具有微-纳转变特性的多级递药系统构建及用于治疗肺转移的研究

Current drug delivery strategies for the treatment of lung metastases are inefficient. It has been reported by many researchers that microparticles can accumulate in lung after intravenous administration, but poor penetration in tumor significantly limits their application. In order to achieve higher distribution in lung and to further enhance the penetration and uptake of the drug carriers, we will develop a micrometer-to-nanometer size-transformable drug delivery system “MCluster” in this project. Polymeric materials will be synthesized by using degradable linkers as bridge unit to connect polycaprolactone (PCL) with platinum prodrug conjugated polyamidoamine (PAMAM) dendrimers, which will be further formulated into MCluster with microfluidic technology. MCluster will accumulate in lung after intravenous injection and then undergo micro-to-nano size transformation when chemically degradable polymer bonds are broken, which will trigger the discharge of PAMAM, facilitate penetration and cell internalization of the therapeutics. The size of MCluster is going to be regulated by varying the channel width of microfluidic chips or flow rates of organic and aqueous solutions, while the speed of micro-to-nano transformation will be adjusted by altering the molecular weight, composition as well as the degradable linkers of the polymeric materials. In addition to the preparation and properties, we will intensively investigate the process in which MCluster accumulates at pulmonary tissue and penetrates into the metastatic sites in vivo. Furthermore, the therapeutic efficacy of MCluster against lung metastases will be studied in order to reveal how size and the speed of micro-to-nano transformation affect this drug delivery system. This project will lay a good foundation for the development of drug carriers against lung metastases.

目前针对肺转移的药物递送效率较低。考虑到微米载体在静脉注射后能富集于肺部，但其肿瘤渗透性十分有限，为了增加载体在肺部的分布，同时提高药物的渗透与摄取，进而治疗肺转移，本项目拟将PCL与表面偶连顺铂的PAMAM间通过敏感化学键桥连，利用微流控技术构建具有微-纳转变特性的多级递药系统MCluster。给药后，微米尺度的MCluster在肺部富集；随着敏感化学键的断裂，触发微-纳转变，MCluster将释放载药小颗粒渗透至转移灶杀伤肿瘤。项目拟通过改变微流控芯片通道直径及各相流速，调控MCluster的尺寸；通过改变聚合物分子量、配比及连接的结构，调控MCluster的微-纳转变特性；在动物水平重点研究MCluster在肺部的富集并渗透至转移灶的过程，评价MCluster对肺转移的疗效，揭示载体尺寸、微-纳转变速率与其体内命运、治疗效果间的关系。本项目将为治疗肺转移的药物研发提供新思路。

微米载体在静脉注射后能富集于肺部，但其肿瘤渗透性十分有限，为了增加载体在肺部的分布，同时提高药物的渗透与摄取，本项目利用微流体技术构建了具有微-纳转变特性的多级递药系统；通过3-甲基马来酸酐-2-丙酸酯-聚己内酯(PCL-CDM)与聚酰胺-胺树枝状高分子(PAMAM)反应，获得可降解酰胺键桥连的两亲性高分子PCL-Dlinkm-PAMAM；通过控制二者投料比制备得到了接枝不同数量PCL的两亲性高分子(PCL-Dlinkm)n-PAMAM (n=1-5)。项目利用微流体技术，成功将(PCL-Dlinkm)n-PAMAM制备成微米组装体imCluster。imCluster主要通过PCL疏水相互作用组装形成，通过调控水相和油相的流速，可实现尺寸从14-400 μm的精确控制；使用(PCL-Dlinkm)n-PAMAM (n=1-5)制备imCluster，当n=1或2时，高分子组装形成形状不规则的微米级碎片；当n≥3时，高分子可组装形成稳定的球形imCluster. 当可降解酰胺键Dlinkm断裂后，PAMAM纳米颗粒可逐渐从imCluster释放。本项目发展了一类具可控尺寸、可缓释纳米颗粒的微米组装体，在《高分子学报》发表SCI论文1篇。