A high capacity polymeric micelle of paclitaxel: Implication of high dose drug therapy to safety and in vivo anti-cancer activity

Biomaterials. 2016 Sep;101:296-309. doi: 10.1016/j.biomaterials.2016.06.002. Epub 2016 Jun 4.

Abstract

The poor solubility of paclitaxel (PTX), the commercially most successful anticancer drug, has long been hampering the development of suitable formulations. Here, we present translational evaluation of a nanoformulation of PTX, which is characterized by a facile preparation, extraordinary high drug loading of 50% wt. and PTX solubility of up to 45 g/L, excellent shelf stability and controllable, sub-100 nm size. We observe favorable in vitro and in vivo safety profiles and a higher maximum tolerated dose compared to clinically approved formulations. Pharmacokinetic analysis reveals that the higher dose administered leads to a higher exposure of the tumor to PTX. As a result, we observed improved therapeutic outcome in orthotopic tumor models including particularly faithful and aggressive "T11" mouse claudin-low breast cancer orthotopic, syngeneic transplants. The promising preclinical data on the presented PTX nanoformulation showcase the need to investigate new excipients and is a robust basis to translate into clinical trials.

Keywords: Efficacy; In vitro; In vivo; Multi-drug resistant cancer; Paclitaxel nanoformulation; Polyoxazolines.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / administration & dosage*
  • Antineoplastic Agents, Phytogenic / pharmacokinetics*
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Breast Neoplasms / drug therapy
  • Drug Carriers / chemistry*
  • Female
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Micelles
  • Ovarian Neoplasms / drug therapy
  • Oxazoles / chemistry*
  • Paclitaxel / administration & dosage*
  • Paclitaxel / pharmacokinetics*
  • Paclitaxel / therapeutic use

Substances

  • Antineoplastic Agents, Phytogenic
  • Drug Carriers
  • Micelles
  • Oxazoles
  • poly(2-oxazoline)
  • Paclitaxel