A polymyxin B loaded hypoxia-responsive liposome with improved biosafety for efficient eradication of bacterial biofilms  

作　　者：Fang Liu Lingyun Zou Yongcheng Chen Zuolong Liu Yue Huang Qiao Jin Jian Ji 

机构地区：[1]MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education,Department of Polymer Science and Engineering,Zhejiang University,Hangzhou 310027,China [2]State Key Laboratory of Transvascular Implantation Devices,The Second Affiliated Hospital Zhejiang University School of Medicine,Hangzhou 310009,China

出　　处：《Nano Research》2024年第9期8325-8336,共12页纳米研究（英文版）

基　　金：supported by the National Natural Science Foundation of China(Nos.52293381 and 52273154);the Key Project of Natural Science Foundation of Zhejiang Province(No.LZ23B040002).

摘　　要：Biofilm-associated bacterial infection brings serious threats to global public health owing to serious antibiotic resistance.It is urgently needed to develop innovative strategies to combat biofilm-associated bacterial infections.Polymyxins stand out as the last line of defense against Gram-negative bacteria.However,serious nephrotoxicity of polymyxins severely limits their clinical utility.Herein,a hypoxia-responsive liposome is designed as the nanocarrier of polymyxin B(PMB)to combat biofilms developed by Gram-negative bacteria.A metronidazole modified lipid(hypoxia-responsive lipid(HRLipid))is synthesized to fabricate hypoxia-responsive liposomes(HRLip).PMB loaded hypoxia-responsive liposomes(HRL-PMB)is then prepared to mitigate the nephrotoxicity of PMB while preserving its excellent bactericidal activity.HRL-PMB shows very low hemolysis and cytotoxicity due to liposomal encapsulation of PMB.PMB can be readily released from HRL-PMB in response to hypoxic biofilm microenvironment,exerting its bactericidal activity to realize biofilm eradication.The excellent in vivo antibiofilm ability of HRL-PMB is confirmed by a Pseudomonas aeruginosa infected zebrafish model and a P.aeruginosa pneumonia infection model.Meanwhile,HRL-PMB can greatly reduce the nephrotoxicity of PMB after intravenous injection.The hypoxia-sensitive liposomes held great promise to improve the biosafety of highly toxic antibiotics while preserving their intrinsic bactericidal ability,which may provide an innovative strategy for combating biofilm-associated infections.

关 键 词：bacterial biofilm HYPOXIA LIPOSOME polymyxin B NEPHROTOXICITY 

分 类 号：Q73[生物学—分子生物学]