Citation: Jing Gao, Hanwu Zhang, Fengqi Zhou, Bo Hou, Meiwan Chen, Zhigang Xie, Haijun Yu. Acid-activatible micelleplex delivering siRNA-PD-L1 for improved cancer immunotherapy of CDK4/6 inhibition[J]. Chinese Chemical Letters, ;2021, 32(6): 1929-1936. doi: 10.1016/j.cclet.2020.12.009 shu

Acid-activatible micelleplex delivering siRNA-PD-L1 for improved cancer immunotherapy of CDK4/6 inhibition

Jing Gao ^{a, b, c, 1} ,
Hanwu Zhang ^{a, 1} ,
Fengqi Zhou ^a ,
Bo Hou ^a ,
Meiwan Chen ^d ,
Zhigang Xie ^e ,
Haijun Yu ^{a, *,}

a.
State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
b.
Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Ultrasound Research and Education Institute, Tongji University School of Medicine, Tongji University Cancer Center, Shanghai 200072, China
c.
Peking University Shenzhen Institute, Shenzhen 518055, China
d.
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China
e.
State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China

hjyu@simm.ac.cn

Received Date: 20 September 2020
Revised Date: 4 December 2020
Accepted Date: 7 December 2020
Available Online: 11 December 2020

Figures(6)

Cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) have been demonstrated to trigger antitumor immunity for tumor regression. However, the therapeutic performance of CDK4/6i-meadiated cancer immunotherapy was impaired by the immunosuppressive tumor microenvironment (ITM) due to overexpression of programmed death ligand 1 (PD-L1) on the surface of cancer cell membrane. To improve the immunotherapeutic performance of CDK4/6i, we herein developed endosomal acid-activatable micelleplex for siRNA delivery and PD-L1 knockdown in the tumor cells in vitro and in vivo. We further demonstrated that the combination of PD-L1 knockdown and CDK4/6 inhibition facilitated intratumoral infiltration of cytotoxic T lymphocytes (CTLs), and elicited protective immune response and efficiently suppressed tumor growth in vivo. This study revealed the importance of molecular design of the micelleplex for highly efficient siRNA delivery, which might provide a novel insight for RNAi-based cancer immunotherapy.
- Cancer immunotherapy,
- siRNA delivery,
- Acid-activatible micelleplex,
- CDK4/6 inhibitor,
- PD-L1 knockdown
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