Theranostics 2020; 10(15):6581-6598. doi:10.7150/thno.45528

Research Paper

Proinflammatory macrophage-derived microvesicles exhibit tumor tropism dependent on CCL2/CCR2 signaling axis and promote drug delivery via SNARE-mediated membrane fusion

Ling Guo1,2, Ye Zhang1,2, Runxiu Wei1,2, Xiaochen Zhang1,2, Cuifeng Wang1,2✉, Min Feng1,2✉

1. School of Pharmaceutical Sciences, Sun Yat-sen University, University Town, Guangzhou, 510006, P.R. China
2. Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou, 510006, P.R. China

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Citation:
Guo L, Zhang Y, Wei R, Zhang X, Wang C, Feng M. Proinflammatory macrophage-derived microvesicles exhibit tumor tropism dependent on CCL2/CCR2 signaling axis and promote drug delivery via SNARE-mediated membrane fusion. Theranostics 2020; 10(15):6581-6598. doi:10.7150/thno.45528. Available from http://www.thno.org/v10p6581.htm

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Abstract

Background: Exosome (Exo)-based chemotherapeutic drug delivery systems have been extensively investigated; however, the therapeutic potential of other subtypes of extracellular vesicles (EVs), in particular microvesicles (MiV), seem to be overlooked. Moreover, despite a general agreement on organ tropism of EVs, few studies have clearly demonstrated that EVs specifically target tumor tissue.

Methods: Proinflammatory macrophage-derived EV subpopulations comprising apoptotic bodies (ApB), MiV and Exo were isolated under differential ultracentrifugation, and further analyzed using comparative proteomic and lipid approach.

Results: On the basis of EV biogenesis pathways, our data demonstrated that MiV acquire the tumor-targeting capacity probably through inheritance of CCR2-enriched cell membrane which also drives the recruitment of donor cells to tumor sites. Further, our data validate MiV utilize SNARE-mediated membrane fusion to directly discharge doxorubicin to nucleus and bypass endocytic degradation.

Conclusions: Compared with other EV subtypes, MiV loaded with doxorubicin gain significant benefits in chemotherapeutic outcomes including survival rate improvements in metastatic ovarian cancer. Therefore, MiV represent a potent alterative to Exo and synthetic liposomes (Lipo) for tumor-targeting drug delivery.

Keywords: microvesicles, proinflammatory macrophages, CCL2/CCR2 signaling, SNARE-mediated membrane fusion, metastatic ovarian cancer