多肽自组装的设计及其对抗癌药物的控制释放研究

Efficient treatment of cancer is of crucial importance. However, many anticancer drugs are required for high dose leading to less effective and serious side effects.In this project, we aim to design multifunctional peptides,which not only load anticancer drugs through self-assembly, but also target and controlled release the loaded drugs on cancer cells/tissues. The main work in this project includes:.(1) Design and synthesize of peptides which consist of β-sheet segment, and then drug loading via self-assembly of pepetides and drugs;.(2) Finding out the mechanism of self-assembly of peptide with drugs;.(3) Getting insight into the relationship between the activity of loaded drugs and the structure of the assembling peptide..The innovation of the project includes: firstly, the introduction of unnatural amino acids improve the flexibility and the resistance to enzymatic hydrolysis of the peptide; secondly, to achieve high loading and controlled release of the drugs, dendritic, thiol, and pH-sensitive amino acids are employed; thirdly, a targeting ligand specifically binding to cancer cell is also attached to the backbone of the peptide..Overall, in this project, we are trying to provide a novel strategy to improve the chemotherapeutic efficacy of the anticancer drugs. This kind of anticancer drug delivery system will increase the circulation of drugs, target the desired cells/tissues and release the drugs triggered by the intracellular environment of cancer cells/tissues. As a result, the therapeutic efficacy of the anticancer drugs will be improved and the side-effects will diminish.

针对目前临床使用的常规化疗药物普遍存在剂量大、药效低、毒副作用高的缺点，本项目拟设计多功能的多肽分子，通过自组装的方式对药物进行包覆，制成纳米药物，使其具有靶向性和控制释放的特性。主要内容主要包括：(1)设计能形成β-折叠的多肽序列，通过与药物自组装实现药物的包覆；(2)研究多肽与药物自组装的机理；(3)从分子层面探讨多肽分子结构与纳米药物药效之间的关系。项目的创新点：其一是在多肽中引入非天然氨基酸，以改善多肽链的柔性及抗酶解能力；其次是引入树枝状氨基酸、含巯基的氨基酸和pH敏感的氨基酸序列，实现多肽对药物的有效包覆和控制释放。这种多功能多肽自组装包覆的抗癌药物，易克服生理屏障，进入肿瘤细胞内部，并借助多功能多肽对肿瘤环境的敏感特性调控药物释放，以期在解决如何提高抗癌药物的药效、降低毒副作用等问题和关键技术上取得突破，为高效抗癌药物的研发提供相关科学依据。

目前临床使用的常规化疗药物普遍存在剂量大、药效低、毒副作用高的缺点。针对上述问题，本项目设计了多种多功能的多肽分子，无机-有机杂化分子等通过自组装的方式对药物进行包覆，制成多功能纳米药物，使其具有靶向性、控制释放、光动力治疗和热动力治疗的特性。本项目的主要内容及取得的主要研究结果有：. (1) 合成了系列的多肽分子，研究了其自组装行为和刺激响应特性，并将其作为抗肿瘤药物载体，赋予抗肿瘤药物靶向性、荧光特性等；. (2) 制备了无机-有机杂化材料，作为高负载药物载体，并实现了光疗、热疗及化疗等多模式治疗。如以二维黑鳞片作为抗肿瘤药物载体，其负载量高达970%，实现了光疗、热疗和化疗联合治疗；. (3)在多肽或者高分子中嵌入荧光及巯基响应基团，利用细胞中GSH、Cys等肽或氨基酸作为刺激因子，有效地控制药物的释放，并且能够在线实时观察药物的释放行为，为诊疗一体化提供了一种新的解决途径；. (4) 通过自组装将短肽分子形成各种有序的纳米结构材料，以其为软模板，得到了系列纳米结构的功能分子，并将其用于生物传感、催化剂以及纳米器件等方面。.本项目所取得的成果为多功能药物载体的设计提供了新的策略，为高效、低毒副作用的抗癌药物的研发奠定了坚实的基础。

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