超临界流体技术构建共载siRNA和紫杉醇的微镶纳多孔高分子微球及其在肺癌治疗中的应用

项目名称： 超临界流体技术构建共载siRNA和紫杉醇的微镶纳多孔高分子微球及其在肺癌治疗中的应用

项目编号： No.31470927

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 陈爱政

作者单位： 华侨大学

项目金额： 82万元

中文摘要： 为克服目前肺癌治疗存在多药耐药性以及传统方法制备肺部给药用多孔高分子微球存在的缺点，本项目拟利用超临界流体技术构建具有微镶纳结构的多孔高分子微球共载siRNA和紫杉醇用于肺癌的治疗。首先采用复凝聚法制备负载siRNA的壳聚糖纳米粒，然后利用超临界流体抗溶剂法制得siRNA以被壳聚糖纳米粒包覆的形式镶嵌在基质中负载紫杉醇的多孔高分子微球，以保护siRNA载药和给药过程中的活性；经吸入给药直达肺癌病灶，siRNA发挥干扰作用，沉默编码泵蛋白基因，从根本上解除癌细胞对药物的屏蔽，克服多药耐药性。通过优化制备工艺参数，使制得的多孔高分子微球符合肺部给药的要求且较好地保持siRNA的活性；对共载siRNA和紫杉醇的微球进行系统的理化性能表征。在细胞、整体以及分子水平评价微球的生物相容性，并对其医用功能性尤其是药效学进行详细的研究，初步探索siRNA和紫杉醇的协同作用机制以及克服多药耐药性的机理。

中文关键词： 超临界流体技术；药物载体；多孔高分子微球；联合给药；肺癌治疗

英文摘要： To overcome the multidrug resistance (MDR) in the lung cancer therapy and the shortcoming in the use of traditional methods to produce porous polymer microspheres (PPMs) for pulmonary drug delivery, we attempt to employ the supercritical fluid technology (SFT) to produce the PPMs with a nanoparticles (NPs)-inlaid structure to co-deliver siRNA and paclitaxel (PTX) for lung cancer therapy. The chitosan (CS) NPs containing siRNA will be prepared by complex coacervation in the first place, and then the siRNA-CS NPs will be encapsulated in the PTX-loaded PPMs by supercritical fluid antisolvent process, which could protect the activity of siRNA during the processes of drug loading and drug delivery. After the direct inhalation of the PPMs co-loaded with siRNA and PTX into the lungs, the pump gene will be silenced by siRNA, thus unlocking the barrier of cancer cells to drugs and overcoming the MDR. By optimizing the operating parameters, the PPMs which meet the requirements of pulmonary drug delivery and loaded with siRNA with a good maintenance of activity will be achieved; the physicochemical properties of the resulting PPMs co-loaded with siRNA and PTX will also be characterized. The biocompatibility of the PPMs will be evaluated at various levels of cellular, integrated and molecular; and studies on their medical functions, particularly the pharmacodynamics, will be carried out in detail to investigate the synergistic effects of siRNA and PTX and mechanism on overcoming the MDR.

英文关键词： supercritical fluid technology;drug carrier;porous polymer microspheres;combined administration;lung cancer therapy