starvation therapy

The combination of photodynamic therapy (PDT) and chemodynamic therapy (CDT) have attracted a great deal of interest, but tumor hypoxia and glutathione (GSH) overproduction still limit their further applications. Herein, an intelligent reactive oxygen species (ROS) nanogenerator Ce6/GOx@ZIF-8/PDA@MnO2 (denoted as CGZPM; Ce6, GOx, ZIF-8, PDA, MnO2 are chlorin e6, glucose oxidase, zeolitic imidazolate framework-8, polydopamine and manganese dioxide respectively) with O2-generating and GSH-/glucose-depleting abilities was constructed by a facile and green one-pot method. After intake by tumor cells, the outer MnO2 was rapidly degraded by the acidic pH, and the overexpression of hydrogen peroxide (H2O2) and GSH with abundant Mn2+ and O2 produced would eventually achieve multifunctionality. The Mn2+ acted as an ideal Fenton-like agent and magnetic resonance (MR) imaging contrast agent, while the O2 promoted the PDT via hypoxia relief and facilitated the intratumoral glucose oxidation by GOx for starvation therapy (ST). Benefiting from the GOx-based glycolysis process, sufficient H2O2 was generated to improve the CDT efficacy through Mn2+-mediated Fenton-like reaction. Notably, MnO2 and PDA could decrease the tumor antioxidant activity by consuming GSH, resulting in remarkably enhanced PDT/CDT. Such a novel cascade bioreactor with tumor microenvironment (TME)-modulating capability opens new opportunities for ROS-based and combinational treatment paradigms.

Biodegradable Calcium Phosphate Nanotheranostics with Tumor‐Specific Activatable Cascade Catalytic Reactions‐Augmented Photodynamic Therapy

AbstractPhotodynamic therapy (PDT) is exploited as a promising strategy for cancer treatment. However, the hypoxic solid tumor and the lack of tumor‐specific photosensitizer administration hinder the further application of oxygen (O2)‐dependent PDT. In this study, a biodegradable and O2 self‐supplying nanoplatform for tumor microenvironment (TME)‐specific activatable cascade catalytic reactions‐augmented PDT is reported. The nanoplatform (named GMCD) is constructed by coloading catalase (CAT) and sinoporphyrin sodium (DVDMS) in the manganese (Mn)‐doped calcium phosphate mineralized glucose oxidase (GOx) nanoparticles. The GMCD can effectively accumulate in tumor sites to achieve an “off to on” fluorescence transduction and a TME‐activatable magnetic resonance imaging. After internalization into cancer cells, the endogenous hydrogen peroxide (H2O2) can be catalyzed to generate O2 by CAT, which not only promotes GOx catalytic reaction to consume more intratumoral glucose, but also alleviates tumor hypoxia and enhances the production of cytotoxic singlet oxygen from light‐triggered DVDMS. Moreover, the H2O2 generated by GOx‐catalysis can be converted into highly toxic hydroxyl radicals by Mn2+‐mediated Fenton‐like reaction, further amplifying the oxidative damage of cancer cells. As a result, GMCD displays superior therapeutic effects on 4T1‐tumor bearing mice by a long term cascade catalytic reactions augmented PDT.

A dual-catalytic nanoreactor for synergistic chemodynamic-starvation therapy toward tumor metastasis suppression.

Tumor metastasis is extremely deadly for cancer patients and developing effective treatments for deep metastatic tumors remains a major challenge. In this study, we demonstrated a dual-catalytic nanoreactor for tumor metastasis suppression by synergistic Fenton reaction activated chemodynamic therapy (CDT) and glucose oxidase (GOx) initiated starvation therapy. GOx on the surface of hollow mesoporous silica nanoparticles can catalyze the decomposition of intratumoral glucose to generate gluconic acid and H2O2, while Fe3O4 nanoparticles as a Fenton reaction catalyst can in situ catalyze H2O2 to produce highly toxic hydroxyl radicals (˙OH). The oxygen-carrying perfluorohexane (PFC) in the hole of the hollow structures can alleviate the hypoxic environment and promote dual-catalytic reactions. After being disguised by the cancer cell membrane, the delivery efficiency and biological safety of the nanoreactor were effectively improved. The nanoreactor can realize sequential glucose depletion and ˙OH aggregation, which effectively suppress tumor metastasis with negligible side effects.

Biodegradable Multifunctional Nanotheranostic Based on Ag2S-Doped Hollow BSA-SiO2 for Enhancing ROS-Feedback Synergistic Antitumor Therapy.

Stimuli-responsive silica nanoparticles are an attractive therapeutic agent for effective tumor ablation, but the responsiveness of silica nanoagents is limited by intrastimulation level and silica framework structure. Herein, a biodegradable hollow SiO2-based nanosystem (Ag2S-GOx@BHS NYs) is developed by a novel one-step dual-template (bovine serum albumin (BSA) and cetyltrimethylammonium bromide (CTAB)) synthetic strategy for image-guided therapy. The Ag2S-GOx@BHS NYs can be specifically activated in the tumor microenvironment via a self-feedback mechanism to achieve reactive oxygen species (ROS)-induced multistep therapy. In response to the inherent acidity and H2O2 at the tumor sites, Ag2S-GOx@BHS would accelerate the structural degradation while releasing glucose oxidase (GOx), which could efficiently deplete intratumoral glucose to copious amounts of gluconic acid and H2O2. More importantly, the sufficient H2O2 not only acts as a reactant to generate Ag+ from Ag2S for metal-ion therapy and improves the oxidative stress but also combines with gluconic acid results in the self-accelerating degradation process. Moreover, the released Ag2S nanoparticles can help the Ag2S-GOx@BHS NYs realize the second near-infrared window fluorescence (NIR-II FL) and photoacoustic (PA) imaging-guided precise photothermal therapy (PTT). Taken together, the development of a self-feedback nanosystem may open up a new dimension for a highly effective multistep tumor therapy.

Pd@Pt-GOx/HA as a Novel Enzymatic Cascade Nanoreactor for High-Efficiency Starving-Enhanced Chemodynamic Cancer Therapy.

Glucose oxidase (GOx)-mediated starvation therapy has demonstrated good application prospect in cancer treatment. However, the glucose- and oxygen-depletion starvation therapy still suffers from some limitations like low therapeutic efficiency and potential side effects to normal tissues. To overcome these disadvantages, herein a novel enzymatic cascade nanoreactor (Pd@Pt-GOx/hyaluronic acid (HA)) with controllable enzymatic activities was developed for high-efficiency starving-enhanced chemodynamic cancer therapy. The Pd@Pt-GOx/HA was fabricated by covalent conjugation of GOx onto Pd@Pt nanosheets (NSs), followed by linkage with hyaluronic acid (HA). The modification of HA on Pd@Pt-GOx could block the GOx activity, catalase (CAT)-like and peroxidase (POD)-like activities of Pd@Pt, reduce the cytotoxicity to normal cells and organs, and effectively target CD44-overexpressed tumors by active targeting and passive enhanced permeability and retention (EPR) effect. After endocytosis by tumor cells, the intracellular hyaluronidase (Hyase) could decompose the outer HA and expose Pd@Pt-GOx for the enzymatic cascade reaction. The GOx on the Pd@Pt-GOx could catalyze the oxidation of intratumoral glucose by O2 for cancer starvation therapy, while the O2 produced from the decomposition of endogenous H2O2 by the Pd@Pt with the CAT-like activity could accelerate the O2-dependent depletion of glucose by GOx. Meanwhile, the upregulated acidity and H2O2 content in the tumor region generated by GOx catalytic oxidation of glucose dramatically facilitated the pH-responsive POD-like activity of the Pd@Pt nanozyme, which then catalyzed degradation of the H2O2 to generate abundant highly toxic •OH, thereby realizing nanozyme-mediated starving-enhanced chemodynamic cancer therapy. In vitro and in vivo results indicated that the controllable, self-activated enzymatic cascade nanoreactors exerted highly efficient anticancer effects with negligible biotoxicity.