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-SSMM-VIP 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.