Citation: An Lu, Yuhao Guo, Yi Yan, Lin Zhai, Xiangyu Wang, Weiran Cao, Zijie Li, Zhixia Zhao, Yujie Shi, Yuanjun Zhu, Xiaoyan Liu, Huining He, Zhiyu Wang, Jian-Cheng Wang. Nanomedicine integrating the lipidic derivative of 5-fluorouracil, miriplatin and PD-L1 siRNA for enhancing tumor therapy[J]. Chinese Chemical Letters, ;2024, 35(6): 108928. doi: 10.1016/j.cclet.2023.108928 shu

Nanomedicine integrating the lipidic derivative of 5-fluorouracil, miriplatin and PD-L1 siRNA for enhancing tumor therapy

An Lu ^{a, 1} ,
Yuhao Guo ^{a, 1} ,
Yi Yan ^{a, 1} ,
Lin Zhai ^a ,
Xiangyu Wang ^a ,
Weiran Cao ^b ,
Zijie Li ^c ,
Zhixia Zhao ^d ,
Yujie Shi ^a ,
Yuanjun Zhu ^a ,
Xiaoyan Liu ^a ,
Huining He ^b ,
Zhiyu Wang ^c ,
Jian-Cheng Wang ^{a, e, *,}

a.
Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
b.
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
c.
Department of Immuno-oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China
d.
Department of Pharmacy, Clinical Trial Research Center, China-Japan Friendship Hospital, Beijing 100029, China
e.
Laboratory of innovative formulations and pharmaceutical excipients, Ningbo Institute of Marine Medicine, Peking University, Ningbo 315832, China

wang-jc@bjmu.edu.cn

Received Date: 8 May 2023
Revised Date: 2 August 2023
Accepted Date: 9 August 2023
Available Online: 12 August 2023

Figures(5)

Immunosuppressive microenvironments present critical problems in clinical chemotherapy. To regulate the tumor immune microenvironment for enhancing antitumor effect, a combination of immune checkpoint inhibitors (ICIs) with chemotherapeutics has been applied clinically. In this study, miriplatin (MiPt), the lipidic derivative of 5-fluorouracil (Fu-OA), as well as the programmed death ligand 1 (PD-L1) target siRNA (siPD-L1) were integrated into Lip-Pt/Fu@siPD-L1 nanoparticles (NPs) for chemo-immunotherapy. In vitro results showed that Lip-Pt/Fu@siPD-L1 NPs could exhibit effective siRNA gene silencing and promote the phagocytosis of tumor cells by macrophages. Furthermore, in vivo results revealed that Lip-Pt/Fu@siPD-L1 NPs showed significantly higher anti-tumor efficiency than that of the physical mixing of MiPt, 5-fluorouracil, and Lip@siPD-L1 NPs (delivery of siPD-L1 by liposomes). The best anti-tumor efficiency of Lip-Pt/Fu@siPD-L1 NPs resulted from the synergistic immunotherapeutic effects of MiPt and siPD-L1 based on the inhibition of CD47 expression and the downregulation of PD-L1 in tumor cells, which elicited a robust anti-tumor immune response through the activation of macrophage phagocytosis and immune checkpoint inhibition. The Lip-Pt/Fu@siPD-L1 NPs provide a potential strategy for tumor chemo-immunotherapy.
- Chemo-immunotherapy,
- Immune checkpoint inhibition,
- Gene silencing,
- Miriplatin,
- Macrophage phagocytosis,
- Nanotechnology
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