长循环脂质化策略增强达托霉素抗耐甲氧西林金葡菌全身感染(英文)  

Long-circulating liposomal daptomycin enhances protection against systemic methicillin-resistant Staphylococcus aureus infection with improved therapeutic potential

作　　者：黄兴亮[1] 吴瑾[1] 苏婷婷[1] 李艳红[1] 陈章宝[1] 李翀[1] 

机构地区：[1]西南大学药学院,重庆400716

出　　处：《药学学报》2014年第5期701-710,共10页Acta Pharmaceutica Sinica

基　　金：Project supported by the Program for Innovative Research Teams at the University of Chongqing(2013);the Fundamental Research Funds for Central Universities(XDJK2013A010,A025);the Foundation for University Key Teachers by the Chongqing Municipal Education Commission;the doctoral fund of Southwest University(SWU110028)

摘　　要：随着病原体耐药的控制难度持续增大,除不断研发新型抗生素之外,对已有抗生素进行递送研究与新制剂创制具有同等重要性。达托霉素是近年来上市的一种新型脂肽类抗生素,目前仅有其普通溶液型注射剂用于临床。本文采用聚乙二醇修饰的脂质体作为载体,考察并系统评价经优化制备的长循环达托霉素脂质体(PLD)抗耐甲氧西林金葡菌(MRSA252)全身感染。通过优化制备得到的达托霉素脂质体粒径小[(111.5±15.4)nm]、载药量较高[(5.81±0.19)%],并具有良好稳定性。体内外评价结果显示,在相同剂量下PLD与达托霉素原料药及普通脂质体制剂相比,对MRSA252有更持久的抑制效果,并能显著提高耐甲氧西林金葡菌全身感染模型小鼠的存活率。此外,PLD能显著提高达托霉素在肺部的分布并显示良好的安全性。上述研究结果提示,长循环脂质化达托霉素对抗MRSA严重感染(血源性肺炎等)具有良好的应用前景,可为达托霉素新制剂的研发及临床相关研究提供重要参考。In the face of escalating problems with pathogen control, the development of proper formulations of existing antibiotics is as important as the development of novel antibiotics. Daptomycin is a lipopeptide antibiotic with potent activity against Gram-positive bacteria. Currently, only injectable solution of daptomycin has been approved for clinical use. In the present study, the formulation of PEGylated liposomal daptomycin （PLD） was prepared and optimized, and its efficacy against methicillin-resistant Staphylococcus aureus （MRSA252） strains was investigated. The obtained PLD had a mean vesicle diameter of （111.5 ± 15.4） nm and a mean percent drug loading of （5.81 ± 0.19） % with high storage stability. Potent activity of PLD against MRSA was demonstrated in vitro with a more sustained effect than that of conventional liposomal daptomycin and daptomycin solution. In addition, intravenous administration of a single dose （equal to human use） of PLD significantly increased the survival of mice in a MRSA252 systemic infection model compared with other formulations. Drug distribution in the lung was significantly enhanced following administration of PLD, and no measurable tissue lesions or pathological changes were detected during PLD treatment. Taken together, PEGylated liposomes loaded with daptomycin may represent a promising approach to reduce MRSA252 infections, especially those involving bloodstream dissemination, such as hematogenous pulmonary infection.

关 键 词：达托霉素 长循环脂质体 耐甲氧西林金葡菌 全身感染 

分 类 号：R917[医药卫生—药物分析学]