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

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

Author information

1
Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC, 27599, USA.
2
Professur für Makromolekulare Chemie, Department Chemie, Technische Universität Dresden, Mommsenstr. 4, 01069, Dresden, Germany.
3
Nanotechnology Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD, USA.
4
Department of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
5
Department of Radiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
6
Lineberger Comprehensive Cancer Center, The Animal Study Core, University of North Carolina at Chapel Hill, NC, 27599, USA.
7
Functional Polymer Materials, Chair for Chemical Technology of Materials Synthesis, Julius-Maximilians-Universität Würzburg, Röntgenring 11, 97070, Würzburg, Germany. Electronic address: robert.luxenhofer@uni-wuerzburg.de.
8
Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC, 27599, USA; Laboratory of Chemical Design of Bionanomaterials, Faculty of Chemistry, M.V. Lomonosov Moscow State University, Moscow, 119992, Russia. Electronic address: kabanov@email.unc.edu.

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

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