Furin Enzyme-Responsive siRNA Delivery System for Efficient Anti-Hypoxia-Assisted Cancer Photodynamic Therapy  

作　　者：Shuyue Ye Yali Feng Yuqi Zhang Jing Fang Anna Wang Chaoxiang Cui Jinfeng Zhu Liangsheng Guo Guohua Fan Haibin Shi 

机构地区：[1]State Key Laboratory of Radiation Medicine and Protection,School for Radiological and Interdisciplinary Sciences(RAD-X)and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions,Soochow University,Suzhou 215123 [2]Department of Radiology,The Second Affiliated Hospital of Soochow University,Suzhou 215004 [3]Department of Obstetrics and Gynecology,The Second Affiliated Hospital of Soochow University,Suzhou 215004

出　　处：《CCS Chemistry》2024年第4期999-1010,共12页中国化学会会刊（英文）

基　　金：the National Science Foundation of China(grant no.22077092);the Open Project Program of the State Key Laboratory of Radiation Medicine and Protection(grant no.GZK1202140);Science and Technology Development Plan of Suzhou(grant no.SLJ2022018);Scientific Research Project of Suzhou Commission of Health(grant no.GSWS2020028);a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

摘　　要：RNA interfering therapy has emerged as a promising therapeutic modality to treat cancer.The specific and efficient delivery of RNA into a tumor is crucial for achieving effective cancer gene therapy but remains a huge challenge.Herein,we report a novel furin-responsive small interfering RNA(siRNA)delivery vehicle with multiple functions for colorectal tumor treatment.A peptide-based siRNA delivery vehicle RVRR-P18-Gd,consisting of furin enzyme-specific peptide substrate Arg-Val-Arg-Arg(RVRR)with positive charge for siRNA binding,a Gd(III)chelated 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid(DOTA)(DOTA-Gd)for magnetic resonance imaging,and purpurin 18 as photosensitizer for photodynamic therapy(PDT),was rationally designed and synthesized.Taking advantage of the cationic amphiphilic feature,RVRR-P18-Gd molecules spontaneously self-assembled with negatively charged Hif-1αsiRNA into stable nanoparticles via attractive electrostatic interaction,which effectively prevented siRNA degradation by nucleases,prolonged the circulation half-life,and enhanced tumor accumulation.Moreover,the specific release of Hif-1αsiRNA mediated by endogenous furin significantly downregulated Hif-1αexpression in colorectal cancer cells,resulting in enhanced therapeutic susceptibility,and with the PDT effect,effectively suppressed HCT116 tumor growth in living mice.This work highlights a powerful and universal approach to precisely deliver siRNA to targeted tumors for efficient synergistic therapy.

关 键 词：SELF-ASSEMBLY RNA interfering enzymeresponsive delivery ANTI-HYPOXIA photodynamic therapy 

分 类 号：R735.7[医药卫生—肿瘤]