Poly(2-oxazoline) based micelles with high capacity for 3rd generation taxoids: preparation, in vitro and in vivo evaluation.

Abstract

The clinically and commercially successful taxanes, paclitaxel and docetaxel suffer from two major drawbacks, namely their very low aqueous solubility and the risk of developing resistance. Here, we present a method that overcomes both drawbacks in a very simple manner. We formulated 3rd generation taxoids, able to avoid common drug resistance mechanisms with doubly amphiphilic poly(2-oxazoline)s (POx), a safe and highly efficient polymer for the formulation of extremely hydrophobic drugs. We found excellent solubilization of different 3rd generation taxoids irrespective of the drug's chemical structures with essentially quantitative drug loading and final drug to polymer ratios around unity. The small, highly loaded micelles with a hydrodynamic diameter of less than 100nm are excellently suited for parenteral administration. Moreover, a selected formulation with the taxoid SB-T-1214 is about one to two orders of magnitude more active in vitro than paclitaxel in the multidrug resistant breast cancer cell line LCC6-MDR. In contrast, in wild-type LCC6, no difference was observed. Using a q4d×4 dosing regimen, we also found that POx/SB-T-1214 significantly inhibits the growth of LCC6-MDR orthotropic tumors, outperforming commercial paclitaxel drug Taxol and Cremophor EL formulated SB-T-1214.

• Authors: Zhijian He, Anita Schulz, Xiaomeng Wan, Joshua Seitz, Herdis Bludau, Daria Y Alakhova, David B Darr, Charles M Perou, Rainer Jordan, Iwao Ojima, Alexander V Kabanov, Robert Luxenhofer
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 208 Pg. 67-75 (Jun 28 2015) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 25725361 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Delayed-Action Preparations
• Micelles
• Oxazoles
• Taxoids
• poly(2-oxazoline)

Topics

• Animals
• Antineoplastic Agents, Phytogenic (chemistry, pharmacology)
• Breast Neoplasms (drug therapy)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Chemistry, Pharmaceutical
• Delayed-Action Preparations
• Female
• Humans
• Mice
• Mice, Nude
• Micelles
• Oxazoles (chemistry)
• Particle Size
• Taxoids (chemistry, pharmacology)
• Xenograft Model Antitumor Assays