功能化生物膜修饰共价有机框架材料用于肿瘤治疗研究

Inspired by the special biological functions of natural organisms, this work constructs a series of nano-medicine platforms to simulate the biological functions through biomimetic strategy, which can improve the targeting and biocompatibility of drug carriers to maximize the therapeutic effect of tumor and reduce side effects. Based on this, we intend to modify the protein particles by using biosynthetic technology, which makes the bacteria express a series of fluorescent proteins, transmembrane proteins and targeted peptides that can stay in the bacterial membrane. This strategy can realize the editing of the protein expression on the bacterial membrane and synthesize the biological membrane with different functions. The edited bacterial membrane can be extracted and the bioactivity of the proteins on the membrane and the integrity of the lipopolysaccharide layer can be well remained. Furthermore, we will design a series of new covalent organic frameworks as drug carriers, which can be modified by the functional biofilm for solve the problems of poor dispersion in aqueous phase, short metabolic cycle and poor tumor targeting, so as to achieve efficient biological imaging and tumor treatment. Meanwhile, we investigate the synergistic effect between covalent organic frameworks and the immune response mediated by lipopolysaccharide layer on the bacterial membrane in vitro and in vivo, which can obtain the personalized therapy for the optimized mode, dose and process of tumor treatment.

本课题受自然界生物体各种特殊生物功能的启发，利用生物仿生策略修饰药物载体模拟相关生物功能，提高药物载体靶向性和生物相容性，以最大程度发挥肿瘤治疗效果并降低副作用。基于此，我们拟利用合成生物学技术对蛋白质粒的进行修饰，使细菌可以表达一系列能够停留于细菌膜的荧光蛋白、穿膜蛋白以及靶向肽，实现对细菌膜上蛋白表达的编辑，从而合成具有不同功能的生物膜结构。然后，对编辑后的细菌膜进行提取，保护其膜上蛋白的生物活性以及脂多糖层的完整性。进一步，我们将设计一系列新型共价有机框架材料作为药物载体，通过功能化的生物膜的修饰，解决这种有序多孔的聚合物在水相中分散性差、代谢周期短以及肿瘤靶向性差等问题，实现高效的生物成像以及肿瘤治疗。同时，在体外以及小鼠体内研究细菌膜中脂多糖层在肿瘤区域引起的免疫反应，与药物载体的协同治疗效果，实现对肿瘤治疗方式优化、剂量优化、过程优化的个性化治疗。

在前期多孔纳米生物材料取得重要进展基础上，进一步深入研究多孔纳米材料结构与性能的关系以及多孔纳米材料在生物医学应用中的关键材料化学问题，为实现多孔纳米材料在生物医学领域的应用打下坚实基础。通过对有机构筑单元的功能设计，合成了一系列新型的多孔框架材料，着重发展了具有良好光电性能的多孔框架材料，将多孔框架材料的光激发范围从可见光区域扩展到了近红外区域。合成了具有双光子诱导效应的荧光共价有机框架材料，展现了大的π电子共轭体系和跃迁偶极距，能够同时吸收两个光子使其前线轨道的电子跃迁到高能级。这种共价有机框架材料具有独特的层层堆积结构，能够有效地减弱发光团之间的π-π堆积作用，展现了高效的双光子诱导荧光性能，实现了有效的双光子诱导荧光生物成像。