期刊
JOURNAL OF CONTROLLED RELEASE
卷 196, 期 -, 页码 222-233出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2014.10.012
关键词
RGD peptide; integrin; cisplatin; liposome; drug delivery; bone metastasis
资金
- National Natural Science Foundation of China [31471141, 81401506]
- National Important Science Research Program of China [2011CB933503]
- National Key Technology Research and Development Program of China [2012BAI23B02]
- Natural Science Foundation of the higher Education Institutions of Jiangsu Province [12KJD310004]
- Applied Basic Research Project Foundation of Nantong [BK2012064]
Targeting alpha v beta 3 integrin is particularly promising for the treatment of bone metastases by targeting integrin-rich tumor cells and by inhibiting integrin-involved bone metastases. In this work, a liposomal drug delivery system conjugated with cyclic arginine-glycine-aspartic acid-tyrosine-lysine peptide (cRGDyk) as alpha v beta 3 integrin ligand was thus developed to improve therapeutic efficacy in a mice model of bone metastasis from prostate cancer. The resultant liposomeswere characterized in terms of size, morphology, zeta potential, stability, drug encapsulation percentage and loading efficiency, and drug release. Compared with free cisplatin and cRGDyk-free liposomes, cRGDyk conjugated liposomes showed significantly higher cellular uptake and higher cytotoxicity of loaded cisplatin, as evidenced by in vitro cell experiments. In vivo results revealed that free cisplatin and free cRGDyk could relieve tumor-induced pain but had no contributions to tumor regression and overall survival improvement. cRGDyk-free liposomal drug system with prolonged blood circulation time could accumulated in the tumor sites in the bone through enhanced permeability and retention (EPR) effects and however, did not exhibit desirable therapeutic efficacy superior to free cisplatin and free cRGDyk. This strongly suggested that ERP effects were not effective in treating metastases. By taking advantages of targeted drug delivery and synergistic antitumor activity of cRGDyk and loaded cisplatin, cRGDyk conjugated liposomal drug system could inhibit osteoclastic and osteoblastic bone lesions, relieve pain, and improve overall survival. Inspired by their enhanced therapeutic efficacy and low organ toxicity, cRGDyk conjugated liposomes could serve as an effective drug system for targeted and synergistic therapy of bone metastases. (C) 2014 Elsevier B.V. All rights reserved.
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