Mitochondria-specific near-infrared photoactivation of peroxynitrite upconversion luminescent nanogenerator for precision cancer gas therapy  

作　　者：Hui Yu Aliya Tiemuer Xufeng Yao Mingyuan Zuo Hai-Yan Wang Yi Liu Xiaoyuan Chen 

机构地区：[1]Department of Biomedical Engineering,School of Engineering,China Pharmaceutical University,Nanjing 211198,China [2]School of Mechanical Engineering,Southeast University,Nanjing 211189,China [3]Departments of Diagnostic Radiology,Surgery,Chemical and Biomolecular Engineering,and Biomedical Engineering,Yong Loo Lin School of Medicine and College of Design and Engineering,National University of Singapore,Singapore 119074,Singapore [4]Clinical Imaging Research Centre,Centre for Translational Medicine,Yong Loo Lin School of Medicine,National University of Singapore,Singapore 117599,Singapore [5]Nanomedicine Translational Research Program,Yong Loo Lin School of Medicine,National University of Singapore,Singapore 117597,Singapore [6]Institute of Molecular and Cell Biology,Agency for Science,Technology,and Research(A*STAR),Proteos,Singapore 138673,Singapore

出　　处：《Acta Pharmaceutica Sinica B》2024年第1期378-391,共14页药学学报（英文版）

基　　金：This work was financially supported by the National Natural Science Foundation of China(82272148,China);the“Double First-Class”University Project(CPUQNJC22-03,China);the Jiangsu Funding Program for Excellent Postdoctoral Talent(2022ZB301,China);the National University of Singapore(NUHSRO/2020/133/Startup/08,NUHSRO/2023/008/NUSMed/TCE/LOA,NUHSRO/2021/034/TRP/09/Nanomedicine);National Medical Research Council(MOH-OFIRG23jan-0005,CG21APR1005);Singapore Ministry of Education(MOE-000387-00);National Research Foundation(NRF-000352-00).

摘　　要：Gas therapy is emerging as a highly promising therapeutic strategy for cancer treatment.However,there are limitations,including the lack of targeted subcellular organelle accuracy and spatiotemporal release precision,associated with gas therapy.In this study,we developed a series of photoactivatable nitric oxide(NO)donors NRh-R-NO(R=Me,Et,Bn,iPr,and Ph)based on an N-nitrosated upconversion luminescent rhodamine scaffold.Under the irradiation of 808 nm light,only NRh-Ph-NO could effectively release NO and NRh-Ph with a significant turn-on frequency upconversion luminescence(FUCL)signal at 740 nm,ascribed to lower N-N bond dissociation energy.We also investigated the involved multistage near-infrared-controlled cascade release of gas therapy,including the NO released from NRh-Ph-NO along with one NRh-Ph molecule generation,the superoxide anion O_(2)^(⋅−)produced by the photodynamic therapy(PDT)effect of NRh-Ph,and highly toxic peroxynitrite anion(ONOO‒)generated from the co-existence of NO and O_(2)^(⋅−).After mild nano-modification,the nanogenerator(NRh-Ph-NO NPs)empowered with superior biocompatibility could target mitochondria.Under an 808 nm laser irradiation,NRh-Ph-NO NPs could induce NO/ROS to generate RNS,causing a decrease in the mitochondrial membrane potential and initiating apoptosis by caspase-3 activation,which further induced tumor immunogenic cell death(ICD).In vivo therapeutic results of NRh-Ph-NO NPs showed augmented RNS-potentiated gas therapy,demonstrating excellent biocompatibility and effective tumor inhibition guided by real-time FUCL imaging.Collectively,this versatile strategy defines the targeted RNS-mediated cancer therapy.

关 键 词：Near infrared Photo-triggered Mitochondrion Upconversion luminescent bioimaging PEROXYNITRITE NANOGENERATOR Gas therapy In vivo 

分 类 号：R73[医药卫生—肿瘤] R45[医药卫生—临床医学]