Engineering prodrug nanomicelles as pyroptosis inducer for codelivery of PI3K/mTOR and CDK inhibitors to enhance antitumor immunity.
10.1016/j.apsb.2022.02.024
- Author:
Qichao YANG
1
;
Xianbin MA
2
;
Yao XIAO
1
;
Tian ZHANG
2
;
Leilei YANG
1
;
Shaochen YANG
1
;
Mengyun LIANG
2
;
Shuo WANG
1
;
Zhizhong WU
1
;
Zhigang XU
2
;
Zhijun SUN
1
Author Information
1. The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei- MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
2. Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, School of Materials and Energy & Chongqing Engineering Research Center for Micro-Nano Biomedical Materials and Devices, Southwest University, Chongqing 400715, China.
- Publication Type:Journal Article
- Keywords:
Immunotherapy;
Prodrug;
Pyroptosis;
Stimuli-responsive;
Targeted therapy;
Tumor microenvironment
- From:
Acta Pharmaceutica Sinica B
2022;12(7):3139-3155
- CountryChina
- Language:English
-
Abstract:
Aberrant activation of oncogenic signaling pathways in tumors can promote resistance to the antitumor immune response. However, single blockade of these pathways is usually ineffective because of the complex crosstalk and feedback among oncogenic signaling pathways. The enhanced toxicity of free small molecule inhibitor combinations is considered an insurmountable barrier to their clinical applications. To circumvent this issue, we rationally designed an effective tumor microenvironment-activatable prodrug nanomicelle (PNM) for cancer therapy. PNM was engineered by integrating the PI3K/mTOR inhibitor PF-04691502 (PF) and the broad spectrum CDK inhibitor flavopiridol (Flav) into a single nanoplatform, which showed tumor-specific accumulation, activation and deep penetration in response to the high glutathione (GSH) tumoral microenvironment. The codelivery of PF and Flav could trigger gasdermin E (GSDME)-based immunogenic pyroptosis of tumor cells to elicit a robust antitumor immune response. Furthermore, the combination of PNM-induced immunogenic pyroptosis with anti-programmed cell death-1 (αPD-1) immunotherapy further boosted the antitumor effect and prolonged the survival time of mice. Collectively, these results indicated that the pyroptosis-induced nanoplatform codelivery of PI3K/mTOR and CDK inhibitors can reprogram the immunosuppressive tumor microenvironment and efficiently improve checkpoint blockade cancer immunotherapy.
