细胞微环境双重响应的光动力药物载体的构建与应用研究

Photodynamic therapy is a method using light and photosensitive drugs (photosensitizers) to treat tumors. The drug concentration in the cancer cells is a key factor which determines the therapeutic effect. Until now, published vectors for photodynamic therapy are suffering from slow drug release rate. To achieve controllable drug release rate, a dual responsive drug delivery vector will be constructed by this project. One kind of charged peptide and one kind of oppositely charged protein will be used as the assembly units. These two units can spontaneous assembly by electrostatic attraction to form nanoparticles, which can be used as drug delivery vector. Moreover, cellular microenvironment-responsive properties, both pH-sensitivity and glutathione-sensitivity, can be introduced during design. Electrostatic assembly is a kind of controlled assembly, which means the size, the potential and the drug release rate under cellular microenvironment of the vector can be controlled by changing the assembly conditions. Thus, the structure-property relationships of the vector can be revealed. To study the impact of the drug release rate on the drug pharmacokinetic in tumor cells, in vitro and in vivo experiments will be carried out. The obtained data about the highest intracellular drug concentrations and the time period when the highest concentrations occur will be analyzed. By the analysis and optimizing the irradiation condition, photodynamic therapy of the tumor-bearing mice will be carried out. Based on the above results, the relationship of the properties of the vector and the therapy effect will be discussed. The outcomes of this project will be benefit for constructing of highly efficient drug delivery vectors for photodynamic therapy both theoretically and experimentally.

光动力疗法是一种用光激发光敏药物（光敏剂）治疗肿瘤的方法。光照时光敏剂在肿瘤细胞中的浓度是决定治疗效果的关键因素。目前普遍采用的光动力载体释药速率较慢，不利于细胞中获得高浓度的光敏剂。本项目计划优选带相反电荷的多肽和蛋白，通过静电组装构建一种新型的纳米粒子，并向其中引入谷胱甘肽和pH双重响应，作为光动力药物载体，以实现细胞微环境中可控释药。研究不同组装条件下所得载体的粒径、电位、释药速率等关键参数的变化规律，揭示组装体结构与性能之间的内在联系。通过细胞和小鼠实验，研究释药速率与肿瘤细胞中药物代谢动力学的关系，获取细胞中光敏剂浓度的高峰和高峰出现的时间区间。在此基础上，优化光照条件，进行荷瘤小鼠的光动力治疗。总结并建立载体性质与光动力治疗效果之间的关系，为构建用于光动力治疗的高效药物载体提供理论和实验依据。

光动力疗法是一种用光激发光敏剂治疗肿瘤的方法。光照时光敏剂在肿瘤细胞中的浓度是决定治疗效果的关键因素。纳米载体能增强光敏剂的水溶性，并提高光敏剂在血液中的稳定性，因而备受关注。目前普遍采用的光动力载体释药速率较慢，不利于细胞中获得高浓度的光敏剂。本项目通过发展可控自组装的策略，设计细胞微环境响应的药物载体并研究其在肿瘤光动力治疗方面的应用。以蛋白和肽等生物分子作为组装单元，通过多种可控自组装的策略，制备了响应性的纳米组装体。构建的组装体系具备GSH、pH和酶三重响应性质，对多种光敏剂药物具有良好的装载和递送能力。重点研究了体系的组装机制、生物相容性、载药性能和可控释放性能。通过活体实验研究了纳米药物在肿瘤处响应性释放光敏剂的效果和机制，增强了光动力抗肿瘤治疗效果，为提高现有光动力治疗对肿瘤的疗效提供重要的依据。本项目发展的自组装策略可有效应用于响应性纳米药物的构建，在药物输送和组织工程等生物医学领域具有广阔的前景。本项目的研究成果，共发表SCI学术论文10篇，包括J. Am. Chem. Soc. 1篇，Angew. Chem. Int. Ed. 2篇，Adv. Mater. 3篇。撰写题为“Peptide-Based Supramolecular Chemistry”的著作章节（新加坡Springer Nature出版社）。相关技术获得专利授权2项。