VIP-targeted cytotoxic nanomedicine for breast cancer

Aparna Dagar,Marin Sekosan,Antonina Kuzmis,Hayat Onyuksel,Israel Rubinstein

doi:10.1007/s13346-012-0107-x

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-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.

Highlights

The efficacy of cancer chemotherapy is hampered by dose limiting toxicity to healthy tissues
We have shown that the optimum molar ratio of DSPE-PEG2000 and PC for sterically stabilized mixed micelles (SSMM) was 90:10 [8,32] and at this ratio paclitaxel was solubilized at 1.5 fold higher concentrations when compared to simple DSPE-PEG2000 micelles [7]
We believe our proposed paclitaxel formulation, P-SSMMVIP that uses safe biocompatible excipients as the vehicle with steric stabilization and active targeting should be superior to currently available paclitaxel formulations with respect to the drug safety and efficacy. These studies demonstrated for the first time the feasibility of in vivo active targeting using human vasoactive intestinal peptide surface conjugated to nanomicelles

Summary

Introduction

The efficacy of cancer chemotherapy is hampered by dose limiting toxicity to healthy tissues. Compounding this problem is the fact that potent cytotoxic drugs, such as paclitaxel, are sparsely water-soluble and are, formulated with cosolvents, such as Cremophor EL®, which are toxic themselves [1]. Developing alternate therapeutic modalities, that increase selective anti-cancer efficacy of cytotoxic drugs while minimizing their systemic toxicity, is urgently needed. Given these issues, targeted delivery of cytotoxic drugs to the site of action using safe biocompatible materials could represent an important means to overcome this problem. Particles with size of ~15nm, similar to SSM and SSMM, were estimated to possess most favorable balance between systemic clearance and vascular extravasation, resulting in improved tumor accumulation [11]

Methods

Results

Conclusion