Improved antileishmanial activity and cytotoxicity of a novel nanotherapy for N-iodomethyl-N,N-dimethyl-N-(6,6-diphenylhex-5-en-1-yl) ammonium iodide

The N-iodomethyl-N, N-Dimethyl-N-(6,6-diphenylhex-5-en-1-yl) ammonium iodide (C6I) is a new chemical entity (NCE) with demonstrated in vitro and in vivo antileishmanial activity. As many others NCE, C6I is poorly water soluble (Class II of the Biopharmaceutical Classification System), thus its oral administration is potentially compromised. To overcome the issue, nanotechnology is a real and useful tool. Moreover, nanotechnology can improve C6I internalization by macrophages, the drug targets, therefore increasing its antileishmanial activity. The present work aimed to develop a potential suitable oral nanodrug delivery system for C6I to improve its antileishmanial activity. For this purpose, polymeric and solid lipid nanoparticles were developed. Polylactic-co-glycolic acid polyester (PLGA) were prepared by nanoprecipitation while solid lipid nanoparticles made of glycerol tripalmitate (Trp) and glyceryl tristearate (Trs) were obtained by emulsion-solvent evaporation method. Physicochemical characterization of all formulations was performed, as well as stability studies. A lyophilization procedure was also established. Biological activity was evaluated by antileishmanial activity and cytotoxicity in vitro assays. Five types of commercial PLGA to encapsulate C6I were tested. The best results were obtained using PLGA 7525 and n-alpha-Tocopheryl polyethylene glycol 1000 succinate (TPGS), the water-soluble form of vitamin E. Particles around 220 nm in diameter and encapsulation efficiency (EE) up to 60% were obtained. Solid lipid nanoparticles based on Trs and Trp lipids were also in the nanoscale showing a low polydispersity index and EE% >60%. Both types of nanoformulations, polymeric and lipidic, thd C6I cytotoxicity in human and hamster macrophages cell cultures. In vitro assays with PLGA loaded-C6I showed a noticeable improved antileishmanial activity on intracellular amastigotes of L. (V.) panamensis, with the following EC50 values: PLGA < Trs-SLN free C6I < Trp-SLN. In conclusion, PLGA nanoformulation could be a suitable candidate for preclinical evaluation in animal model.

Automated summary

The study aimed to develop a suitable oral nano drug delivery system for C6I to enhance its antileishmanial activity. Polymeric and solid lipid nanoparticles were prepared using nanotechnology, showing good biocompatibility and high encapsulation efficiency.