GSH-responsive camptothecin prodrug-based hybrid micellar nanoparticles enable antitumor chemo-immunotherapy by PD-L1 knockdown  

作　　者：Xi Tan Hong Zhou Chenhui Wang Xuhan Liu Xiangliang Yang Wei Liu 

机构地区：[1]College of Life Science and Technology,Huazhong University of Science and Technology,Wuhan 430074,China [2]The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine,Sichuan Provincial People’s Hospital,University of Electronic Science and Technology of China,Chengdu 611731,China [3]Department of Emergency Medicine,Shenzhen University General Hospital,Shenzhen University Clinical Medical Academy,Shenzhen 518060,China [4]National Engineering Research Center for Nanomedicine,Huazhong University of Science and Technology,Wuhan 430074,China

出　　处：《Nano Research》2023年第1期834-848,共15页纳米研究（英文版）

基　　金：The authors acknowledge the support by the National Basic Research Program of China(Nos.2020YFA0710700 and 2018YFA0208900);the National Natural Science Foundation of China(No.31470968).

摘　　要：The combinational chemo-immunotherapy as a novel treatment strategy has been widely studied and applied in clinic to enhance antitumor therapeutic efficacy and relieve side effects.RNA interference(RNAi)targeting PD-L1 via inhibiting novo production of PD-L1 will overcome the innate and adaptive PD-L1 expression during chemotherapy,thus enable sustained and efficient immune checkpoint blockade(ICB)to active antitumor immune response.Herein,we designed a glutathione(GSH)-responsive camptothecin(CPT)prodrug-based hybrid micellar nanoparticles(siPD-L1@HM-CPT)to achieve synergistic antitumor chemoimmunotherapy by PD-L1 knockdown.siPD-L1@HM-CPT derived from the one-step loading PD-L1 siRNA(siPD-L1)into the CPT prodrug-based hybrid micelles(HM-CPT)which were co-assembled from biodegradable polyphosphoesters-based prodrug CPT-ss-PAEEP15 and stabilizer DSPE-PEG,showed high loading efficiency,GSH-responsive drug release,and excellent stability and biosafety.siPD-L1@HM-CPT achieved simultaneously the co-delivery of CPT and siPD-L1 in vitro and in vivo,high accumulation at the tumor sites,and rapid intracellular release to promote antitumor efficacy via sensitizing CPT chemotherapy,inducing strong immunogenic cell death(ICD)and sustained ICB to improve intratumoral CD8+T cells infiltration.In addition,the antitumor immunity response limited by the differentiated immunogenicity,intrinsic PD-L1 expression,and intracellular GSH level was facilitated by efficient ICD and ICB from silencing PD-L1 and synergistic CPT chemosensitization in our experimental B16-F10 and 4T1 tumor models.Our study might offer a perspective on designing novel co-delivery nanoparticles by convenient and controllable preparation for antitumor chemo-immunotherapy.

关 键 词：camptothecin prodrug hybrid micellar nanoparticles glutathione(GSH)-responsive PD-L1 knockdown chemoimmunotherapy 

分 类 号：R730.51[医药卫生—肿瘤]