Table of Contents
Chemotherapy Research and Practice
Volume 2011 (2011), Article ID 213848, 7 pages
http://dx.doi.org/10.1155/2011/213848
Research Article

Optimizing Liposomal Cisplatin Efficacy through Membrane Composition Manipulations

Department of Preformulation, Celator Pharmaceuticals Corp., 1779 West 75th Avenue, Vancouver, BC, Canada V6P 6P2

Received 27 August 2010; Revised 7 December 2010; Accepted 17 December 2010

Academic Editor: G. J. Peters

Copyright © 2011 Natalia Zisman et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The first liposomal formulation of cisplatin to be evaluated clinically was SPI-077. Although the formulation demonstrated enhanced cisplatin tumor accumulation in preclinical models it did not enhance clinical efficacy, possibly due to limited cisplatin release from the formulation localized within the tumor. We have examined a series of liposomal formulations to address the in vivo relationship between cisplatin release rate and formulation efficacy in the P388 murine leukemia model. The base formulation of phosphatidylcholine: phosphatidylglycerol: cholesterol was altered in the C18 and C16 phospholipid content to influence membrane fluidity and thereby impacting drug circulation lifetime and drug retention. Phase transition temperatures (Tm) ranged from 42–55°C. The high Tm formulations demonstrated enhanced drug retention properties accompanied by low antitumor activity while the lowest Tm formulations released the drug too rapidly in the plasma, limiting drug delivery to the tumor which also resulted in low antitumor activity. A formulation composed of DSPC : DPPC : DSPG : Chol; (35 : 35 : 20 : 10) with an intermediate drug release rate and a cisplatin plasma half-life of 8.3 hours showed the greatest antitumor activity. This manuscript highlights the critical role that drug release rates play in the design of an optimized drug delivery vehicle.