High-performance lung-targeted bio-responsive platform for severe colistin-resistant bacterial pneumonia therapy  

作　　者：Decui Cheng Rui Tian Tingting Pan Qiang Yu Li Wei Jiaozhi Liyin Yunqi Dai Xiaoli Wang Ruoming Tan Hongping Qu Min Lu 

机构地区：[1]Department of Critical Care Medicine,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,197 Ruijin Er Road,Shanghai,200025,China [2]Department of Orthopaedics,Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases,Shanghai Institute of Traumatology and Orthopaedics,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China

出　　处：《Bioactive Materials》2024年第5期517-533,共17页生物活性材料（英文）

基　　金：supported by the Natural Science Foundation of Shanghai[grant number 23ZR1456800];the Interdisciplinary Program of Shanghai Jiao Tong University[grant number YG2021ZD07];the Science and Technology Commission of Shanghai Municipality[grant number 20Y11901100];the Clinical Science and Technology Innovation Project of SHCD[grant number SHDC22021212];the National Natural Science Foundation of China[grant number 82002188];the Scientific Research Project Plan of Shanghai Municipal Health Commission[grant number 20204Y0145];the Guangci Discipline Group Construction of Public Health and Disaster Emergency Center[grant number XKQ-09].

摘　　要：Polymyxins are the last line of defense against multidrug-resistant(MDR)Gram-negative bacterial infections.However,this last resort has been threatened by the emergence of superbugs carrying the mobile colistin resistance gene-1(mcr-1).Given the high concentration of matrix metalloproteinase 3(MMP-3)in bacterial pneumonia,limited plasma accumulation of colistin(CST)in the lung,and potential toxicity of ionic silver(Ag+),we designed a feasible clinical transformation platform,an MMP-3 high-performance lung-targeted bio-responsive delivery system,which we named“CST&Ag@CNMS”.This system exhibited excellent lung-targeting ability(>80%in lungs),MMP-3 bio-responsive release property(95%release on demand),and synergistic bactericidal activity in vitro(2-4-fold minimum inhibitory concentration reduction).In the mcr-1+CST-resistant murine pneumonia model,treatment with CST&Ag@CNMS improved survival rates(70%vs.20%),reduced bacteria burden(2-3 log colony-forming unit[CFU]/g tissue),and considerably mitigated inflammatory response.In this study,CST&Ag@CNMS performed better than the combination of free CST and AgNO3.We also demonstrated the superior biosafety and biodegradability of CST&Ag@CNMS both in vitro and in vivo.These findings indicate the clinical translational potential of CST&Ag@CNMS for the treatment of lung infections caused by CST-resistant bacteria carrying mcr-1.

关 键 词：Colistin-resistant bacteria MCR-1 Lung targeting Matrix metalloproteinase 3 Synergistic action Bacterial severe pneumonia 

分 类 号：R563[医药卫生—呼吸系统]