Drug Delivery and Translational Research

, Volume 2, Issue 6, pp 454–462

VIP-targeted cytotoxic nanomedicine for breast cancer

  • Aparna Dagar
  • Antonina Kuzmis
  • Israel Rubinstein
  • Marin Sekosan
  • Hayat Onyuksel
Research Article

DOI: 10.1007/s13346-012-0107-x

Cite this article as:
Dagar, A., Kuzmis, A., Rubinstein, I. et al. Drug Deliv. and Transl. Res. (2012) 2: 454. doi:10.1007/s13346-012-0107-x
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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 (∼15 nm) 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 (5 mg/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 (1 mg/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.

Keywords

Phospholipid mixed micellesTargeted drug deliveryHuman vasoactive intestinal peptideBreast cancerPaclitaxelMNU-induced breast cancer

Supplementary material

13346_2012_107_MOESM1_ESM.pdf (103 kb)
ESM 1(PDF 103 kb)

Copyright information

© Controlled Release Society 2012

Authors and Affiliations

  • Aparna Dagar
    • 1
    • 5
  • Antonina Kuzmis
    • 1
  • Israel Rubinstein
    • 3
    • 4
  • Marin Sekosan
    • 3
    • 6
  • Hayat Onyuksel
    • 1
    • 2
  1. 1.Department of Biopharmaceutical Sciences, College of PharmacyUniversity of Illinois at ChicagoChicagoUSA
  2. 2.Department of BioengineeringUniversity of Illinois at ChicagoChicagoUSA
  3. 3.Department of MedicineUniversity of Illinois at ChicagoChicagoUSA
  4. 4.Jesse Brown VA Medical CenterChicagoUSA
  5. 5.Fresenius Kabi USASchaumburgUSA
  6. 6.John H. Stroger, Jr. HospitalChicagoUSA