Bioinspired Exosome-Mimetic Nanovesicles for Targeted Delivery of Chemotherapeutics to Malignant Tumors

被引:834
作者
Jang, Su Chul [1 ]
Kim, Oh Youn [1 ]
Yoon, Chang Min [1 ]
Choi, Dong-Sic [1 ]
Roh, Tae-Young [1 ]
Park, Jaesung [2 ]
Nilsson, Jonas [3 ]
Lotvall, Jan [4 ]
Kim, Yoon-Keun [1 ]
Gho, Yong Song [1 ]
机构
[1] Pohang Univ Sci & Technol, Dept Life Sci, Pohang 790784, Gyeongbuk, South Korea
[2] Pohang Univ Sci & Technol, Dept Mech Engn, Pohang 790784, Gyeongbuk, South Korea
[3] Univ Gothenburg, Sahlgrenska Univ Hosp, Sahlgrenska Acad, Dept Clin Chem & Transfus Med,Inst Biomed, S-41345 Gothenburg, Vastergotland, Sweden
[4] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Internal Med,Krefting Res Ctr, S-40530 Gothenburg, Vastergotland, Sweden
关键词
exosome-mimetics; exosomes; extracellular vesicles; biomimicry; drug delivery systems; DRUG-DELIVERY; MEMBRANE-VESICLES; CELL-ADHESION; LEUKOCYTE ADHESION; ENDOTHELIAL-CELLS; MESSENGER-RNAS; CANCER; MICROVESICLES; ANGIOGENESIS; THERAPEUTICS;
D O I
10.1021/nn402232g
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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 mu m). 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-alpha-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.
引用
收藏
页码:7698 / 7710
页数:13
相关论文
共 54 条
[1]   Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes [J].
Alvarez-Erviti, Lydia ;
Seow, Yiqi ;
Yin, HaiFang ;
Betts, Corinne ;
Lakhal, Samira ;
Wood, Matthew J. A. .
NATURE BIOTECHNOLOGY, 2011, 29 (04) :341-U179
[2]   Angiogenesis in cancer and other diseases [J].
Carmeliet, P ;
Jain, RK .
NATURE, 2000, 407 (6801) :249-257
[3]   Proteomic analysis of microvesicles derived from human colorectal cancer cells [J].
Choi, Dong-Sic ;
Lee, Jae-Min ;
Park, Gun Wook ;
Lim, Hyeon-Woo ;
Bang, Joo Young ;
Kim, Yoon-Keun ;
Kwon, Kyung-Hoon ;
Kwon, Ho Jeong ;
Kim, Kwang Pyo ;
Gho, Yong Song .
JOURNAL OF PROTEOME RESEARCH, 2007, 6 (12) :4646-4655
[4]   Proteomics, transcriptomics and lipidomics of exosomes and ectosomes [J].
Choi, Dong-Sic ;
Kim, Dae-Kyum ;
Kim, Yoon-Keun ;
Gho, Yong Song .
PROTEOMICS, 2013, 13 (10-11) :1554-1571
[5]   Immunocytes as a Biocarrier to Delivery Therapeutic and Imaging Contrast Agents to Tumors [J].
Choi, Jinhyang ;
Woo, Ha-Na ;
Ju, Eun Jin ;
Jung, Joohee ;
Chung, Hye-Kyung ;
Park, Jaesook ;
Park, Seok Soon ;
Shin, Seol Hwa ;
Park, Hye Ji ;
Lee, Jin Seong ;
Song, Si Yeol ;
Jeong, Seong-Yun ;
Choi, Eun Kyung .
JOURNAL OF NANOMATERIALS, 2012, 2012
[6]   Nanoparticle therapeutics: an emerging treatment modality for cancer [J].
Davis, Mark E. ;
Chen, Zhuo ;
Shin, Dong M. .
NATURE REVIEWS DRUG DISCOVERY, 2008, 7 (09) :771-782
[7]   Impact of Nanotechnology on Drug Delivery [J].
Farokhzad, Omid C. ;
Langer, Robert .
ACS NANO, 2009, 3 (01) :16-20
[8]   Angiogenesis as a therapeutic target [J].
Ferrara, N ;
Kerbel, RS .
NATURE, 2005, 438 (7070) :967-974
[9]   Beyond drug delivery [J].
Ferrari, Mauro .
NATURE NANOTECHNOLOGY, 2008, 3 (03) :131-132
[10]  
Gho YS, 1999, CANCER RES, V59, P5128