OTHER FUNCTIONS - R&D BIOMEDICAL (BASIC RESEARCH)

本项目旨在开发一种稳定的埃博霉素B（Epo B）-负载胶束，用于静脉内递送Epo B至实体瘤。数据应证明Epo B包封在胶束内，重量负载在1- 5%wt/wt Epo B范围内。将交联化学作用应用于Epo B-负载胶束以产生交联的、稳定的Epo B胶束。预计胶束的粒径将在30- 100 nm之间。基于以前的研究与铁交联胶束，pH依赖性释放的Epo B预期在体外。在体外，交联的Epo B胶束在血清中比未交联的胶束更稳定。在体外将交联胶束施用于癌细胞应表现出与游离Epo B相似（如果不是相同的话）的细胞毒性。体内表征应导致：（a）测定Epo B胶束在裸鼠中的最大耐受剂量（MTD）;（B）Epo B胶束与游离Epo B相比在裸鼠中的药代动力学;和（c）胶束在两种异种移植模型中的抗肿瘤功效。预期Epo B胶束在与游离Epo B相比具有更高的MTD、上级的药代动力学和改善的抗肿瘤功效方面将优于游离药物。

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.