智能型Type-I光敏分子构效设计及其抗耐药性感染研究

细菌耐药问题已经成为威胁人类健康的重大挑战之一。光动力抗菌疗法能够在一定程度上克服细菌耐药性，但是传统光敏剂具有氧气依赖性高和选择性不足的问题，严重限制了该疗法的临床应用。本项目针对以上问题并基于前期研究基础，首先拟基于氧族重原子设计光敏共轭寡聚物作为母核，利用重原子效应增强Type-I光动力反应，降低氧气依赖性。再以二茂铁作为淬灭剂为母核设计应激启动开关，合成智能型Type-I光敏分子，并通过构效关系研究，提高二茂铁的淬灭效率。利用组织间微环境差异，使二茂铁只在感染组织向二茂铁阳离子转化并激活光动力反应，增强光敏分子的选择性。最后制备成无载体纳米药物，将Type-I光动力治疗、微环境选择性激活与可视化纳米释放等关键环节有机结合，实现非氧依赖的选择性高效光动力抗菌。本项目拟在智能型Type-I光敏剂设计方面提出创新设想，将为实现对耐药细菌感染的精准、安全和高效光动力治疗提供新策略。

The issue of bacterial multi-drug resistance has become one of the major challenges threatening human health. Photodynamic antimicrobial therapy can overcome antibiotic resistance to a certain extent, but traditional photosensitizers have the problems of high oxygen dependence and poor selectivity, which seriously limit the clinical application of this therapy. In this project, we will propose to design photosensitive conjugated oligomers based on chalcogen heavy atoms as the core structures to enhance the Type-I photodynamic reaction and reduce the oxygen dependence by using the heavy atom effect. Then, the intelligent Type-I photosensitive molecule will be synthesized by designing a stimulus initiation switch using ferrocene as the quenching agent for the core structures, and the quenching efficiency of ferrocene was improved by the studies of structure-activity relationship. The selectivity of the photosensitive molecules will be improved by using the microenvironmental differences between tissues to convert ferrocene to ferrocenium only in infected tissues and then activate the photodynamic reaction. Finally, a carrier-free nanomedicine will be prepared, which organically combines the key aspects of Type-I photodynamic therapy, microenvironmental selective activation and visualized nano-release to achieve selective and oxygen-independent efficient photodynamic antibacterial therapy. This project will propose an innovative idea in the design of intelligent Type-I photosensitizers which will provide a new strategy to achieve precise, safe and efficient photodynamic therapy for antibiotic-resistant infections.