金属离子调控寡肽自组装及其用于光动力治疗的机制研究

Self-assembling peptides are highly attractive in the areas of nanoarchitectonics and biomedicines due to their advantages of ease in construction, controllable structures, and good biocompatibility. In this project, we will design and synthesize short peptides, which can interact with metal ions. Then, we will use metal ions to tune the self-assembly of the peptides toward the fabrication of nanostructures suitable for antitumor drug delivery. The nanostructures will be applied for loading of photosensitizers and the obtained nanodrugs will be applied for antitumor photodynamic therapy. The self-assembled structures designed in this project mimic the organization model of metalloproteins in nature. Hence, they have good biocompatibility. Also, they have the advantage of triggered release of photosensitizers in tumor microenvironments, leading to efficient delivery of photosensitizers to tumors and enhanced antitumor photodynamic therapy. Importantly, the released metal ions are expected to enhance the antitumor effect through regulating the activity of p53 proteins, providing a method to generate synergetic antitumor therapy. Firstly, this project aims to develop a method for controllable fabrication of supramolecular systems suitable for in vivo drug delivery based on metal ions tuned self-assembly of short peptides. Secondly, this project aims to study and establish the mechanisms of self-assembled nanostructures in enhancing the antitumor photodynamic therapy effects. Finally, this project aims to construct nanodrugs with the advantages of high aqueous stability, good biocompatibility, and efficient antitumor effect for photodynamic therapy. The outcomes of this project will provide theoretical and experimental knowledge for constructing of highly efficient nanodrugs and nanoformulations.

自组装肽具有制备相对简单、结构可控性强、生物相容性好的优点，在纳米结构构筑和生物医药领域具有广泛的应用前景。本项目拟设计、合成具备金属配位能力的寡肽分子，通过金属离子调控寡肽分子的自组装，构筑用于向肿瘤中递送药物的自组装结构，并负载光敏剂，制备光动力治疗纳米药物。此自组装纳米药物模拟生物体中金属蛋白的组织形式，在肿瘤微环境中具备快速响应性释放光敏剂的性能，可实现向肿瘤细胞中高效递送光敏剂，增强光动力治疗的效果；同时，释放出来的金属离子可调控p53蛋白的活性，增强肿瘤细胞死亡，实现对肿瘤的协同增强杀伤。本项目旨在通过对金属离子调控寡肽自组装的研究，发展自组装纳米药物的可控制备方法，同时研究并建立通过自组装结构增强光动力抗肿瘤效果的机制，实现生理环境稳定、生物相容性好、抗肿瘤效率高的光动力治疗纳米药物的构筑，为构建高效纳米药物及剂型的研究提供理论和实验依据。

自组装肽具有制备相对简单、结构可控性强、生物相容性好的优点，在纳米结构构筑和生物医药领域具有广泛的应用前景。约三分之一的天然蛋白中含有金属离子，受此启发，金属离子与肽分子的配位自组装成为一种有效的自组装纳米结构构建方法。然而，如何合理地设计肽分子，并通过金属离子的调控，实现自组装体结构、功能和应用的整合还面临着较大的挑战。本项目设计、合成了具备金属配位能力的寡肽分子，通过金属离子调控寡肽分子的自组装，构筑用于向肿瘤中递送药物的自组装结构，并负载光敏剂，制备光动力治疗纳米药物。重点研究了组装体形成的机制、组装体在不同溶液环境中的稳定性及药物释放性能、抗肿瘤治疗的效果和机制。在血液环境中，组装体结构稳定性高；在肿瘤微环境中，组装体在谷胱甘肽和pH的作用下具备快速响应性释放光敏剂的性能。细胞和小鼠实验证实组装体增强了光敏剂对肿瘤和细胞的递送，增强了光动力抗肿瘤治疗的效果。本项目的研究成果，加深了对仿生组装构筑功能自组装体系的理解，在光敏剂药物新剂型和光动力治疗等生物医药领域具有广阔的应用前景。本项目的研究成果共发表SCI学术论文7篇，包括J. Am. Chem. Soc. 1篇、Angew. Chem. Int. Ed. 1篇、Chem. Eng. J. 1篇、Small 1篇等。