Hemisynthetic trifluralin analogues incorporated in liposomes for the treatment of leishmanial infections
Hemisynthetic trifluralin analogues incorporated in liposomes for the treatment of leishmanial infections
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DOI：
10.1016/j.ejpb.2015.04.018
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发表时间：
2015-06-01
影响因子：
4.9
通讯作者：
Cruz, M. Eugenia M.
中科院分区：
文献类型：
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作者：
Carvalheiro, Manuela;Alexandra Esteves, M.;Cruz, M. Eugenia M.
利什曼病是一种由利什曼原虫引起的媒介传播寄生虫病，是药物发现和开发方面最被忽视的热带疾病之一。目前的治疗基于有限数量的化疗药物，所有这些药物都存在耐药性问题、与延长治疗方案相关的严重毒性和不良反应以及高昂的治疗成本。二硝基苯胺类药物是一类新型药物，已被证明具有体外抗利什曼活性。在之前的工作中，发现一种二硝基苯胺（TFL）的脂质体制剂对内脏利什曼病（VL）鼠模型中的利什曼原虫寄生虫具有活性，并且在治疗实验性犬利什曼病中具有活性。在这项研究中，我们研究了与脂质体相关的二硝基苯胺类似物 (TFL-A) 的使用，作为进一步提高 TFL 抗利什曼活性的方法。体外评估了脂质体制剂对抗婴儿利什曼原虫前鞭毛体和细胞内无鞭毛体的潜力，并在体内人畜共患 VL 小鼠模型中评估了脂质体制剂的潜力。游离 TFL-A 和脂质体 TFL-A 在体外具有抗利什曼原虫寄生虫的活性，并且还表现出降低的细胞毒性和溶血活性。与未治疗的对照组相比，用脂质体 TFL-A 治疗受感染的小鼠，脾脏中的无鞭毛体负荷减少了 97%。这些发现表明，与使用自然靶向患病器官的纳米药物输送系统相关的新分子的化学合成可能是有效管理 VL 的有前途的策略。 (C) 2015 Elsevier B.V. 保留所有权利。
Leishmaniasis, a vector-borne parasitic disease caused by Leishmania protozoa, is one of the most neglected tropical diseases in terms of drug discovery and development. Current treatment is based on a limited number of chemotherapeutic agents all of which present either/or resistance issues, severe toxicities and adverse reactions associated with extended treatment regimens, and high cost of therapy. Dinitroanilines are a new class of drugs with proven in vitro antileishmanial activity. In previous work a liposomal formulation of one dinitroaniline (TFL) was found to be active against Leishmania parasites in a murine model of visceral leishmaniasis (VL) and in the treatment of experimental canine leishmaniasis. In this study we have investigated the use of dinitroaniline analogues (TFL-A) associated to liposomes, as means to further improve TFL antileishmanial activity. The potential of the liposomal formulations was assessed in vitro against Leishmania infantum promastigotes and intracellular amastigotes and in vivo in a murine model of zoonotic VL. Free and liposomal TFL-A were active in vitro against Leishmania parasites, and they also exhibited reduced cytotoxicity and haemolytic activity. Treatment of infected mice with liposomal TFL-A reduced the amastigote loads in the spleen up to 97%, compared with the loads for untreated controls. These findings illustrate that chemical synthesis of new molecules associated with the use of Nano Drug Delivery Systems that naturally target the diseased organs could be a promising strategy for effective management of VL. (C) 2015 Elsevier B.V. All rights reserved.