基于高凝集素亲和性载体的抗生素吸入粉雾剂用于高效治疗细菌生物膜相关肺部感染  

Polymyxin B sulfate inhalable microparticles with high-lectin-affinity sugar carriers for efficient treatment of biofilm-associated pulmonary infections

作　　者：周钥 黄嘉元 王冠林 翟紫照 Maizbha Uddin Ahmed 夏晓 刘岑峰 金玉珍 潘昕 黄莹 吴传斌 张雪娟 Yue Zhou;Jiayuan Huang;Guanlin Wang;Zizhao Zhai;Maizbha Uddin Ahmed;Xiao Xia;Cenfeng Liu;Yuzhen Jin;Xin Pan;Ying Huang;Chuanbin Wu;Xuejuan Zhang(State Key Laboratory of Bioactive Molecules and Druggability Assessment,Jinan University,Guangzhou 510006,China;College of Pharmacy,Jinan University,Guangzhou 510006,China;School of Medicine,Shenzhen Campus of Sun Yat-sen University,Shenzhen 518107,China;School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China;Department of Industrial and Physical Pharmacy,College of Pharmacy,Purdue University,West Lafayette IN 47907,USA)

机构地区：[1]State Key Laboratory of Bioactive Molecules and Druggability Assessment,Jinan University,Guangzhou 510006,China [2]College of Pharmacy,Jinan University,Guangzhou 510006,China [3]School of Medicine,Shenzhen Campus of Sun Yat-sen University,Shenzhen 518107,China [4]School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China [5]Department of Industrial and Physical Pharmacy,College of Pharmacy,Purdue University,West Lafayette IN 47907,USA

出　　处：《Science Bulletin》2023年第24期3225-3239,M0006,共16页科学通报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82104072 and 82373802);the Guangzhou Municipal Science and Technology Project(202201010424)。

摘　　要：多重耐药细菌引发的肺部感染对人类健康构成了严重威胁.细菌生物膜加剧了肺部感染的持续和复发,限制了抗生素的可及性和有效性.基于凝集素竞争策略和颗粒表面修饰策略,本研究设计了一种硫酸多粘菌素B(PMBS)的吸入粉雾剂(DPI)用于治疗肺部感染.该制剂的载体是具有高凝集素亲和性(HLA)的小分子糖(如棉子糖),可靶向细菌凝集素,限制生物膜的扩展.该制剂的粒径约为3μm,其表面褶皱程度和药物与载体的比例有关.处方F_(5)(PMBS:棉子糖=10:90)表现出最高的微细粒子分数(FPF=64.86%),表明其具备显著增强的肺部药物递送效率.通过添加棉子糖,制剂在抑制生物膜形成和清除成熟生物膜方面的效果显著提高.在急性和慢性肺部感染的大鼠模型中,相较于喷雾干燥的PMBS,处方F_(5)表现出更强的抗菌效果,并引起更低炎症反应.综上,基于HLA载体的抗生素DPI具有治疗细菌生物膜相关肺部感染的良好前景.Pulmonary infections caused by multidrug-resistant bacteria have become a significant threat to human health.Bacterial biofilms exacerbate the persistence and recurrence of pulmonary infections,hindering the accessibility and effectiveness of antibiotics.In this study,a dry powder inhalation(DPI)consisting of polymyxin B sulfate(PMBS)inhalable microparticles and high-lectin-affinity(HLA)sugar(i.e.,raffinose)carriers was developed for treating pulmonary infections and targeting bacterial lectins essential for biofilm growth.The formulated PMBS-HLA DPIs exhibited particle sizes of approximately 3 lm,and surface roughness varied according to the drug-to-carrier ratio.Formulation F_(5)(PMBS:raffinose=10:90)demonstrated the highest fine particle fraction(FPF)value(64.86%),signifying its substantially enhanced aerosol performance,potentially attributable to moderate roughness and smallest mass median aerodynamic particle size.The efficacy of PMBS-HLA DPIs in inhibiting biofilm formation and eradicating mature biofilms was significantly improved with the addition of raffinose,suggesting the effectiveness of lectin-binding strategy for combating bacterial biofilm-associated infections.In rat models with acute and chronic pulmonary infections,F_(5) demonstrated superior bacterial killing and amelioration of inflammatory responses compared to spray-dried PMBS(F_(0)).In conclusion,our HLA carrierbased formulation presents considerable potential for the efficient treatment of multidrug-resistant bacterial biofilm-associated pulmonary infections.

关 键 词：Pulmonary infections Polymyxin B Dry powder formulation BIOFILM High-lectin-affinity sugar 

分 类 号：R563.1[医药卫生—呼吸系统]