抗生素自交联纳米胶束用于改善药物毒性和治疗败血症

新型抗菌生物材料能够解决日益增长的抗药性细菌感染问题。多粘菌素是具有强力杀菌能力的抗生素，是治疗细菌感染的最后“杀手锏”，但是它会引起极强的肾毒性和神经毒性。为了利用多粘菌素治疗抗药性细菌感染并且降低药物毒性，我们设计了一种用抗生素本身作交联剂并将其包裹在高分子聚合物普朗尼克胶束中的方法来制备ABC-胶束 (AntiBiotic-Crosslinked Micelles)，该方法具有简单易行、在水相中快速进行等优点。深入研究小分子多粘菌素和其ABC-胶束的最大耐药剂量、肾毒性和神经毒性等生物学参数，利用小鼠动物模型探讨ABC-胶束治疗抗药性细菌感染引起的败血症的效果，阐明多粘菌素-ABC胶束的抗菌机制。本项目的成功实施将为治疗抗药性细菌感染的研究提供理论基础和实验依据，具有重要的科学意义和临床应用前景。

New antibacterial biomaterials and formulations of existing drugs hold potential to address the rising threat of antibiotic resistance. We designed antibiotic-crosslinked micelles (termed ABC-micelles) by crosslinking the Pluronic F127 block copolymers using the antibiotic itself, via a novel one-pot synthesis in aqueous solution. ABC micelles enhanced drug encapsulation and reduced systemic toxicity. Using colistin, a hydrophilic, potent “last-resort” antibiotic, ABC-micelle encapsulation yield will be significantly enhanced with good stability over time. Maximum tolerated dose, colistin-induced nephrotoxicity and neurotoxicity of free colistin and colistin ABC-micelles will be investigated and compared. The antibacterial efficacy of colistin ABC-micelles will be examined in a mouse model of sepsis. Collectively, drug crosslinked micelles show the potential of new biomaterials formed from existing antibiotics, and represent a simple and versatile approach for formulating amine-containing drugs.