Carvalheiro Manuela, Esteves M Alexandra, Santos-Mateus David, Lopes Rui M, Rodrigues M Armanda, Eleutério Carla V, Scoulica Effie, Santos-Gomes Gabriela, Cruz M Eugénia M
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
Solar Energy Unit, National Laboratory for Energy and Geology (LNEG), Estrada do Paço do Lumiar, 1649-038 Lisbon, Portugal.
Eur J Pharm Biopharm. 2015 Jun;93:346-52. doi: 10.1016/j.ejpb.2015.04.018. Epub 2015 May 1.
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.
利什曼病是一种由利什曼原虫引起的媒介传播寄生虫病，在药物研发方面是最被忽视的热带疾病之一。目前的治疗基于有限的几种化疗药物，所有这些药物都存在耐药性问题、严重毒性以及与延长治疗方案相关的不良反应，且治疗成本高昂。二硝基苯胺是一类新的药物，已证实具有体外抗利什曼原虫活性。在先前的研究中，发现一种二硝基苯胺（TFL）的脂质体制剂在内脏利什曼病（VL）的小鼠模型以及实验性犬利什曼病的治疗中对利什曼原虫具有活性。在本研究中，我们研究了与脂质体相关的二硝基苯胺类似物（TFL-A）的用途，作为进一步提高TFL抗利什曼原虫活性的手段。在体外评估了脂质体制剂对婴儿利什曼原虫前鞭毛体和细胞内无鞭毛体的活性，并在动物源性VL的小鼠模型中进行了体内评估。游离和脂质体形式的TFL-A在体外对利什曼原虫具有活性，并且它们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治疗感染小鼠可使脾脏中的无鞭毛体负荷降低高达97%。这些发现表明化学合成新分子并结合使用天然靶向患病器官的纳米药物递送系统可能是有效管理VL的一种有前景的策略。
