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VIP-targeted Cytotoxic Nanomedicine for Breast Cancer

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Title: VIP-targeted Cytotoxic Nanomedicine for Breast Cancer
Author(s): Dagar, Aparna; Kuzmis, Antonina; Rubinstein, Israel; Sekosan, Marin; Onyuksel, Hayat
Subject(s): phospholipid mixed micelles targeted drug delivery human vasoactive intestinal peptide
Abstract: Cancer chemotherapy is hampered by serious toxicity to healthy tissues. Conceivably, encapsulation of cytotoxic drugs in actively-targeted, biocompatible nanocarriers could overcome this problem. Accordingly, we used sterically stabilized mixed micelles (SSMM) composed of biocompatible and biodegradable phospholipids to solubilize paclitaxel (P), a hydrophobic model cytotoxic drug, and deliver it to breast cancer in rats. To achieve active targeting, the surface of SSMM was grafted with a ligand, human vasoactive intestinal peptide (VIP) that selectively interacts with its cognate receptors overexpressed on breast cancer cells. We found that even in vitro cytotoxicity of P-SSMM-VIP was 2-fold higher that that of free paclitaxel (p<0.05). Given the unique attributes of P-SSMM and P-SSMM-VIP, most notable small hydrodynamic diameter (~15nm) and stealth properties, biodistribution of paclitaxel was significantly altered. Accumulation of paclitaxel in breast tumor was highest for P-SSMM-VIP, followed by P-SSMM and Cremophor based paclitaxel (PTX). Importantly, bone marrow accumulation of paclitaxel encapsulated in both SSMM-VIP and SSMM was significantly less than that of PTX. Administration of clinically-relevant dose of paclitaxel (5mg/kg) as P-SSMMVIP and P-SSMM eradicated carcinogen-induced orthotopic breast cancer in rats, whereas PTX decreased tumor size by only 45%. In addition, a 5-fold lower dose (1mg/kg) of paclitaxel in actively targeted P-SSMM-VIP was associated with ~80% reduction in tumor size while the response to PTX and P-SSMM was significantly less. Hypotension was not observed when VIP was grafted onto SSMM. Based on our findings, we propose further development of effective and safe VIP-grafted phospholipid micelle nanomedicines of anti-cancer drugs for targeted treatment of solid tumors in humans.
Issue Date: 2012-12
Publisher: Springer Verlag
Citation Info: Dagar A, Kuzmis A, Rubinstein I, Sekosan M, Onyuksel H. VIP-targeted Cytotoxic Nanomedicine for Breast Cancer. Drug Delivery and Translational Research. 2012 Dec 1;2(6):454-462. doi: 10.1007/s13346-012-0107-x
Type: Article
Description: Post print version of article may differ from published version. The final publication is available at springerlink.com; DOI:10.1007/s13346-012-0107-x
URI: http://hdl.handle.net/10027/10690
ISSN: 2190-393X
Sponsor: This study was supported, in part, by National Institutes of Health (NIH) grants CA121797 and AG024026, and Department of Veterans Affairs Merit Review Program. The investigation was conducted in a facility constructed with support from Research Facilities Improvement Grant CO6RR15482 from National Center for Research Resources NIH.
Date Available in INDIGO: 2014-04-15
 

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