Hongxiang Wei,1,* Fei Chen,1,* Jinyuan Chen,2,* Huangfeng Lin,1 Shenglin Wang,1 Yunqing Wang,1 Chaoyang Wu,1 Jianhua Lin,1 Guangxian Zhong1 1Department of Orthopaedics, Fujian Institute of Orthopaedics, the First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, People’s Republic of China; 2The Centralab, the First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guangxian Zhong; Jianhua Lin, Tel/Fax +86 591 87981029, Email zhongguangxian@163.com; jianhual@126.comPurpose: The objective of this study was to investigate the antitumor activity, targeting capability, and mechanism of the developed nanodrug consisting of doxorubicin and exosome (Exo-Dox) derived from mesenchymal stem cells in vitro and in vivo.Methods: The exosomes were isolated with Exosome Isolation Kit, and the Exo-Dox was prepared by mixing exosome with Dox-HCl, desalinizing with triethylamine and then dialyzing against PBS overnight. The exosome and Exo-Dox were examined by nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). The antitumor activity, targeting capability, and mechanism of the developed Exo-Dox were evaluated by cell viability assay, histological and immunofluorescence analysis and in vivo imaging system.Results: NTA results showed the size of the exosomes had increased from 141.6 nm to 178.1 nm after loading with doxorubicin. Compared with free Dox, the Exo-Dox exhibited higher cytotoxicity against osteosarcoma MG63 cells, HOS cells, and 143B cells than free Dox, the half-maximal inhibitory concentrations (IC50) of Dox, Exo-Dox were calculated to be 0.178 and 0.078 μg mL− 1 in MG63 cells, 0.294 and 0.109μg mL− 1 in HOS cells, 0.315 and 0.123 μg mL− 1 in 143B cells, respectively. The in vivo imaging showed that MSC derived Exo could serve as a highly efficient delivery vehicle for targeted drug delivery. The immunohistochemistry and histology analysis indicated that compared with the free Dox group, the Ki67-positive cells and cardiotoxicity in Exo-Dox group were significantly decreased.Conclusion: Our results suggested that MSC-derived Exo could be excellent nanocarriers used to deliver chemotherapeutic drug Dox specifically and efficiently in osteosarcoma, resulting in enhanced toxicity against osteosarcoma and less toxicity in heart tissue. We further demonstrated the targeting capability of Exo was due to the chemotaxis of MSC-derived exosomes to osteosarcoma cells via SDF1-CXCR4 axis.Keywords: targeted therapy, exosome, doxorubicin, osteosarcoma, nanocarrier
