Journal
ACTA PHARMACEUTICA SINICA B
Volume 11, Issue 4, Pages 1069-1082Publisher
INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2020.06.013
Keywords
Nanoassembly; Glutathione response; Intracellular aggregation; Chemotherapy; Combinational immunotherapy
Categories
Funding
- State Key Program of National Natural Science Foundation of China [31930067]
- National Natural Science Fund for Distinguished Young Scholar (China) [NSFC31525009]
- National Natural Science Funds (China) [NSFC31771096, NSFC31871008, NSFC31500809]
- China Postdoctoral Science Foundation [2018M643484]
- 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (China) [ZYGD18002]
- Post-Doctor Research Project, West China Hospital, Sichuan University (China) [18HXBH038]
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This study demonstrates the intracellular immobilization of nanoparticles by synthesizing a cisplatin prodrug and utilizing a GSH-activated linker to induce aggregation of a nanoassembly. In vivo evaluations show that enhancing chemotherapeutic accumulation and retention in the tumor site through intracellular aggregation leads to increased therapeutic activity and immunocyte activation, ultimately inhibiting pulmonary metastasis.
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 peptide-containing 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. (C) 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
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