基于脑胶质瘤的长效靶向仿生纳米递药系统研究

鉴于脑胶质瘤的传统化疗很大程度上受到血-脑屏障（BBB）、血-脑肿瘤屏障（BBTB）的影响，迄今临床上仅有替莫唑胺（TMZ）可用且易发生耐药，故克服BBB、BBTB屏障、提高药物到达脑部肿瘤区域的剂量是实现脑胶质瘤药物治疗的有效举措。本课题拟将跨BBB脑靶向分子肉豆蔻酸（MC）与兼具跨BBTB和肿瘤细胞靶向的生物稳定靶向多肽分子DA7R进行共价连接组合（MC-DA7R），赋予其脑肿瘤多功能靶向性能，并将其修饰于红细胞膜包覆纳米递药系统表面，在利用红细胞膜延长纳米递药系统血循环时间的同时，稳定发挥跨BBB、BBTB后的肿瘤细胞靶向递药功能，实现对脑胶质瘤的高效安全药物治疗，具有潜在的临床应用价值；通过阐明红细胞膜包覆纳米递药系统长循环与靶向分子稳定性的协同长效靶向机制，为脑部肿瘤的主动靶向递药系统设计与优化提供理论与实践依据。

Traditional therapeutic paradigms work poorly in treating glioblastoma(GBM) largely due to the hindrance to drug permeability caused by the two barriers unique to the brain: blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB). In addition, temozolomide (TMZ), the only effective therapeutic in treating GBM in clinic so far, is easy to be resistant. Therefore, one effective strategy to achieve the treatment of glioma is to overcome BBB/BBTB barriers and then increase drug concentration in glioma site..This project plans to covalently conjugate Myristic acid (MC) which was previously proved to possess the ability of brain targeting and DA7R, a fully proteolysis-resistant peptide, which was proved to possess the ability of BBTB and glioma targeting to synthesize a multi-targeting molecule termed MC-DA7R. Then, MC-DA7R will be modified on the surface of the red blood cell (RBC) membrane coated drug delivery system, which would extend the circulation time in vivo, to play a role in crossing the BBB/BBTB barriers, target glioma and finally achieve the effective and low toxic treatment of glioma..This project also focuses on the study of synergistic long term targeting mechanism of long circulation RBC membrane coated nanoparticles and stability of targeting molecules, which would provide a theoretical and practical basis for the design and optimization of the active targeting drug delivery systems.