Modulating the therapeutic activity of nanoparticle delivered paclitaxel by manipulating the hydrophobicity of prodrug conjugates

Steven M. Ansell, Sharon A. Johnstone, Paul G. Tardi, Lily Lo, Sherwin Xie, Yu Shu, Troy O. Harasym, Natashia L. Harasym, Laura Williams, David Bermudes, Barry D. Liboiron, Walid Saad, Robert K. Prud'homme, Lawrence D. Mayer

Research output: Contribution to journalArticle

93 Scopus citations

Abstract

A series of paclitaxel prodrugs designed for formulation in lipophilic nanoparticles are described. The hydrophobicity of paclitaxel was increased by conjugating a succession of increasingly hydrophobic lipid anchors to the drug using succinate or diglycolate cross-linkers. The prodrugs were formulated in well defined block copolymer-stabilized nanoparticles. These nanoparticles were shown to have an elimination half-life of approximately 24 h in vivo. The rate at which the prodrug was released from the nanoparticles could be controlled by adjusting the hydrophobicity of the lipid anchor, resulting in release half-lives ranging from 1 to 24 h. The diglycolate and succinate cross-linked prodrugs were 1-2 orders of magnitude less potent than paclitaxel in vitro. Nanoparticle formulations of the succinate prodrugs showed no evidence of efficacy in HT29 human colorectal tumor xenograph models. Efficacy of diglycolate prodrug nanoparticles increased as the anchor hydrophobicity increased. Long circulating diglycolate prodrug nanoparticles provided significantly enhanced therapeutic activity over commercially formulated paclitaxel at the maximum tolerated dose.

Original languageEnglish
Pages (from-to)3288-3296
Number of pages9
JournalJournal of Medicinal Chemistry
Volume51
Issue number11
DOIs
StatePublished - Jun 12 2008

ASJC Scopus subject areas

  • Organic Chemistry

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    Ansell, S. M., Johnstone, S. A., Tardi, P. G., Lo, L., Xie, S., Shu, Y., Harasym, T. O., Harasym, N. L., Williams, L., Bermudes, D., Liboiron, B. D., Saad, W., Prud'homme, R. K., & Mayer, L. D. (2008). Modulating the therapeutic activity of nanoparticle delivered paclitaxel by manipulating the hydrophobicity of prodrug conjugates. Journal of Medicinal Chemistry, 51(11), 3288-3296. https://doi.org/10.1021/jm800002y