This project aims to develop a stabilized epothilone B (Epo B)-loaded micelle for the intravenous delivery of Epo B to solid tumors. The data should demonstrate that Epo B is encapsulated within the micelle with weight-loadings in the range of 1-5% wt/wt Epo B. Crosslinking chemistries will be applied to Epo B-loaded micelles to generate a crosslinked, stabilized, Epo B micelle. It is anticipated that the particle size of micelles will be between 30-100nm. Based on previous studies with iron-crosslinked micelles, pH-dependent release of Epo B is expected in vitro. Crosslinked Epo B micelles are also expected to be more stable in serum than un-crosslinked micelles, in vitro. Administration of crosslinked micelles to cancer cells in vitro should exhibit similar if not identical cytotoxicity as free Epo B. In vivo characterization should result in: (a) determination of the maximum tolerated dose (MTD) of the Epo B micelle in nude mice;(b) the pharmacokinetics of the Epo B micelle compared to free Epo B in nude mice;and (c) the antitumor efficacy of the micelle in two xenograft models. It is anticipated that the Epo B micelle will outperform free drug in terms of having a higher MTD, superior pharmacokinetics, and improved antitumor efficacy compared to free Epo B.
