Low-temperature photothermal-induced alkyl radical release facilitates dihydroartemisinin-triggered“valve-off”starvation therapy

The high nutrient and energy demand of tumor cells compared to normal cells to sustain rapid proliferation offer a potentially auspicious avenue for implementing starvation therapy.However,conventional starvation therapy,such as glucose exhaustion and vascular thrombosis,can lead to systemic toxicity and exacerbate tumor hypoxia.Herein,we developed a new“valve-off”starvation tactic,which was accomplished by closing the valve of glucose transporter protein 1(GLUT1).Specifically,dihydroartemisinin(DHA),2,20-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride(AI),and Ink were co-encapsulated in a sodium alginate(ALG)hydrogel.Upon irradiation with the 1064 nm laser,AI rapidly disintegrated into alkyl radicals(R·),which exacerbated the DHA-induced mitochondrial damage through the generation of reactive oxygen species and further reduced the synthesis of adenosine triphosphate(ATP).Simultaneously,the production of R·facilitated DHA-induced starvation therapy by suppressing GLUT1,which in turn reduced glucose uptake.Systematic in vivo and in vitro results suggested that this radical-enhanced“valveoff”strategy for inducing tumor cell starvation was effective in reducing glucose uptake and ATP levels.This integrated strategy induces tumor starvation with efficient tumor suppression,creating a new avenue for controlled,precise,and concerted tumor therapy.

Employing the thiol-ene click reaction via metal-organic frameworks for integrated sonodynamic-starvation therapy as an oncology treatment

Hypoxia in the tumor microenvironment(TME)greatly limits the tumor-killing therapeutic efficacy of sonodynamic therapy(SDT);this phenomenon is further exacerbated by increased glutathione(GSH)levels in cancer cells.Simultaneously,cancer starvation therapy is increasingly recognized nowadays as a promising clinical translation,but the efficacy of glucose oxidase(GOx)-based starvation therapy is also limited by the lack of oxygen in the tumor.Glyceraldehyde-3-phosphate dehydrogenase(GAPDH)is a key glycolytic enzyme and can therefore be a target for starvation therapy in the absence of oxygen engagement.Here,we proposed thiol-ene click reactions based on a two-dimensional metal-organic framework(MOF)modification for tumor treatments to enable the combination of SDT and starvation therapy.Experimental studies demonstrated that the prepared material could consume GSH and GAPDH free from oxygen in TME,which benefited from the thiol-ene click reactions between the MOFs and thiol substances in cancer cells.Further experiments in vitro and in vivo indicated the prepared MOF materials could kill cancer cells efficiently.This study is expected to create a promising avenue for thiol-ene click reactions in SDT and starvation therapy for cancer.

Manganese silicate nanospheres-incorporated hydrogels:starvation therapy and tissue regeneration

To prevent postoperative skin tumor recurrence and repair skin wound,a glucose oxidase(GOx)-loaded manganese silicate hollow nanospheres(MS HNSs)-incorporated alginate hydrogel(G/MS-SA)was constructed for starvation-photothermal therapy and skin tissue regeneration.The MS HNSs showed a photothermal conversion efficiency of 38.5%,and endowed composite hydrogels with satisfactory photothermal effect.Taking advantage of the catalytic activity of Mn ions,the composite hydrogels could decompose hydrogen peroxide(H2O2)into oxygen(O2),which can alleviate the problem of tumor hypoxia microenvironment and endow GOx with an ability to consume glucose in the presence of O2 for tumor starvation.Meanwhile,hyperthermia triggered by near infrared(NIR)irradiation could not only accelerate the reaction rate of H2O2 decomposition by MS HNSs and glucose consumption by GOx,but also ablate tumor cells.The anti-tumor results showed that synergistic effect of starvation-photothermal therapy led to the highest death rate of tumor cells among all groups,and its anti-tumor effect was obviously improved as compared with that of single photothermal treatment or starvation treatment.Interestingly,the introduction of MS HNSs into hydrogels could distinctly promote the epithelialization of the wound beds by releasing Mn ions as compared with the hydrogels without MS HNSs.It is expected that such a multifunctional platform with starvation-photothermal therapy will be promising for treating tumor-caused skin defects in combination of its regeneration bioactivity in the future.

Light-triggered plasmonic vesicles with enhanced catalytic activity of glucose oxidase for programmable photothermal/starvation therapy

Glucose oxidase(GOx)-based nanotheranostic agents hold great promise in tumor starvation and its synergistic therapy. Self-assembled plasmonic gold vesicles(GVs) with unique optical properties, large hollow cavity, and strong localized surface plasmon resonance, can be used as multi-functional nanocarriers for synergistic therapy. Herein,GOx-loaded GVs(GV-GOx) were developed for light-triggered GOx release as well as enhanced catalytic activity of GOx, achieving programmable photothermal/starvation therapy. Under near-infrared laser irradiation, the GV-GOx generated strong localized hyperthermia due to plasmon coupling effect of GVs, promoting the release of encapsulated GOx and increasing its catalytic activity, resulting in enhanced tumor starvation effect. In addition, the high photothermal effect improved the cellular uptake of GV-GOx and allowed an efficient monitoring of synergistic tumor treatment via photoacoustic/photothermal duplex imaging in vivo. Impressively, the synergistic photothermal/starvation therapy demonstrated complete tumor eradication in 4 T1 tumorbearing mice, verifying superior synergistic anti-tumor therapeutic effects than monotherapy with no apparent systemic side effects. Our work demonstrated the development of a light-triggered nanoplatform for cancer synergistic therapy.

When starvation therapy meets chemodynamic therapy

In recent years,starvation-primed chemodynamic therapies(ST-CDT)have become a hot topic in the wake of many discoveries related to the aberrant metabolism of cancer cells and their resistance to traditional chemother-apies,as well as altered redox signaling within tumor cells.Nanotechnology platforms are in a unique position to exploit these interrelated phenomena to realize a therapeutic effect;few therapeutic modalities are able to deliver multiple drugs simultaneously outside of nanotechnology,a basic requirement when striving to exploit a complex,interactive system such as a cancer cell.In this review,the pertinent mechanisms of ST and CDT,as well as the important interactions between these two therapies,are discussed.We outline how these therapies may work synergistically or antagonistically,depending on both the therapeutic design and the system of reactions involved.Lastly,specific applications that nanotechnology is particularly well-suited are given,which may offer improvement over clinical state-of-the-art.Such considerations are important,as nanotechnology has historically encountered great difficulty in clinical translation.

Development of an intelligent heterojunction fenton catalyst for chemodynamic/starvation synergistic cancer therapy

Chemodynamic therapy(CDT)as an emerging modality in cancer treatment,its implementation remains a daunting challenge by the lack of smart Fenton catalyst under acidic tumor microenvironments.Herein,we have successfully constructed a Fe_(3)O_(4)@MIL-100 heterojunction by growing Fe-based metal-organic framework(MIL-100)onto the surface of Fe_(3)O_(4) nanoparticles.The as-made heterojunction after encapsu-lating glucose oxidase(termed FMG)is demonstrated as a pH-responsive intelligent Fenton nanosystem with the synergistic effect of starvation therapy(ST).Density functional theory(DFT)calculations reveal that such heterojunction could greatly reduce the energy barrier of the Fenton reaction,which better ex-plains the mechanism of Fenton performance improvement.Moreover,the encapsulated glucose oxidase has successfully activated the ST process,in which its generated H_(2)O_(2) and gluconic acid further improve the CDT efficiency.More O_(2) from the enhanced CDT in turn promotes the enzymatic reaction of glucose oxidase.The Fenton/cascade enzymatic reaction operates in a self-feedback manner as proposed.In vitro and in vivo experiments demonstrate that such intelligent Fenton nanoreactors provide a powerful anti-cancer mechanism for effective tumor ablation with enough safety.This work provides insights into the developments of MOF-based heterojunctions as powerful anticancer treatment nanoreactors.

Gold mineralized“hybrid nanozyme bomb”for NIR-Ⅱtriggered tumor effective permeation and cocktail therapy

Lung cancer is one of the most common malignant tumors with the fastest increase in the incidence rate and mortality.Even after maximum tumor resection assistance with a radiotherapy and chemotherapy combination,the recurrence of non-small cell lung cancer is still inevitable.In addition,low targeting efficiency and poor permeability of drug delivery systems strongly affect the therapeutic efficiency of anti-cancer drugs on non-small cell lung cancer.Here we designed a gemcitabine(GEM)loaded arginineglycine-aspartic acid-cysteine(RGDc)-modified gold mineralization“hybrid nanozyme bomb”(RGTG)to overcome those obstacles.RGDc modification improved the active targeting of liposomes to the tumor tissues with the second near-infrared(NIR-Ⅱ)-triggered gold-shell disruption and GEM release.The collapsed gold-shell particles with a smaller size could penetrate the tumor solid barrier and act as photothermal therapy(PTT)agents to improve PTT therapy and starvation therapy via generating gluconic acid and reactive oxygen species(ROS).Moreover,the resting reversal effect of gold particles on tumor fibroblasts can achieve accelerating tumor penetration of gold particles and GEM.Compared to monotherapy,RGTG showed significant improvement in tumor inhibition,with a tumor volume reduction of 83%compared to the control group,which provides a promising tumor treatment platform for non-small cell lung cancer(NSCLC).

Synergistic enhancement of ultrasound therapy for tumors using hypoxia-activated 6-diazo-5-oxo-L-norleucine(DON)prodrug nanoparticles

Ultrasound(US)has been applied in clinical practice for its non-invasive and high selectivity.However,it is difficult to achieve a satisfactory anti-tumor effect with US alone.Meanwhile,the use of US therapy alone can exacerbate tumor hypoxia.In this study,we prepared hypoxia-activated 6-diazo-5-oxo-L-norleucine(DON)prodrug nanoparticles(HDON-NPs)to improve US therapeutic effects.In an H22 murine liver cancer model,US therapy selectively disrupted tumor blood vessels,leading to increased tumor hypoxia and a 1.67-fold increase in the expression of nitroreductase(NTR).The combination therapy of US and HDON-NPs demonstrated a synergistic effect,resulting in a tumor suppression rate(TSR)of 90.2%±6.4%,which was 5.93-fold higher than that of US therapy alone.The combined treatment selectively blocked the glutamine metabolism of the tumor cells while simultaneously activating the T cells in the tumor microenvironment,thereby exerting a robust anti-tumor effect.

ZIF-8 coated gold nanospheres: A multi-responsive drug delivery system promoting the killing effect of photothermal therapy against osteosarcoma cells

Photothermal therapy(PTT)has been widely used in the treatment of tumors,but its efficacy is greatly limited by the inability of precise drug delivery and the increase of heat shock proteins(HSPs)caused by high temperature.This article describes a therapeutic strategy to enhance PTT with starvation therapy in conjunction with ferroptosis mechanism.A nanoparticle platform ZIF-8@GA was constructed by wrapping together glucose oxidase(GOX)and gold nanospheres(AuNPs)loaded with dihydroartemisinin(DHA)with zeolitic imidazolate framework-8(ZIF-8).This platform can take advantage of the micro-environment of osteosarcoma(OS)cells,featuring low pH and high reactive oxygen species(ROS),for precision drug delivery.GOX can effectively catalyze glucose to produce gluconic acid and H_(2)O_(2),and DHA can also induce ROS production in OS cells.ROS produced by GOX and DHA can further generate lipid peroxidation(LPO)and lead to ferroptosis of OS cells.At the same time,ROS and LPO produced can inhibit the expression of HSPs,thereby increasing the therapeutic effect of PTT.In vitro experiments show that the nanoparticles are pH and ROS responsive.1μg/mL GOX combined with 0.2μg/mL DHA promotes ferroptosis of OS cells,and increases the killing effect of near-infrared(NIR)on OS cells.Further in vivo experiments showed that the nano drug-delivery platform combined with PTT can effectively inhibit the growth of OS cells.Meanwhile,this study provides a new idea for the treatment of OS with biomaterials combined with various treatment methods.

Degradable nanocatalyst enables antitumor/antibacterial therapy and promotion of wound healing for diabetes via self-enhanced cascading reaction

Diabetic patients often have problems such as residual tumor and wound infection after tumor resection,causing severe clinical problems.It is urgent to develop effective therapies to reach oncotherapy/antiinfection/promotion of wound healing combined treatment.Herein,we propose CS/MnO_(2)-GO_x (CMGO_x)nanocatalysts for the specific catalytic generation of ~·OH to inhibit tumors and bacteria in a hyperglycemic environment.The good biocompatible chitosan (CS),as a carrier for the catalyst,exhibits excellent antibacterial effect as well as promotes wound healing.Glucose oxidase (GO_x) is loaded on the surface of CS nanoparticles to generate H_(2)O_(2) and gluconic acid by consuming glucose (starvation therapy,ST) and O_(2).The MnO_(2) depletes glutathione (GSH) to produce Mn^(2+),amplifying oxidative stress and further promoting the activity of Mn^(2+)-mediated Fenton-like reaction to produce~·OH (chemodynamic therapy,CDT)in weak acidic environment.Moreover,the produced gluconic acid lowers the p H of the environment,enhancing chemodynamic therapy (ECDT).The tumor cells and bacteria are efficiently eliminated by the synergistic effect of ST and ECDT.The MnO_(2) nanoparticles at neutral environment decomposes H_(2)O_(2) into O_(2),which cooperate with CS to promote healing.The self-enhanced cascade reaction of CMGO_x in situ exhibits excellent effects of antitumor/antibacterial therapy and promotion of wound healing,offering a promising integrated treatment for diabetic patients after tumor surgical resection.

Novel nanocarrier for promoting tumor synergistic therapy by down-regulation of heat shock proteins and increased Fe^(3+) supply

With the emergence of new therapeutic methods,synergistic therapy has attracted great attention because it can improve the treatment efficacy,and reduce the toxic side effects.Herein,we developed a nanocarrier BGT by co-loading glucose oxidase(GOD)and transferrin(TRF)on the porous Bi nanoparticles(NPs)for improving tumor synergistic therapy.GOD endows BGT with catalytic capacity of decomposing glucose into gluconic acid and a large amount of H2O2 for starving therapy.H2O2 further destroys TRF structure and releases Fe^(3+),which could react with H2O2 to generate highly toxic·OH for chemodynamic therapy(CDT).In addition,GOD-induced glucose depletion and decreased expression of heat shock proteins(HSPs)can also alleviate the thermotolerance of tumor cells to improve the efficiency of mild photothermal therapy(PTT).Mild temperature can in turn promote the production of reactive oxygen species(ROS)for improving the synergistic therapy.Combined with the excellent targeting ability of TRF,efficient tumor synergistic therapy can be achieved.This work shows that BGT has good photothermal stability and biocompatibility,and can be used as a nanocarrier,providing an effective method for collaborative therapy of tumor.

仿生细胞膜涂层包覆肿瘤阻断代谢物传输

The metabolite transport inhibition of tumor cells holds promise to achieve anti-tumor efficacy.Herein,we presented an innovative strategy to hinder the delivery of metabolites through the in-situ besieging tumor cells with polyphenolic polymers that strongly adhere to the cytomembrane of tumor cells.Simultaneously,these polymers underwent self-crosslinking under the induction of tumor oxidative stress microenvironment to form an adhesive coating on the surface of the tumor cells.This polyphenol coating effectively obstructed glucose uptake,reducing metabolic products such as lactic acid,glutathione,and adenosine triphosphate,while also causing reactive oxygen species to accumulate in the tumor cells.The investigation of various tumor models,including 2D cells,3D multicellular tumor spheroids,and xenograft tumors,demonstrated that the polyphenolic polymers effectively inhibited the growth of tumor cells by blocking key metabolite transport processes.Moreover,this highly adhesive coating could bind tumor cells to suppress their metastasis and invasion.This work identified polyphenolic polymers as a promising anticancer candidate with a mechanism by impeding the mass transport of tumor cells.

Programmable starving-photodynamic synergistic cancer therapy

Synergistic therapy combines multiple therapeutic approaches in one shot,thus could significantly amplify the therapeutic effects.However,how to design the desirable combination to maximize the synergistic effect is still a big challenge in cancer management.Herein,a nanoagent composed of glucose oxidase(GOx)and upconversion nanoparticles(UCNPs)were constructed for programmable starving-photodynamic synergistic cancer therapy through cascade glucose oxidation and hydrogen peroxide photolysis.In this nanoagent,GOx modulated the tumor glucose metabolism and consumed the β-D-glucose to produce H2O2.The glucose depletion induced"starvation"in cancer cells and caused cell death.Afterwards,the generated H2O2 was photolyzed by the invisible ultraviolet emission of UCNPs under near-infrared light excitation at 980 nm.The toxic hydroxyl radicals produced by photolysis further induced cancer cell death.Both in vitro and in vivo experiments confirmed that this starving-photodynamic synergistic therapy significantly outran any single therapy.This study paves an avenue to design programmable starving-photodynamic synergistic therapy for cancer management.

Redox-responsive micelles integrating catalytic nanomedicine and selective chemotherapy for effective tumor treatment

Chemotherapy is one of the most conventional modalities for cancer therapy.However,the high multidrug resistance of tumor cells still limited the clinical application of current chemotherapy.Considering the ability of nitric oxide(NO) to modulate potent P-glycoprotein to inhibit multi-drug resistance,a synergistic methodology combining chemotherapy and sustained NO generation is an ideal way to further promote the chemotherapy.Herein,a multi-functional micelle with tumor-selective chemotherapy driven by redox-triggered doxorubicin(DOX) release and drug resistance inhibition based on intracellular NO generation was fabricated for effective tumor treatment.The micelle consists of DOX as core,arginine/glucose oxidase(Arg/GOx) as shell and redox-responsive disulfide bond as a linker,which is denoted as micelle-DOX-Arg-GOx.The Arg serves as the biological precursor of nitric oxide for inhibition of multi-drug resistance to promote chemotherapy and GOx catalyzes glucose to produce hydrogen peroxide(H_(2) O_(2)) for increasing the generation of NO.Moreover,the glucose supply could be simultaneously blocked by the catalytic process,which further enhanced therapeutic efficiency.This micelle requests a tumor-specific microenvironment(a considerable amount of GSH) to perform synergistic therapeutics including chemotherapy,starvation therapy(catalytic medicine),and gas therapy for tumor treatment,which resulted in significant cytotoxicity to tumor tissue.

一种智能纳米酶工厂作为诊疗纳米平台用于协同癌症治疗

多模态疗法是结合多种疗法治疗通常复杂而隐蔽的肿瘤组织的最有希望的策略之一.尽管多功能纳米材料已被设计用于构建多模态疗法,但普遍存在的各组成部分之间的不充分协调可能导致协同治疗效果不佳,并妨碍其充分实现临床潜力.在此,受可控“集束炸弹”模型的启发,我们设计了一种智能、生物相容、多功能的纳米工厂系统(PDA@GOx@MnO_(2)-PEG),它封装了多种纳米试剂,以达到对肿瘤组织的高破坏效率.刺激反应性的外层二氧化锰作为“炸弹”的外壳可触发级联催化反应,并与GOx形成一个自给自足的环形催化链.PDA作为一种具有良好蛋白质携带能力的基质,实现了高的GOx负载.同时,其高效的光热转换效率显示了低温(~45℃)进一步提高GOx酶活性的潜力.值得注意的是,内部的GOx就像一个“子炸弹”,通过控制释放来增加肿瘤缺氧部位的积累,并在充足的氧气和低热度的帮助下充分发挥其葡萄糖消耗能力进行饥饿治疗.在这个体系中,各种纳米试剂相互配合,层层推进,充分发挥其威力,形成了一个自给自足的纳米工厂模型,通过协同策略实现了良好的低温光热-饥饿协同治疗.此外,该纳米复合材料表现出三态成像能力,可用于敏感诊断和实时监控治疗.这项研究为设计生物相容性和智能治疗纳米平台提供了新的见解,使精准医疗中的多模式治疗效果最大化.

Design and therapeutic application of sodium alginate-based hydrogel with biodegradability and catalytic activity

How to efficiently treat cancer in a minimally invasive manner has become one of the major focuses of recent developments in biomedicine.In this research,biodegradable sodium alginate(SA)hydrogel encapsulated with NaHCO_(3)and glucose oxidase(GOX)was synthesized using Fe^(3+)as the crosslinker for the tumor chemodynamic therapy(CDT)and starvation therapy(ST).Material safety assessments revealed that this hydrogel possesses good in vitro and in vivo security.In tumor microenvrionment(TME),the Fe^(3+)further reacted with the intracellular glutathione and was transformed into Fe^(2+),which triggered the Fenton reaction with the H_(2)O_(2)within TME and produced abundant highly toxic·OH(hydroxyl radicals)for efficient tumor CDT.Furthermore,the GOXcatalyzed the enzymolysis of glucose to consume the nutrient of the tumor and enhance the H_(2)O_(2)level in TME.Besides,the CO_(2)bubbles that were generated from the decomposing of NaHCO_(3)promoted the contact between glucose and GOX.Findings in this research would have important implications for the present status of tumor therapy.