Carrier-free nanoprodrug for p53-mutated tumor therapy via concurrent delivery of zinc-manganese dual ions and ROS  

作　　者：Jinping Wang Chang Qu Xinyue Shao Guoqiang Song Jingyu Sun Donghong Shi Ran Jia Hailong An Hongjun Wang 

机构地区：[1]Key Laboratory of Molecular Biophysics of Hebei Province,Institute of Biophysics,School of Health Sciences and Biomedical Engineering,Hebei University of Technology,300401,Tianjin,PR China [2]Department of Biomedical Engineering,Stevens Institute of Technology,Hoboken,NJ,07030,United States [3]Department of Chemistry and Chemical Biology,Stevens Institute of Technology,Hoboken,NJ,07030,United States [4]Center for Healthcare Innovation,Stevens Institute of Technology,Hoboken,NJ,07030,United States [5]Key Laboratory of Molecular Biophysics of Hebei Province,Institute of Biophysics,School of Sciences,Hebei University of Technology,300401,Tianjin,PR China [6]State Key Laboratory of Reliability and Intelligence of Electrical Equipment,School of Electrical Engineering,Hebei University of Technology,Tianjin,300130,PR China

出　　处：《Bioactive Materials》2023年第2期404-417,共14页生物活性材料（英文）

基　　金：supported by the NIAMS award number 1R01AR067859;National Natural Science Foundation of China(82102208,81830061);Program for Excellent Innovative Talents in Universities of Hebei Province(BJ2021019);Natural Science Foundation of Hebei Province(H2021202002,H2020202005);the Natural Science Foundation of Tianjin(19JCYBJC28300).

摘　　要：Human cancers typically express a high level of tumor-promoting mutant p53 protein(Mutp53)with a minimal level of tumor-suppressing wild-type p53 protein(WTp53).In this regard,inducing Mutp53 degradation while activating WTp53 is a viable strategy for precise anti-tumor therapy.Herein,a new carrier-free nanoprodrug(i.e.,Mn-ZnO_(2)nanoparticles)was developed for concurrent delivery of dual Zn-Mn ions and reactive oxygen species(ROS)within tumor to regulate the p53 protein for high anti-tumor efficacy.In response to the mild tumor acidic environment,the released Zn^(2+)and H_(2)O_(2)from Mn-ZnO_(2)NPs induced ubiquitination-mediated proteasomal degradation of Mutp53,while the liberative Mn^(2+)and increased ROS level activated the ATM-p53-Bax pathway to elevate WTp53 level.Both in vitro and in vivo results demonstrated that pH-responsive decomposition of Mn-ZnO2 NPs could effectively elevate the intracellular dual Zn-Mn ions and ROS level and subsequently generate the cytotoxic hydroxyl radical(·OH)through the Fenton-like reaction.With the integration of multiple functions(i.e.,carrier-free ion and ROS delivery,tumor accumulation,p53 protein modulation,toxic·OH generation,and pH-activated MRI contrast)in a single nanosystem,Mn-ZnO_(2)NPs demonstrate its superiority as a promising nanotherapeutics for p53-mutated tumor therapy.

关 键 词：p53-mutated tumor therapy Wild-type p53 protein Carrier-free nanoprodrug Mn-ZnO_(2)nanoparticle Reactive oxygen species 

分 类 号：TB383.1[一般工业技术—材料科学与工程]