Elaborate construction of pH-sensitive polymyxin B loaded nanoparticles for safe and effective treatment of carbapenem-resistant Klebsiella pneumoniae  

作　　者：Wen Zhong Dan Zheng Xukun Liao Yadi Zhou Yan Jiang Ting Gao Ming Li Chengli Yang 

机构地区：[1]Department of Clinical Pharmacy,School of Pharmaceutical Sciences,Guizhou Medical University,Guiyang 550025,China [2]Department of Pharmacy,The Affiliated Hospital of Guizhou Medical University,Guiyang 550004,China [3]Department of Clinical Microbiology and Immunology,School of Clinical Laboratory Science,Guizhou Medical University,Guiyang 550004,China [4]Department of Clinical Laboratory,The Affiliated Hospital of Guizhou Medical University,Guiyang 550004,China

出　　处：《Chinese Chemical Letters》2025年第3期402-406,共5页中国化学快报(英文版)

基　　金：supported by the National Natural Science Foundation of China(Nos.81860543,32360237);Guizhou Provincial Science and Technology Projects(Nos.ZK[2024]235,ZK[2023]Key Project 041).

摘　　要：The escalation in the incidence of multidrug-resistant Gram-negative bacteria is becoming a pressing global concern.Polymyxin B(PMB),a conventional antibiotic with notable therapeutic efficacy against Gram-negative bacterial infections,serves as a crucial final recourse against carbapenem-resistant Klebsiella pneumoniae(CRKP)infections.Nevertheless,the clinical usage of PMB is impeded by its pronounced nephrotoxicity and poor infection site targeting.This investigation is geared to construct a nanoparticle formulation(named HA-PMB@H)comprising hyaluronic acid(HA)and PMB via a simple Schiff base reaction and further coating HA by electrostatic action.HA-PMB@H shows an average size of(153.8±24.3)nm,and a mean zeta potential of(−25.6±5.2)mV.Additionally,PMB can be released from HA-PMB@H more thoroughly and efficiently at pH 5.5 compared to pH 7.4,which demonstrates the Schiff base modification of PMB paves the way for its release at focus of infection.The uptake ratio of HA-PMB@H by alveolar epithelial cells(RLE-6TN)surpassed that of free PMB devoid of HA,which facilitates to the intracellular sterilization of PMB.Furthermore,the employment of HA-PMB@H ameliorated the toxicity of PMB towards human embryonic kidney cells(HEK 293)and pulmonary microvascular endothelial cells(HULEC-5a).What is more,HA-PMB@H effectively managed severe pneumonia induced by CRKP samples from clinical patients diagnosed with CRKP infection in vivo,substantially enhancing the survival rate of mice.Consequently,this nano-delivery system holds promising clinical significance in the combat against drug-resistant bacterial infections.

关 键 词：Polymyxin B pH-sensitive modification Carbapenem-resistant Klebsiella pneumoniae ANTIBACTERIAL Biological security 

分 类 号：R917[医药卫生—药物分析学] R96[医药卫生—药学]