高分子胶束两种被动靶向和两种主动靶向的对比研究

To improve targeting and to reduce the side effects of drugs is the key to improve the efficacy of chemotherapy. "Polymer micelle drug" is the hot topic in the field of anticancer drugs in recent years. Based on the understanding of the liver reticuloendothelial system (RES), the principle of tumor EPR passive targeting effect, the selective uptake of the organ, and active targeting, this project will design and prepare polymer platinum drug conjugates and in situ liver cancer models, and compare the partitions of the nano-micelles in the cancerous tissue and in the healthy part of the liver due to the RES capture and the EPR effect, or due to the lactose-mediated targeting and the folic acid or AFP (alfa-fetoprotein) mediated targeting. Based on the results from these comparative studies, optimization of the liver-targeting nano-micellular drug delivery system will be made and the efficacy and safety of the system will be evaluated systematically. The results of this project will lead to not only establishment of the improved liver-cancer-targeting nano-micellular drug delivery system, but also new knowledge of utilizing the advantages of the both passive targeting and active targeting and avoiding mutual cancelling of them. This is beneficial for investigation of anti-hepatitis drugs and other targeted drug delivery systems and for development of the polymer-conjugate pharmacology.

提高药物的靶向性和降低药物的毒副作用是提高化疗效果的关键。"高分子胶束药"技术是近年抗肿瘤药物研究领域的热门课题，本项目根据肝脏网状内皮系统（RES）特点、肿瘤组织EPR被动靶向的原理、脏器自身的选择性摄取和主动靶向的原理，设计并制备高分子铂键合药胶束和原位肝癌模型，对比研究由于肝脏RES截留和由于肿瘤EPR效应造成的药物富集，对比研究乳糖(半乳糖)介导的肝脏靶向及叶酸和甲胎蛋白抗体介导的肝癌细胞靶向，寻求利用这些靶向效应构建新的抗癌药和新的剂型的可能性。在此研究的基础上，优化针对原位肝癌的靶向纳米胶束药物输送体系，对该体系进行有效性和安全性评价。此研究不仅获得具有临床应用前景的肝癌靶向药物剂型，而且会获得如何利用被动靶向和主动靶向各自的优势，避免它们相克的设计理念和技术措施，有利于肝炎药和其它高分子键合抗癌药的研制，推动高分子键合药物学的发展。

本项目根据肝脏网状内皮系统（RES）特点、肿瘤组织EPR被动靶向的原理、脏器自身的选择性摄取和主动靶向的原理，设计合成了带有功能基团的嵌段共聚物聚乙二醇-b-聚（烯丙基缩水甘油醚），聚乙二醇-聚乳酸-聚赖氨酸和聚乙二醇-聚乳酸-聚谷氨酸。聚合物侧链上的功能基团进一步键合了抗癌药和荧光分子，通过自组装的方法得到纳米颗粒用于荧光示踪和肿瘤治疗。通过调控聚合物的比例得到了不同粒径和表面电荷的纳米胶束，通过细胞实验、荷瘤小鼠的动物体内实验系统评价了被动靶向和主动靶向的选择性摄取。并进一步制备了RGD靶向和EGFP靶向的功能胶束，并对载药体系进行了有效性和安全性评价。本项目的研究为高分子抗癌药的研制提供理论指导，推动了高分子键和药物学的发展。