Lanza Juliane S, Vallejos Virginia M R, Ramos Guilherme S, de Oliveira Ana Carolina B, Demicheli Cynthia, Rivas Luis, Pomel Sébastien, Loiseau Philippe M, Frézard Frédéric
Faculty of Pharmacy, Antiparasite Chemotherapy, UMR 8076 CNRS BioCIS, University Paris-Saclay, F-92296 Chatenay-Malabry, France.
Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, MG, Brazil.
Pharmaceutics. 2022 Aug 21;14(8):1743. doi: 10.3390/pharmaceutics14081743.
This work aims to evaluate whether nanoassemblies (NanoSb) made from antimony(V) complexes with octanoyl--methylglucamide (SbL8) or decanoyl--methylglucamide (SbL10) would effectively target the infection sites in visceral and cutaneous leishmaniases (VL and CL). NanoSb were investigated regarding stability at different pHs, accumulation of Sb in the macrophage host cell and liver, and in vitro and in vivo activities in models of leishmaniasis. The kinetic stability assay showed that NanoSb are stable at neutral pH, but release incorporated lipophilic substance after conformational change in media that mimic the gastric fluid and the parasitophorous vacuole. NanoSb promoted greater accumulation of Sb in macrophages and in the liver of mice after parenteral administration, when compared to conventional antimonial Glucantime. SbL10 was much more active than Glucantime against intramacrophage amastigotes and less cytotoxic than SbL8 against macrophages. The in vitro SbL10 activity was further enhanced with co-incorporated miltefosine. NanoSb showed high antileishmanial activity in the murine VL after parenteral administration and moderate activity in the murine CL after topical treatment. This study supports the ability of NanoSb to effectively deliver a combination of Sb and co-incorporated drug to host cell and infected tissues, in a better way than Glucantime does.
这项工作旨在评估由五价锑与辛酰基 - 甲基葡糖酰胺（SbL8）或癸酰基 - 甲基葡糖酰胺（SbL10）形成的纳米组装体（NanoSb）是否能有效靶向内脏利什曼病和皮肤利什曼病（VL和CL）的感染部位。研究了NanoSb在不同pH值下的稳定性、锑在巨噬细胞宿主细胞和肝脏中的积累情况，以及在利什曼病模型中的体外和体内活性。动力学稳定性测定表明，NanoSb在中性pH下稳定，但在模拟胃液和寄生泡的介质中发生构象变化后会释放掺入的亲脂性物质。与传统抗锑药物葡甲胺相比，NanoSb经肠胃外给药后能促进锑在小鼠巨噬细胞和肝脏中更多地积累。SbL10对巨噬细胞内无鞭毛体的活性比葡甲胺高得多，且对巨噬细胞的细胞毒性比SbL8小。同时掺入米替福新可进一步增强SbL10的体外活性。NanoSb经肠胃外给药后在小鼠VL模型中表现出高抗利什曼活性，经局部治疗后在小鼠CL模型中表现出中等活性。这项研究支持了NanoSb能够比葡甲胺更好地将锑和同时掺入的药物有效地递送至宿主细胞和感染组织的能力。
