Author:
Ge Xiaoyan,Hao Yanyun,Li Hui,Zhao Huajun,Liu Yang,Liu Yutong,Li Xia,Chen Hongfei,Zou Jing,Zhang Shiying,Huang Lingling,Shan Gang,Zhang Zhiyue
Abstract
Abstract
Background
Immunosuppressive tumor immune microenvironment (TIME) lowers immunotherapy effectiveness. Additionally, low penetration efficiency and unpredictable drug release in tumor areas restrict tumor therapy.
Methods
A triblock copolymeric micelle (NanoPCPT+PIMDQ) was developed to carry the chemotherapeutic drug camptothecin (CPT) and the TLR7/8 agonist 1-(4-(aminomethyl)benzyl)-2-butyl-1H-imidazo[4,5-c] quinoline-4-amine (IMDQ) to achieve deep tumor penetration and on-demand drug release by responding to acid and reduction stimuli sequentially. The synergistic antitumour efficacy of NanoPCPT+PIMDQ was assessed both in vitro and in vivo.
Results
NanoPCPT+PIMDQ is composed of a hydrophilic PEG(polyethylene glycol) outer layer, an acid-sensitive EPEMA middle layer, and a drug inner core. Upon intratumoral injection, (i) NanoPCPT+PIMDQ first responds to the acidic tumor microenvironment and disintegrates to PIMDQ and PCPT, penetrating deep regions of the tumor; (ii) tumor cells are killed by the released CPT; (iii) DCs are activated by PIMDQ to increase the infiltration of cytotoxic T lymphocyte (CTL); and (iv) both downregulated Foxp3+ Tregs by CPT and repolarized M2 macrophages by PIMDQ can relieve the TIME.
Conclusion
This pH/GSH-responsive triblock polymer-drug conjugate reduces immunosuppression and enhances the infiltration of CTLs by codelivering CPT and IMDQ in a controllable manner, providing a promising platform for synergistic tumor chemoimmunotherapy.
Funder
Shandong Provincial Natural Science Foundation
Natural Science Foundation of China
Publisher
Springer Science and Business Media LLC
Subject
Pharmaceutical Science,Applied Microbiology and Biotechnology,Biomedical Engineering,Molecular Medicine,Medicine (miscellaneous),Bioengineering
Cited by
2 articles.
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