期刊
JOURNAL OF CONTROLLED RELEASE
卷 341, 期 -, 页码 498-510出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2021.12.002
关键词
Micelles; Targeted delivery; Triple negative breast cancer; Immunogenic cell death; Immunoadjuvant
资金
- National Natural Science Foundation of China [NSFC 51861145310, 52033006, 51773146, 51633005]
ATN-MPTX, constructed with the clinically validated ATN peptide as a ligand and reduction-sensitive biodegradable micelles as a vehicle, demonstrates strong and selective induction of ICD and chemo-immunotherapy for TNBC, showing superior tumor accumulation and treatment efficacy compared to controls in therapeutic studies.
Triple negative breast cancer (TNBC) with easy metastasis, cold tumor immune microenvironment, and lack of targeted therapy remains poorly prognosed. Chemo-immunotherapy deemed as a potential treatment for TNBC is however confronted by low TNBC selectivity, pronounced systemic toxicity, and limited immunogenic cell death (ICD) induction. Here, employing clinically validated ATN peptide as a ligand and reduction-sensitive biodegradable micelles as a vehicle we constructed alpha 5131 integrin-targeted micellar paclitaxel (ATN-MPTX) to elicit strong and selective ICD and chemo-immunotherapy of TNBC. ATN-MPTX exhibited evident targetability and prominent uptake in alpha 5131 integrin-positive 4 T1 cells and induced significantly stronger ICD than free PTX and non-targeted MPTX. The therapeutic studies in 4 T1 TNBC model demonstrated that ATN-MPTX caused superior tumor accumulation and treatment efficacy to all controls. Of note, ATN-MPTX plus nano-STING agonist further augmented the immunotherapeutic effects by increasing secretion of proinflammatory cytokines and CD4+ and CD8+ T cells in the tumor and spleen while reducing Treg, leading to significantly improved inhibition of 4 T1 primary tumor and more interestingly mitigated lung metastases. This strong and selective ICD induction of ATNMPTX renders it an interesting tool to enhance chemo-immunotherapy of TNBC.
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