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VIP-targeted Cytotoxic Nanomedicine for Breast Cancer

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journal contribution
posted on 15.04.2014 by Aparna Dagar, Antonina Kuzmis, Israel Rubinstein, Marin Sekosan, Hayat Onyuksel
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.

Funding

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.

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Publisher Statement

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

Publisher

Springer Verlag

Language

en_US

issn

2190-393X

Issue date

01/12/2012

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