期刊
PHARMACEUTICS
卷 14, 期 6, 页码 -出版社
MDPI
DOI: 10.3390/pharmaceutics14061263
关键词
PD-1; nanovesicles; immunotherapy; gemcitabine; breast cancer
资金
- National Natural Science Foundation of China [81970145, 82001698]
- Natural Science Foundation of Guangdong Province [2020A1515011465, 2020A151501467]
- Science, Technology & Innovation Commission of Shenzhen Municipality [JCYJ20190807151609464, JCYJ20200109142605909, JCYJ20210324120007020, JCYJ20180228175150018]
- Sun Yat-sen University [20ykzd17]
- International Collaboration of Science and Technology of Guangdong Province [2020A0505100031]
- Guangdong Provincial Key Laboratory of Digestive Cancer Research [2021B1212040006]
This study developed a cell membrane-derived PD-1 nanovesicle encapsulating low-dose gemcitabine, which synergistically inhibited the proliferation of triple-negative breast cancer cells, improved tumor targeting ability, and increased CD8(+) T cell activation, leading to delayed tumor growth and prolonged survival in mice.
PD-1 inhibitor Keytruda combined with chemotherapy for Triple-negative breast cancer (TNBC) has been approved for FDA, successfully representing the combination therapy of immunotherapy and chemotherapy for the first time in 2020. However, PD-L1 inhibitor Tecentriq combined with albumin paclitaxel using the similar strategy failed to achieve the expected effect. Therefore, it is still necessary to explore new effective immunotherapy and chemotherapy-based combined strategies. We developed a cell membrane-derived programmed death-ligand 1(PD-1) nanovesicle to encapsulate low-dose gemcitabine (PD-1&GEM NVs) to study the effect on breast cancer in vitro and in vivo. We found that engineered PD-1&GEM NVs could synergistically inhibit the proliferation of triple-negative breast cancer, which interacted with PD-L1 in triple-negative breast cancer to disrupt the PD-L1/PD-1 immune inhibitory axis and promoted cancer cell apoptosis. Moreover, PD-1&GEM NVs had better tumor targeting ability for PD-L1 highly-expressed TNBC cells, contributing to increasing the drug effectiveness and reducing toxicity. Importantly, gemcitabine-encapsulated PD-1 NVs exerted stronger effects on promoting apoptosis of tumor cells, increasing infiltrated CD8(+) T cell activation, delaying the tumor growth and prolonging the survival of tumor-bearing mice than PD-1 NVs or gemcitabine alone. Thus, our study highlighted the power of combined low-dose gemcitabine and PD-1 in the nanovesicles as treatment to treat triple-negative breast cancer.
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