Quite a great proportion of known tumor cells carry mutation in TP53 gene,expressing mutant p53 proteins(mutp53)missing not only original genome protective activities but also acquiring gain-of-functions that favor tu...Quite a great proportion of known tumor cells carry mutation in TP53 gene,expressing mutant p53 proteins(mutp53)missing not only original genome protective activities but also acquiring gain-of-functions that favor tumor progression and impede treatment of cancers.Zinc ions were reported as agents cytocidal to mutp53-carrying cells by recovering p53 normal functions and abrogating mutp53.Meanwhile in a hyperthermia scenario,the function of wild type p53 is required to ablate tumors upon heat treatment hence the effects might be hindered in a mutp53 background.We herein synthesized zinc-doped Prussian blue(ZP)nanoparticles(NPs)to combine Zn 2+based and photothermal therapeutic effects.An efficient release of Zn 2+in a glutathione-enriched tumor intracellular microenvironment and a prominent photothermal conversion manifested ZP NPs as zinc ion carriers and photothermal agents.Apoptotic death and autophagic mutp53 elimination were found to be induced by ZP NPs in R280K mutp53-containing MDA-MB-231 cells and hyperthermia was rendered to ameliorate the treatment in vitro through further mutp53 elimination and increased cell death.The combinatorial therapeutic effect was also confirmed in vivo in a mouse model.This study might expand zinc delivery carriers and shed a light on potential interplay of hyperthermia and mutp53 degradation in cancer treatment.展开更多
Glucose oxidase(GOx)-based starvation therapy has emerged as a promising strategy in tumor therapy.However,the non-specific catalytic activity and premature degradation of GOx during systemic circulation have limited ...Glucose oxidase(GOx)-based starvation therapy has emerged as a promising strategy in tumor therapy.However,the non-specific catalytic activity and premature degradation of GOx during systemic circulation have limited its therapeutic efficacy in tumor regions.In this study,we present the synthesis of ultrasound/glutathione dual-responsive ZIF-8-GOx@copper-polydopamine@liposome-L-arginine(ZGCLL)nanoparticles,designed to concurrently achieve ion interference therapy,starvation therapy,and ultrasound-catalyzed gas therapy.The ZIF-8-GOx nanoparticles are prepared via a co-precipitation method,followed by the encapsulation of a copper-polydopamine(Cu-PDA)shell on the particle surface.Subsequently,liposomes and L-arginine are incorporated to form ZGCLL.The Cu-PDA shell exhibits responsiveness to the elevated level of glutathione in tumor microenvironment,leading to its degradation,mitigating the risk of unintended degradation and“off-target”effect of GOx in normal tissues.The exposure of ZIF-8 results in zinc overload and activates the catalytic reaction of GOx.The consequent depletion of glucose facilitates starvation therapy,while the generated H2O2,in synergy with zinc ions,intensifies oxidative stress.H_(2)O_(2)can produce more potent reactive oxygen species when exposed to ultrasound,which subsequently react with L-arginine to generate higher levels of nitric oxide for gas therapy.Both in vitro and in vivo studies demonstrate that this platform achieves precise and efficient antitumor effects.This research offers an innovative strategy for the development of cascade catalytic reaction systems and targeted therapeutic platforms.展开更多
基金by the National Natural Science Foundation of China(No.81772278).
文摘Quite a great proportion of known tumor cells carry mutation in TP53 gene,expressing mutant p53 proteins(mutp53)missing not only original genome protective activities but also acquiring gain-of-functions that favor tumor progression and impede treatment of cancers.Zinc ions were reported as agents cytocidal to mutp53-carrying cells by recovering p53 normal functions and abrogating mutp53.Meanwhile in a hyperthermia scenario,the function of wild type p53 is required to ablate tumors upon heat treatment hence the effects might be hindered in a mutp53 background.We herein synthesized zinc-doped Prussian blue(ZP)nanoparticles(NPs)to combine Zn 2+based and photothermal therapeutic effects.An efficient release of Zn 2+in a glutathione-enriched tumor intracellular microenvironment and a prominent photothermal conversion manifested ZP NPs as zinc ion carriers and photothermal agents.Apoptotic death and autophagic mutp53 elimination were found to be induced by ZP NPs in R280K mutp53-containing MDA-MB-231 cells and hyperthermia was rendered to ameliorate the treatment in vitro through further mutp53 elimination and increased cell death.The combinatorial therapeutic effect was also confirmed in vivo in a mouse model.This study might expand zinc delivery carriers and shed a light on potential interplay of hyperthermia and mutp53 degradation in cancer treatment.
基金supported by the National Natural Science Foundation of China(No.52172289)Fundamental Research Funds for the Central Universities,Beijing Life Science Academy(BLSA,No:2023400CA0100)the Funds of the Natural Science Foundation of Hangzhou under Grant No.2024SZRYBH180004.
文摘Glucose oxidase(GOx)-based starvation therapy has emerged as a promising strategy in tumor therapy.However,the non-specific catalytic activity and premature degradation of GOx during systemic circulation have limited its therapeutic efficacy in tumor regions.In this study,we present the synthesis of ultrasound/glutathione dual-responsive ZIF-8-GOx@copper-polydopamine@liposome-L-arginine(ZGCLL)nanoparticles,designed to concurrently achieve ion interference therapy,starvation therapy,and ultrasound-catalyzed gas therapy.The ZIF-8-GOx nanoparticles are prepared via a co-precipitation method,followed by the encapsulation of a copper-polydopamine(Cu-PDA)shell on the particle surface.Subsequently,liposomes and L-arginine are incorporated to form ZGCLL.The Cu-PDA shell exhibits responsiveness to the elevated level of glutathione in tumor microenvironment,leading to its degradation,mitigating the risk of unintended degradation and“off-target”effect of GOx in normal tissues.The exposure of ZIF-8 results in zinc overload and activates the catalytic reaction of GOx.The consequent depletion of glucose facilitates starvation therapy,while the generated H2O2,in synergy with zinc ions,intensifies oxidative stress.H_(2)O_(2)can produce more potent reactive oxygen species when exposed to ultrasound,which subsequently react with L-arginine to generate higher levels of nitric oxide for gas therapy.Both in vitro and in vivo studies demonstrate that this platform achieves precise and efficient antitumor effects.This research offers an innovative strategy for the development of cascade catalytic reaction systems and targeted therapeutic platforms.
