基于星形聚赖氨酸的可溶性微针贴片构建及其用于高效治疗皮肤感染的研究

Skin infection caused by bacteria or fungi is among the top ten diseases with highest incidence in recent years. Complex pathogens, high infection rate of drug-resistant bacteria, and poor curative efficacy of traditional topical antibiotics increase the difficulty and duration of treatment. Antimicrobial peptides are internationally recognized as the most promising alternative to antibiotics. Because electrostatic interactions between positively charged residues of antimicrobial peptides and anionic bacterial membranes contributed to the peptide-bacteria binding, the cationic charge of antimicrobial peptides is considered as one of the key characteristics that affect antimicrobial activity. To prepare antimicrobial peptides with higher charge density and thus better activity, changing the structure of antimicrobial peptides into star shape can overcome the structural limitation of traditional linear antimicrobial peptides. Hence, we design star-shaped polylysines with high charge density as novel antimicrobial peptides, and the structural advantage of these is demonstrated by their structure-property relationship and antimicrobial mechanism study in vitro and vivo. Meanwhile, star-shaped polylysines have the structural characteristics of dissolving microneedle matrix, thus are used as both antimicrobial agents and major matrix material to fabricate microneedles with high drug loading for highly effective treatment of skin infection. Based on the research of formulas, performance and structure-property relationships, this project summarizes the working mechanism of this matrix material, and explore the application potential of formulated microneedles as universal transdermal drug delivery system for other drug molecules.

由细菌或真菌引起的皮肤感染属于近年来10大高发病率疾病。致病菌种类多、耐药菌感染率高和传统外用抗生素治疗效果不够理想等问题，增加了疾病治疗的难度与周期。抗菌肽是目前国际公认最具潜力的抗生素替代品。由于其正电残基可与致病菌带负电的细胞膜产生静电作用，介导抗菌肽与致病菌的结合，所以正电荷是影响其活性的关键性因素之一。把抗菌肽结构设计为星形，可以克服传统线形抗菌肽的结构限制，制备出电荷密度更高且活性更好的抗菌肽。本项目设计了高电荷密度的星形聚赖氨酸作为新型抗菌肽，通过研究其构效关系与体内外杀菌机理，阐明此类抗菌肽的结构优势。同时，由于星形聚赖氨酸具备可溶性微针针尖基质材料的结构特点，本项目以其同时作为抗菌药物与针尖主要基质材料，构建高载药量微针用于治疗皮肤感染，通过针尖处方、性能和构效关系研究，阐明此类基质材料的性能影响机理，并探究由其构建的微针贴片作为通用型经皮给药系统递送其它药物的应用潜力。

致病菌种类多、耐药菌感染率高和传统外用抗生素治疗效果不够理想等问题，是传统策略难以高效治疗皮肤感染的主要原因。近年来，抗菌肽被认为是最具潜力的抗生素替代品。由于其正电残基可与致病菌带负电的细胞膜产生静电作用，介导抗菌肽与致病菌的结合，所以正电荷是影响其活性的关键性因素之一。把抗菌肽结构设计为星形，可以克服传统线形抗菌肽的结构限制，制备出电荷密度更高且活性更好的抗菌肽。本项目设计了高电荷密度的星形聚赖氨酸作为新型抗菌肽，通过研究其构效关系与体内外杀菌机理，阐明此类抗菌肽的结构优势。同时，由于高电荷密度的聚赖氨酸具备可溶性微针针尖基质材料的结构特点，本项目以其同时作为抗菌药物与针尖主要基质材料，构建高载药量微针用于治疗皮肤感染，通过针尖处方、性能和构效关系研究，阐明此类基质材料的性能影响机理，并探究由其构建的微针贴片作为通用型经皮给药系统递送其它药物的应用潜力。研究发现，采用聚赖氨酸与聚乙烯醇配合可构建针尖力学性能好，皮肤穿刺率高，并且抗菌活性物质载药量高的新型抗菌微针贴片。基于聚赖氨酸的抗菌拟肽能采用类似抗生素的破膜机制实现高效杀菌，同时促进小分子药物的胞内富集，因此抗生素强力霉素与聚赖氨酸显著的协同抗菌效果。值得注意的是，强力霉素负载的聚赖氨酸微针可以实现高效的经皮抗菌药物递送，增加聚赖氨酸在感染部位的滞留，有效降低皮肤MRSA含量99.9%以上，同时不引起明显的毒副作用。该设计在提高抗菌药物的体内治疗效果方面具有较大的潜力，有望为下一代局部抗菌制剂的设计提供新的思路。