Short communication
Jinrong Peng, Yao Xiao, Qian Yang, Qingya Liu, Yu Chen, Kun Shi, Ying Hao, Ruxia Han, Zhiyong Qian. Intracellular aggregation of peptidereprogrammed small molecule nanoassemblies enhances cancer chemotherapy and combinatorial immunotherapy[J]. Acta Pharmaceutica Sinica B, 2021, 11(4): 1069-1082

Intracellular aggregation of peptidereprogrammed small molecule nanoassemblies enhances cancer chemotherapy and combinatorial immunotherapy
Jinrong Peng, Yao Xiao, Qian Yang, Qingya Liu, Yu Chen, Kun Shi, Ying Hao, Ruxia Han, Zhiyong Qian
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, And Collaborative Innovation Center of Biotherapy, Chengdu 610065, China
Abstract:
The intracellular retention of nanotherapeutics is essential for their therapeutic activity. The immobilization of nanotherapeutics inside target cell types can regulate various cell behaviors. However, strategies for the intracellular immobilization of nanoparticles are limited. Herein, a cisplatin prodrug was synthesized and utilized as a glutathione (GSH)-activated linker to induce aggregation of the cisplatin prodrug/IR820/docetaxel nanoassembly. The nanoassembly has been reprogrammed with peptidecontaining moieties for tumor-targeting and PD-1/PD-L1 blockade. The aggregation of the nanoassemblies is dependent on GSH concentration. Evaluations in vitro and in vivo revealed that GSH-induced intracellular aggregation of the nanoassemblies enhances therapeutic activity in primary tumors by enhancing the accumulation and prolonging the retention of the chemotherapeutics in the tumor site and inducing reactive oxygen species (ROS) generation and immunogenic cell death. Moreover, the nanoassemblies reinvigorate the immunocytes, especially the systemic immunocytes, and thereby alleviate pulmonary metastasis, even though the population of immunocytes in the primary tumor site is suppressed due to the enhanced accumulation of chemotherapeutics. This strategy provides a promising option for the intracellular immobilization of nanoparticles in vitro and in vivo.
Key words:    Nanoassembly    Glutathione response    Intracellular aggregation    Chemotherapy    Combinational immunotherapy   
Received: 2020-03-05     Revised: 2020-04-15
DOI: 10.1016/j.apsb.2020.06.013
Funds: This work was financially supported by the State Key Program of National Natural Science Foundation of China (31930067), the National Natural Science Fund for Distinguished Young Scholar (NSFC31525009, China), National Natural Science Funds (NSFC31771096, NSFC31871008, and NSFC31500809, China), the China Postdoctoral Science Foundation (2018M643484), 1$3$5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYGD18002, China), and the Post-Doctor Research Project, West China Hospital, Sichuan University (18HXBH038, China).
Corresponding author: Zhiyong Qian, anderson-qian@163.com, zhiyongqian@scu.edu.cn     Email:anderson-qian@163.com, zhiyongqian@scu.edu.cn
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Jinrong Peng
Yao Xiao
Qian Yang
Qingya Liu
Yu Chen
Kun Shi
Ying Hao
Ruxia Han
Zhiyong Qian

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