Nanodisk-associated amphotericin B clears Leishmania major cutaneous infection in susceptible BALB/c mice
Nanodisk-associated amphotericin B clears Leishmania major cutaneous infection in susceptible BALB/c mice
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DOI：
10.1128/aac.50.4.1238-1244.2006
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发表时间：
2006-04-01
影响因子：
4.9
通讯作者：
Titus, R
中科院分区：
文献类型：
--
作者：
Nelson, KG;Bishop, JV;Titus, R
检测了含有毒性和难溶性抗利什曼原虫药物阿朴霉素B（AMB）的纳米级载脂蛋白稳定磷脂双层圆盘复合物（nanodisks [ND]）治疗感染硕大利什曼原虫的BALB B/c小鼠（小家鼠）的疗效。L.将主要感染的小鼠腹膜内（i. p.）在两个实验中，在感染后24 h、48 h和4、7、14和21 d，以0、1和5 mg/kg剂量AMB-ND处理。L.在一个实验中，在感染后24小时、48小时和10天、20天、30天和40天，用磷酸盐缓冲盐水、5 mg/kg AMB-ND或5 mg/kg脂质相关的阿替西汀B（脂质体阿替西汀B，AmBisome）腹膜内处理重度感染的小鼠。在感染后第7、15、210、50、140和250天或第14、30、50、95和140天测定寄生虫数量、足垫病变大小进展和细胞因子反应的发展。以1或5 mg/kg剂量给予AMB-ND的小鼠对L.主要表现为病变大小和寄生虫负荷减少，特别是在5 mg/kg剂量水平。与腹腔注射AmBisome组相比，腹腔注射AMB-ND的BALB/c小鼠完全清除了L.在感染后140至250天内出现严重感染，没有病变残留，也没有从感染动物中分离出寄生虫。与对照组相比，AMB-ND给药后再刺激的混合淋巴细胞培养细胞因子应答（白细胞介素-4 [IL-4]、IL-12、IL-10、NO和γ干扰素）未发生变化。利什曼原虫从易感小鼠品系中的显著清除，而细胞因子反应无明显变化，表明AMB-ND是治疗组织细胞内微生物的潜在有用制剂。
Nanometer-scale, apolipoprotein-stabilized phospholipid bilayer disk complexes (nanodisks [ND]) harboring the toxic and poorly soluble antileishmanial agent amphotericin B (AMB) were examined for efficacy in treatment of Leishmania major-infected BALB/c mice (Mus musculus). L. major-infected mice were intraperitoneally (i.p.) treated with AMB-ND in 0-, 1-, and 5-mg/kg doses at 24 h, 48 h, and 4, 7, 14, and 21 days postinfection in two experiments. L. major-infected mice were i.p. treated with phosphate-buffered saline, 5 mg/kg AMB-ND, or 5 mg/kg lipid-associated amphotericin B (liposomal amphotericin B, AmBisome) at 24 h, 48 h, and 10, 20, 30, and 40 days postinfection in one experiment. Parasite numbers, footpad lesion size progression, and development of cytokine responses were assayed at days 7, 15, 210, 50, 140, and 250 or at days 14, 30, 50, 95, and 140 postinfection. Mice administered AMB-ND in 1- or 5-mg/kg doses were significantly protected from L. major, displaying decreases in lesion size and parasite burden, particularly at the 5-mg/kg dosage level. In contrast to the i.p. treated AmBisome group, BALB/c mice treated with i.p. AMB-ND completely cleared an L. major infection by 140 to 250 days postinfection, with no lesions remaining and no parasites isolated from infected animals. Restimulated mixed lymphocyte culture cytokine responses (interleukin-4 [IL-4], IL-12, IL-10, NO, and gamma interferon) were unchanged by AMB-ND administration compared to controls. The marked clearance of Leishmania parasites from a susceptible strain of mice without an appreciable change in the cytokine response suggests that AMB-ND represent a potentially useful formulation for treatment of intrahistiocytic organisms.