OTHER FUNCTIONS - R&D BIOMEDICAL (BASIC RESEARCH)

本项目旨在开发一种稳定的Epo B （Epo B）负载胶团，用于静脉给药Epo B到实体肿瘤。数据应证明Epo B被封装在胶束内，其重量负载范围为1-5% wt/wt Epo B。交联化学将应用于Epo B负载的胶束，以产生交联的，稳定的Epo B胶束。预计胶束的粒径在30-100nm之间。基于先前对铁交联胶束的研究，Epo B的ph依赖性释放有望在体外实现。在体外实验中，交联的Epo B胶束也比未交联的胶束在血清中更稳定。交联胶束在体外作用于癌细胞应表现出与游离Epo B相似的细胞毒性，如果不是完全相同的话。在体内表征应导致：(a)确定裸鼠中Epo B胶束的最大耐受剂量（MTD）；(b)裸鼠体内Epo b胶束与游离Epo b胶束的药代动力学比较；(c)胶束在两种异种移植物模型中的抗肿瘤效果。预计与游离Epo B相比，Epo B胶束在MTD、药代动力学和抗肿瘤疗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.