具有诊疗一体化功能的智能化抗菌纳米颗粒的构建及应用

According to the drawbacks of current antibacterial therapy, such as the difficulty in the location of inflammatory site and early diagnosis of infection, poor biocompatibility of antibiotic etc., a kind of microenvironment-triggered antibacterial polymeric nanoparticles will be developed for infection imaging and treatment. The outside shell of nanoparticles is consisted of pH-sensitive AMP-structure block and PEG brushes with enzyme-responsive peptide. The obtained nanoparticle is biocompatible in the physic condition since the AMP-structure block is collapsed. And the fluorescence is off because of the fluorescence resonance energy transfer (FRET) effect. While in the bacterial affected area, the quencher is released caused by the breakage of the peptide and the fluorescence is recovered to clearly show the infection area. Meanwhile, the protonated AMP-structure block becomes hydrophilic and interacts with bacterial cell membrane. This project will deeply study the effect of polymer structure on the morphology and antibacterial activity, reveal the regulation rules of the construction and dissociation of the carrier. The research results will take a guiding role in the design and fabrication of stimuli-responsive theranostic antibacterial polymeric nanoparticles.

针对目前抗菌治疗中体内炎症区域定位难、感染早期诊出率低、抗菌药物生物安全性差等问题，本研究拟利用细菌感染组织独特的生理微环境（弱酸性、明胶酶过度分泌），基于FRET技术，设计构建一类具有抗菌肽结构、良好生物安全性和诊疗一体化功能的智能响应抗菌纳米颗粒。该纳米颗粒以酸敏感抗菌肽结构嵌段和含酶响应型多肽的PEG刷为壳，在生理条件下抗菌肽结构嵌段塌缩，颗粒表面近电中性；而在细菌感染组织，受微环境因素促发，多肽链段断裂，淬灭剂逃脱，纳米颗粒呈现荧光，实现对感染组织的灵敏诊断；同时抗菌肽结构嵌段质子化而链舒展，表现出高效抗菌活性。本项目将深入研究聚合物结构对纳米颗粒性质、诊断灵敏度和抗菌活性的影响，阐明该纳米颗粒与生物活性（抗菌活性、生物安全性）的构效关系，为诊疗一体化抗菌材料提供新的策略。

临床中细菌感染性疾病的发病率和病死率很高，感染组织在细菌新陈代谢和宿主免疫应答作用下会分泌出乳酸等酸性物质，使组织呈现弱酸性微环境（pH=5.5~6.5）。针对目前抗菌治疗效率低、抗菌药物生物安全性差等问题，本研究利用细菌感染组织独特的弱酸性生理微环境，设计了pH响应性聚合物材料，系统研究了材料结构与智能抗菌性能之间的构效关系，并在此基础上，发展多模式联合抗菌治疗策略。具体进展如下：（1）通过层层自组装技术制备聚合物多层膜，其在弱酸性条件下呈正点，而pH为7.4时膜呈负电，进而实现在不同pH下杀菌和释菌这两种功能的可逆切换。（2）系统研究了多层膜组装条件、阳/阴离子聚合物类型及分子量、顶层聚合物等对多层膜等电点的影响规律，掌握了聚合物多层膜pH响应性能的调控方法。（3）pH响应性多层膜进一步复合光热粒子，获得在弱酸性条件下光热作用增强的复合多层膜。在光热和表面阳离子的协同作用下，多层膜杀菌率接近100%。本项目利用细菌感染微环境酸度变化的内源刺激和近红外光外场因子的双重调控下，实现高效、安全、可控的抗菌治疗，为非抗生素抗菌策略提供新的思路。