嵌有载药纳米粒的间充质干细胞生物靶向系统的构建及其在脑胶质瘤治疗中的应用

Tumor targeting is one major realm in development of advanced drug delivery system. This project intends to combine the stem cells and drug-loaded nanoparticles based on the tumor homing ability of mesenchymal stem cells (MSCs) as well as biological events of cell endocytosis and exocytosis. Nanoparticles modified with hyaluronic acid will be prepared to target CD44 recptor expressed both on the surface of MSCs and glioma. The nanoparticle could be effeciently embedded into MSCs and actively locate at tumor sites and unload intact nanoparticles via exocytosis/transcytosis and then the released particles would target to kill cancer. Nanoparticle encapsulation and exocytosis/transcytosis can reduce the exposure of MSCs to the drug which means stem cells can maintain their migration capacity and differentiative potential. Nanoparticle transportation between tumor cells and the penetration of drug into tumor spheres will be enhanced through interactions between CD44 and hyaluronic acid. The drug delivery process involving cell uptake and export kinetics in MSCs and tumor cells will be studied. Mechanism of nanoparticle internalization and elimiantion pathways will be investigated. Finally, the safety and anti-tumor activity of MSCs loaded with nanoparticles in glioma will be evaluated in vitro and in vivo. The infiltrating from normal brain parenchyma and migratory property of MSCs based drug delivery system towards glioma in rats will be clarified as well. The use of MSCs as cellular carriers will provide novel ideas for delivery of specific drug-loaded nanoparticles to glioma which is a promising therapeutic strategy for targeting chemotherapy.

肿瘤靶向治疗是新型给药系统研究领域的一大命题。本项目利用间充质干细胞（MSCs）的肿瘤趋向特性，以MSCs与脑胶质瘤细胞表面共表达受体CD44为着眼点，制备透明质酸修饰的载药纳米粒。立足于纳米粒内吞、胞吐/转胞吞的细胞生物学基础，使MSCs高效负载纳米粒，而后携带纳米粒定位于靶部位并有效释出纳米粒，纳米粒再次主动靶向并杀灭肿瘤。通过纳米粒包裹和适时出胞，减少抗肿瘤药物与MSCs的接触，从而维持MSCs的细胞活性、迁移及分化潜能。通过特异性受体介导的入胞和出胞，促进药物在胶质瘤细胞间的传递，增加瘤体渗透深度。研究纳米粒在MSCs与肿瘤细胞间传递的动力学过程，明确透明质酸修饰的纳米粒内化及出胞途径。评价携载纳米粒的MSCs生物靶向系统对脑胶质瘤的体外、体内抗肿瘤作用和安全性，研究该系统向脑肿瘤渗透、迁移的空间定位能力。为纳米药物的脑肿瘤治疗方法开拓新的思路，实现小分子化疗药物的靶向治疗目的。

肿瘤靶向治疗是新型给药系统研究领域的一大命题。本项目利用间充质干细胞（MSCs）的肿瘤趋向特性，以MSCs与脑胶质瘤细胞表面共表达受体CD44为着眼点，合成了系列透明质酸-PLGA共聚物，并制备了负载紫杉醇的缓释纳米粒。立足于纳米粒内吞、胞吐/转胞吞的细胞生物学基础，使MSCs高效负载该纳米粒，而后携带纳米粒定位于靶部位并有效释出纳米粒，纳米粒再次主动靶向并杀灭肿瘤。通过纳米粒包裹和适时出胞，可减少抗肿瘤药物与MSCs的接触，降低毒性。研究明确了MSCs负载纳米粒的有效剂量，在该浓度条件下MSCs-NPs的细胞周期、迁移能力可在5天内恢复正常水平，多向分化能力不受影响。通过对细胞外排动力学建模和分析，发现特异性受体介导的出胞可增加紫杉醇外排总量并减慢外排速度，增强在药物在胶质瘤细胞间的传递，并在3D肿瘤球水平发现MSCs-NPs可增加瘤体渗透深度和抗肿瘤作用。在体内原位脑瘤模型上，脑内对侧注射携载纳米粒的MSCs生物靶向系统可在2天内达到脑瘤组织，并有效释放携载的药物。该系统治疗可使动物达无瘤生存状态，有很好的脑胶质瘤治疗效果。本项目的研究为纳米药物的脑肿瘤治疗方法开拓了新的思路，实现小分子化疗药物的靶向治疗目的。