自适应球形聚多肽纳米颗粒用于细菌感染的成像与治疗

细菌感染主要由生物被膜所造成，并严重威胁人类健康。发展可以在生物被膜内部渗透和停留，选择性杀灭细菌的药物对于感染治疗至关重要。具有α-螺旋的线性阳离子聚多肽具有很好的杀菌能力，但其细胞毒性大，生物被膜渗透性差，严重限制了其在感染治疗中的应用。本项目拟研究一种自适应球形聚多肽纳米颗粒，通过聚多肽二级结构转变来实现生物被膜感染的选择性成像与治疗。拟开展的研究包括：（1）由金纳米颗粒引发合成季胺化聚多肽纳米颗粒，调控聚多肽中季铵盐基团的亲疏水性、芳香性等参数，优化聚多肽纳米颗粒的破膜杀菌性能；（2）在季胺化聚多肽链段中引入感染微环境敏感的负电荷基团构筑自适应纳米颗粒，实现其生物被膜渗透以及选择性破膜杀菌；（3）在聚多肽末端引入荧光基团，通过聚多肽二级结构转变来调控荧光的FRET效应，实现对细菌生物被膜感染的特异性成像。本研究可为设计安全高效的细菌生物被膜感染成像和杀灭体系提供理论和科学依据。

Bacterial infections are mainly caused by biofilms and seriously threaten human health. Developing strategies that penetrate and remain inside the biofilms, and selectively kill bacteria is crucial for infection treatment. Linear cationic polypeptides with α-helix structures possess excellent bactericidal activity, but their cytotoxicity and poor permeability in biofilms severely limit their application in treatment of infections. This project intends to develop the self-adaptive, spherical polypeptide nanoparticles (SASP-NPs), which can selectively image and treat the biofilm-associated infections through the transformation of the secondary structure of the polypeptides. Proposed researches include: (1) synthesis of the polypeptide nanoparticle containing quaternary ammonium groups initiated by the gold nanoparticle, optimizing the bactericidal performance of polypeptide nanoparticles by adjusting the parameters, i.e. hydrophobicity and aromaticity, of quaternary ammonium groups, (2) introducing the infection microenvironment-sensitive, negatively-charged domains into the cationic polypeptides to achieve biofilm penetration and bactericidal selectivity, and (3) anchoring a fluorophore at the end of the polypeptide, and the FRET effect of between the fluorophore and gold core will be regulated by the secondary structure transformation of the polypeptide, thereby achieving specific imaging of biological membrane infection. Therefore, this study can provide theoretical and scientific basis for designing a safe and efficient imaging and killing system for biofilm-associated infections.