基于亚纳米银簇高效杀菌复合药物的设计及其杀菌活性研究

The emergence of multidrug resistance bacteria is threatening people's health seriously, and the world may one day be facing an epidemic of untreatable bacterial infections of cataclysmic proportions, due to the current slow pace of antimicrobial agent development. In this case, the design of a novel and efficient antimicrobial drug is urgently needed. In our previous work, we have developed a novel method to prepare uniform and stable sub-nano Ag clusters (≦1nm) through a silver mirror reaction, and the obtained sub-nano Ag clusters can show some unique properties. In this project, we apply sub-nano silver cluster as the main component of the novel antimicrobial drug, since the antimicrobial activity is significantly enhanced with the decrease of size as reported previously. Moreover, Ag clusters can also play an enhanced synergistic performance by conjugating with bactericidal drug molecule. Finally, the stable and efficient antimicrobial hybrid can be prepared by assembling Ag clusters conjugating with drug molecule on the surface of gold nanorods. During evaluating the antimicrobial activity of antimicrobial hybrid, we can comprehensive study the process of accurate tracking, quantitative dosing, controlled release and efficient sterilization, establishing the relationship between particle size and antimicrobial activity, as well as estimating the conclusive antimicrobial mechanism. This project can lay the foundation of design of novel and efficient antimicrobial drugs.

细菌耐药性和抗药性的出现严重威胁人类的健康，而杀菌药物的研发又相对缓慢难以应对细菌耐药性和抗药性的不断增强，人类世界可能面临大规模细菌感染而无法医治的危险，因此新型高效杀菌药物的设计研发迫在眉睫。本项目在前期工作中发展了一种利用银镜反应制备均匀稳定的亚纳米银簇（≤1nm）的方法，并且表现出独特的性能。在此基础上，利用银的杀菌活性随尺寸的降低而显著增强的特点，以亚纳米银簇作为新型杀菌药物的主要成分，并且与表面接枝的药物分子有效结合发挥协同增效的作用，最后通过与金纳米棒载体的化学组装获得稳定高效的杀菌复合药物。在杀菌活性评价中全面深入的研究复合药物的精确定位、银簇的可控释放、定量给药以及高效杀菌等过程，建立颗粒尺寸与杀菌活性的构效关系，构建完整的杀菌机理理论，为新型高效杀菌药物的设计提供方法借鉴。

针对传统抗菌复合药物研发缓慢难以应对细菌耐药性和抗药性的不断增强等问题，本项目从合成基于亚纳米银簇的多元复合材料以及探索高光热转化效率的新型二维药物载体出发，开发出一系列新型二维材料及其复合物，为新型高效杀菌药物的设计提供方法借鉴。主要研究内容包括（1）设计制备基于亚纳米银簇的三元纳米复合材料BP-Ag/TiO2，该材料通过金属-载体强相互作用将亚纳米银簇可控沉积到纳米二氧化钛表面，并进一步稳定到二维黑磷纳米片表面。获得的材料分别在可见光和近红外光下有效激活Ag/TiO2纳米复合物，高效活化单线态氧进而实现高效的抗菌杀菌的效果；（2）设计了用于肿瘤联合治疗的纳米复合药物，该药物采用聚乙二醇和牛血清白蛋白修饰的金纳米棒，并负载免疫佐剂。能够实现在近红外照射下对小鼠转移性黑色素瘤具有明显的杀伤作用和免疫应答。（3）探索宽光谱响应的二维新药物载体材料，发展出一种基于液相剥离法成功制备出表面光滑的大尺寸二维锑烯的方法，实现锑烯带隙在0.8-1.44eV的精准调控，为研发宽光谱响应的二维药物载体提供新的思路；（4）提出一种拓扑氮化策略制备具有核壳结构的二维片状LaKNaTaO5/LaTaON2材料。深入考察了氮化温度、氮化时间等对片状材料的暴露晶面和表面缺陷态密度的影响，比较传统氮氧化物和LaKNaTaO5/LaTaON2核壳材料对光催化水分解性能的影响，为研发宽光谱相应的纳米二维材料提供新的思路。3年研究工作共发表SCI论文15篇，其中第一作者8篇，影响因子超过10的共6篇（包含国际顶级期刊Angewandte Chemie International Edition 4篇），申请发明专利5件，已授权1件。