Paclitaxel Carrier from Protein Library

描述(申请人提供)：该项目的长期目标是制备一种基于蛋白质的药物载体，可用于实体瘤的药物靶向。研究显示，大分子聚集在快速生长的肿瘤组织周围的泄漏血管中。然而，由于肿瘤周围不利的对流或溶剂阻力，这些分子从它们保留的地方到实际的肿瘤细胞的移动极其缓慢。相反，小分子(&lt；10 kDa)可以利用浓度梯度决定的扩散进入作用部位。这项研究的总体目标是：(1)合成紫杉醇的水溶性生物素化衍生物，(2)通过mRNA展示系统鉴定高亲和力的紫杉醇结合蛋白，(3)进一步筛选当pH降至6.5或温度升高至42℃时将释放紫杉醇的蛋白，(4)将这些蛋白共价偶联到树枝状大分子上，以增加总的相对分子质量，以及(5)最后从紫杉醇结合和释放的角度对组装进行表征。

DESCRIPTION (provided by applicant): The long term objective of this project is to prepare a protein-based drug carrier that can be used in drug targeting to solid tumors. Macromolecules are shown to accumulate in leaky blood vessels surrounding rapidly growing tumor tissue. However, the movement of these molecules from where they are retained to actual tumor cells is extremely slow, due to unfavorable convection, or solvent drag, around the tumor site. In contrast, small molecules (<10 kDa) can utilize diffusion dictated by concentration gradient to access the site of action. The overall goals of the proposed study are to: (1) synthesize water-soluble biotinylated derivative of paclitaxel, (2) identify high-affinity paclitaxel-binding proteins via the mRNA display system, (3) further select those that will release paclitaxel when pH is lowered to 6.5 or temperature is elevated to 42¿C, (4) covalently couple these proteins to a dendrimer to increase the overall MW, and (5) finally characterize the assembly in terms of paclitaxel binding and release.