期刊
JOURNAL OF NANOBIOTECHNOLOGY
卷 17, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s12951-019-0526-7
关键词
Exosome; MicroRNA 159; Doxorubicin; Triple-negative breast cancer; Co-delivery
资金
- Clinical Pharmacy Innovation Research Institute of Shanghai Jiao Tong University School of Medicine [CXYJY2019MS002]
- National Natural Science Foundation of China (NSFC) [81903141, 81672516, 81772749, 81672545]
- Basic Research Projects of Shanghai Science and Technology Commission [18JC1414200]
- Shanghai Municipal Commission of Health and Family Planning-Construction of clinical pharmacy service system [2016ZB0303]
Exosomes (Exo) hold great promise as endogenous nanocarriers that can deliver biological information between cells. However, Exo are limited in terms of their abilities to target specific recipient cell types. We developed a strategy to isolate Exo exhibiting increased binding to integrin alpha(v)beta(3). Binding occurred through a modified version of a disintegrin and metalloproteinase 15 (A15) expressed on exosomal membranes (A15-Exo), which facilitated co-delivery of therapeutic quantities of doxorubicin (Dox) and cholesterol-modified miRNA 159 (Cho-miR159) to triple-negative breast cancer (TNBC) cells, both in vitro and in vivo. The targeted A15-Exo were derived from continuous protein kinase C activation in monocyte-derived macrophages. These cell-derived Exo displayed targeting properties and had a 2.97-fold higher production yield. In vitro, A15-Exo co-loaded with Dox and Cho-miR159 induced synergistic therapeutic effects in MDA-MB-231 cells. In vivo, miR159 and Dox delivery in a vesicular system effectively silenced the TCF-7 gene and exhibited improved anticancer effects, without adverse effects. Therefore, our data demonstrate the synergistic efficacy of co-delivering miR159 and Dox by targeted Exo for TNBC therapy.
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