Novel conjugate of moxifloxacin and carboxymethylated glucan with enhanced activity against Mycobacterium tuberculosis
Novel conjugate of moxifloxacin and carboxymethylated glucan with enhanced activity against Mycobacterium tuberculosis
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DOI：
10.1128/aac.00362-05
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发表时间：
2006-06-01
影响因子：
4.9
通讯作者：
Blinov, V. M.
中科院分区：
文献类型：
--
作者：
Schwartz, Y. S.;Dushkin, M. I.;Blinov, V. M.
结核分枝杆菌是一种细胞内病原体，持续存在于人类宿主的巨噬细胞内。改善结核病 (TB) 治疗的一种方法是使用巨噬细胞受体的配体将抗生素靶向递送至巨噬细胞。莫西沙星缀合的丹磺酰化羧甲基葡聚糖 (M-DCMG) 缀合物是通过将丹酰尸胺 (D) 和莫西沙星 (M) 化学连接至羧甲基葡聚糖 (CMG)（巨噬细胞清道夫受体的已知配体）来制备的。在体外和体内研究了缀合物 M-DCMG 向巨噬细胞的靶向递送和抗结核活性。使用荧光显微镜、荧光测定法和 J774 巨噬细胞系，显示 M-DCMG 通过清道夫受体以剂量依赖性（1 至 50 μg/ml）方式在巨噬细胞中积累。 C57BL/6小鼠静脉注射M-DCMG后，荧光缀合物集中在肺和脾的巨噬细胞中。缀合物的药代动力学分析表明，M-DCMG 比游离莫西沙星在组织中积累更快，更持久。重要的是，C57BL/6 小鼠中分枝杆菌生长的治疗研究表明，M-DCMG 缀合物比游离莫西沙星显着更有效。
Mycobacterium tuberculosis is an intracellular pathogen that persists within macrophages of the human host. one approach to improving the treatment of tuberculosis (TB) is the targeted delivery of antibiotics to macrophages using ligands to macrophage receptors. The moxifloxacin-conjugated dansylated carboxymethylglucan (M-DCMG) conjugate was prepared by chemically linking dansylcadaverine (D) and moxifloxacin (M) to carboxymethylglucan (CMG), a known ligand of macrophage scavenger receptors. The targeted delivery to macrophages and the antituberculosis activity of the conjugate M-DCMG were studied in vitro and in vivo. Using fluorescence microscopy, fluorimetry, and the J774 macrophage cell line, M-DCMG was shown to accumulate in macrophages through scavenger receptors in a dose-dependent (I to 50 mu g/ml) manner. After intravenous administration of M-DCMG into C57BL/6 mice, the fluorescent conjugate was concentrated in the macrophages of the lungs and spleen. Analyses of the pharmacokinetics of the conjugate demonstrated that M-DCMG was more rapidly accumulated and more persistent in tissues than free moxifloxacin. Importantly, therapeutic studies of mycobacterial growth in C57BL/6 mice showed that the M-DCMG conjugate was significantly more potent than free moxifloxacin.