多肽聚合物的亚细胞器定位组装调控及其抗肿瘤性能研究

Nanomaterials were extensively investigated due to their special superiority. In rescent years, in order to promote the retention of nanomaterials in tumor sites, in situ self-assembly of supramolecules in vivo have been powerful strategy to solve the problem. However. the researches of in situ self-assembly were mostly based on the microenvironment of tumor or cell, and self-assembly at subcellular organelle is still irrealizable. Because the anti-cancer drugs could work effectively at the subcellular organelle of cell, the biological effect of in-situ self-assembly nanomaterials in subcellular organelle was an interesting project to research. This project will design and prepare polymer-peptide conjugates that combined the metrits of polymers and peptides. The polymer-peptide conjugates tend to self-assemble into nanoaggregates around the mitochondria upon the stimulus of ROS, which will provide an new approach for tumor therapy. Meanwhile, the project should optimize and build a moderate, and highly effective synthesis methods of stimuli-responsive polymer, and establish a new relationship between chemical structures and biological properties.

纳米材料因其独特的优势而广泛应用于癌症的诊断与治疗。近些年，为了提升纳米材料在肿瘤部位的滞留量，体内原位构筑超分子组装体的概念越来越受到人们的重视。但是，现阶段大部分体内组装的研究都是基于肿瘤微环境或者细胞微环境，还不能实现在某个细胞器上的定位组装。由于大部分抗癌药物的作用靶点在某些细胞器上，因此其原位组装行为对于细胞器生物学效应尚待研究。本项目在活体自组装的理念上进一步拓展，充分结合多肽和聚合物的优势，设计活性氧簇(ROS)响应型多肽聚合物，实现多肽聚合物在线粒体周围的定位组装，为提升抗肿瘤纳米药物的疗效提供了新思路。同时完善温和、高效的刺激响应型多肽聚合物的合成方法，为其化学结构与生物性质关系的建立及优化开辟新途径。

形貌可控的分子组装在生命体中起着关键作用，然而如何在体内实现外源性分子的可控组装，是一个有潜力，而且极具挑战的领域。通过发展肿瘤微环境响应型分子，本研究实现了纳米前药在肿瘤部位发生形貌变构，从而提升药物富集量和疗效。本研究一共分为两个部分，第一部分是设计组织蛋白酶B响应的纳米前药，通过改变其的亲疏水，实现了前药在细胞内的自组装。当体系中形成初级的纳米纤维结构时，后续加入的多肽药物能极为迅速的转变成同样的纳米纤维。通过对其动力学过程的研究发现，其成核生长过程成核期明显缩短。基于这一过程，我们提出了自催化的概念并基于此制定了新的给药策略，实现了纳米药物在肿瘤部位的高效富集。第二部分基于肿瘤细胞的线粒体中活性氧过表达，设计纳米前药分子，实现了其在线粒体的定位形貌变构。通过Hill方程，确定了纳米纤维与线粒体膜更强的多价协同效应，促使细胞毒性肽的治疗效果提升。总之，我们将超分子自组装设计理念用于体内，提升了纳米药物富集和疗效，为重大疾病诊疗提供新策略和新材料。