Veerareddy Prabhakar Reddy, Vobalaboina Venkateswarlu, Ali Nahid
University College of Pharmaceutical Sciences, Kakatiya University, Warangal, India.
J Drug Target. 2009 Feb;17(2):140-7. doi: 10.1080/10611860802528833.
Leishmania parasite resides mainly in the liver and the spleen and multiplies. Effective therapy of leishmaniasis could be achieved by delivering antileishmanial drugs to these sites. Present investigations were aimed at developing lipid nanospheres of amphotericin B (LN-A) anchored with mannose to achieve targeted delivery to the liver. Mannose is specifically involved in the recognition of parasite or appropriate ligands on the macrophage surface LN-A, and mannose-anchored lipid nanospheres (LN-A-MAN) were prepared by homogenization followed by ultrasonication method. Particle size and zeta potential were measured using Malvern Zetasizer. The average particle size after sterilization of LN-A and LN-A-MAN ranged from 193.4 +/- 1.1 to 775.8 +/- 9.1. Leishmaniasis was induced in BALB/c mice by injecting Leishmania donovani parasites intravenously. Infected mice were administered with a single dose (5 mg/kg body weight) of LN-A, LN-A-MAN, and Fungizone (marketed product).The efficacy of the formulations was evaluated by measuring the reduction in parasite burden. Fungizone reduced 82 and 69%, LN-A reduced 90 and 85%, LN-A-MAN reduced 95 and 94% of parasite burden in the liver and the spleen, respectively. LN-A and LN-A-MAN-treated mice did not show any elevation in serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), urea, and creatinine levels as compared with Fungizone. Pharmacokinetic parameters were estimated and the concentration of amphotericin B (AmB) in mice plasma declined biexponentially and AmB concentrations were significantly higher for LN-A- and LN-A-MAN than Fungizone-treated mice (P < 0.05). Tissue distribution patterns were studied in different tissues such as the liver, the spleen, the kidney, and the brain of BALB/c mice. LN-A-MAN was found to distribute more rapidly to the liver and the spleen explaining the reason for higher antileishmanial activity.
利什曼原虫主要寄居于肝脏和脾脏并进行繁殖。通过将抗利什曼原虫药物输送到这些部位，可以实现对利什曼病的有效治疗。目前的研究旨在开发用甘露糖锚定的两性霉素B脂质纳米球（LN-A），以实现对肝脏的靶向递送。甘露糖特异性参与寄生虫或巨噬细胞表面LN-A上适当配体的识别，通过匀浆后超声处理的方法制备了甘露糖锚定的脂质纳米球（LN-A-MAN）。使用马尔文Zetasizer测量粒径和zeta电位。LN-A和LN-A-MAN灭菌后的平均粒径范围为193.4±1.1至775.8±9.1。通过静脉注射杜氏利什曼原虫在BALB/c小鼠中诱导利什曼病。给感染的小鼠单次给药（5mg/kg体重）的LN-A、LN-A-MAN和两性霉素B注射剂（市售产品）。通过测量寄生虫负荷的降低来评估制剂的疗效。两性霉素B注射剂分别降低了肝脏和脾脏中82%和69%的寄生虫负荷，LN-A降低了90%和85%，LN-A-MAN分别降低了95%和94%。与两性霉素B注射剂相比，LN-A和LN-A-MAN处理的小鼠血清谷丙转氨酶（SGPT）、碱性磷酸酶（ALP）、尿素和肌酐水平没有任何升高。估计了药代动力学参数，小鼠血浆中两性霉素B（AmB）的浓度呈双指数下降，LN-A和LN-A-MAN处理的小鼠的AmB浓度显著高于两性霉素B注射剂处理的小鼠（P<0.05）。在BALB/c小鼠的肝脏、脾脏、肾脏和大脑等不同组织中研究了组织分布模式。发现LN-A-MAN更快地分布到肝脏和脾脏，这解释了其更高抗利什曼原虫活性的原因。
