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Functional exosome-mediated co-delivery of doxorubicin and hydrophobically modified microRNA 159 for triple-negative breast cancer therapy

Chunai GongShanghai Ninth People's HospitalJing TianChanghai HospitalZhuo WangChanghai HospitalYuan GaoDepartment of Clinical Pharmacy and Pharmaceutical Management, School of Pharmacy, Fudan University, Shanghai, 201203, People's Republic of ChinaXin WuDepartment of Pharmaceutics, Changhai Hospital, Second Military Medical University, Shanghai, 200433, People's Republic of ChinaXueying DingShanghai First People's HospitalLei QiangDepartment of Pharmaceutics, Changhai Hospital, Second Military Medical University, Shanghai, 200433, People's Republic of ChinaGuorui LiChanghai HospitalZhimin HanChanghai HospitalYongfang YuanDepartment of Pharmacy, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People's Republic of ChinaShen GaoDepartment of Pharmaceutics, Changhai Hospital, Second Military Medical University, Shanghai, 200433, People's Republic of China. [email protected]

2019en

ABI

Annotatsiya

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 αvβ3. 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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DOI: 10.1186/s12951-019-0526-7

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