title: Bioinspired exosome-mimetic nanovesicles for targeted delivery of chemotherapeutics to malignant tumors.
abstract: Exosomes, the endogenous nanocarriers that can deliver biological information between cells, were recently introduced as new kind of drug delivery system. However, mammalian cells release relatively low quantities of exosomes, and purification of exosomes is difficult. Here, we developed bioinspired exosome-mimetic nanovesicles that deliver chemotherapeutics to the tumor tissue after systemic administration. The chemotherapeutics-loaded nanovesicles were produced by the breakdown of monocytes or macrophages using a serial extrusion through filters with diminishing pore sizes (10, 5, and 1 μm). These cell-derived nanovesicles have similar characteristics with the exosomes but have 100-fold higher production yield. Furthermore, the nanovesicles have natural targeting ability of cells by maintaining the topology of plasma membrane proteins. In vitro, chemotherapeutic drug-loaded nanovesicles induced TNF-α-stimulated endothelial cell death in a dose-dependent manner. In vivo, experiments in mice showed that the chemotherapeutic drug-loaded nanovesicles traffic to tumor tissue and reduce tumor growth without the adverse effects observed with equipotent free drug. Furthermore, compared with doxorubicin-loaded exosomes, doxorubicin-loaded nanovesicles showed similar in vivo antitumor activity. However, doxorubicin-loaded liposomes that did not carry targeting proteins were inefficient in reducing tumor growth. Importantly, removal of the plasma membrane proteins by trypsinization eliminated the therapeutic effects of the nanovesicles both in vitro and in vivo. Taken together, these studies suggest that the bioengineered nanovesicles can serve as novel exosome-mimetics to effectively deliver chemotherapeutics to treat malignant tumors.
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology , Pohang, Gyeongbuk 790-784, Republic of Korea.
authors.forename: Su Chul
authors.initials: SC
authors.lastname: Jang
authors.forename: Oh Youn
authors.initials: OY
authors.lastname: Kim
authors.forename: Chang Min
authors.initials: CM
authors.lastname: Yoon
authors.forename: Dong-Sic
authors.initials: DS
authors.lastname: Choi
authors.forename: Tae-Young
authors.initials: TY
authors.lastname: Roh
authors.forename: Jaesung
authors.initials: J
authors.lastname: Park
authors.forename: Jonas
authors.initials: J
authors.lastname: Nilsson
authors.forename: Jan
authors.initials: J
authors.lastname: Lötvall
authors.forename: Yoon-Keun
authors.initials: YK
authors.lastname: Kim
authors.forename: Yong Song
authors.initials: YS
authors.lastname: Gho
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D040761:Biomimetic Materials / Q000138:chemical synthesis*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D055354:Exosomes / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry* / Q000648:ultrastructure; D009369:Neoplasms / Q000188:drug therapy*; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D053769:Nanocapsules; D004317:Doxorubicin