Antitumor activity and molecular dynamics simulations of paclitaxel-laden triazine dendrimers

Jongdoo Lim, Su Tang Lo, Sonia Hill, Giovanni M. Pavan, Xiankai Sun, Eric E. Simanek

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

The antitumor activities of triazine dendrimers bearing paclitaxel, a well-known mitotic inhibitor, are evaluated in SCID mice bearing human prostate cancer xenografts. To increase the activity of a first generation prodrug 1 that contained twelve paclitaxel molecules tethered via an ester linkage, the new construct described here, prodrug 2, tethers paclitaxel with linkers containing both an ester and disulfide. While PEGylation is necessary for solubility, and may improve biocompatibility and increase plasma half-life, it increases the heterogeneity of the sample with an average of eight to nine PEG chains (2 kDa each) incorporated. The heterogeneous population of PEGylated materials was used without fractionation based on models obtained from molecular dynamics simulations. Three models were examined; hexaPEGylated, nonaPEGylated, and dodecaPEGylated constructs. Intravenous delivery of prodrug 2 was performed by single, double or triple dosing regimes with doses spaced by one week. The doses varied from 50 mg of paclitaxel/kg to 200 mg of paclitaxel/kg. Tumor growth arrest and regression was observed over the 10-week treatment period without mortality for mice treated with the 50 mg of paclitaxel/kg treated three times.

Original languageEnglish (US)
Pages (from-to)404-412
Number of pages9
JournalMolecular Pharmaceutics
Volume9
Issue number3
DOIs
StatePublished - Mar 5 2012

Keywords

  • dendrimer
  • drug delivery
  • molecular dynamics
  • paclitaxel
  • prostate cancer
  • simulation
  • triazine
  • xenografts

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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