Development of cationic Isometamidium chloride loaded long-acting lipid nanoformulation: optimization, cellular uptake, pharmacokinetics, biodistribution, and immunohistochemical evaluation

Abstract

The aim of the present work involved the development and evaluation of long-acting Isometamidium chloride (ISMM)-Docusate sodium (DS) complex loaded lipid nanoparticles (LA ISMM-DS LNP). The development involved screening various anionic complexing agents, including DS, dextran sulphate, and sodium alginate. Anionic DS was selected to synthesize hydrophobic ionic complex (ISMM-DS HIC), which was loaded into lipid nanoparticles (LA ISMM-DS LNP) by in situ complexation followed by the solvent evaporation method. 35-5-folds increase in the drug loading of hydrophilic cationic ISMM within nanoparticles was observed due to ISMM-DS HIC. The LA ISMM-DS LNP were non-hemolytic (0–2.52%), cytocompatible (80.6–47.5% cell viability), and enhanced THP-1 cellular uptake (2.3-folds higher) compared with free ISMM. The LA ISMM-DS LNP engender protracted in vivo plasma drug concentration for seven days with enhanced AUC0-ꝏ, MRT0-ꝏ, and t1/2, along with reduced Cl compared with free ISMM. Interestingly, the amount of ISMM was 2.9-, 4.2- and 2.0-folds higher in target reticuloendothelial (RES) organs like liver (Kupffer cells), spleen (spleenotropic macrophages and 15% T-lymphocytes), and lymph nodes (75% T-lymphocytes), respectively in LA ISMM-DS LNP group compared with free ISMM. Furthermore, LA ISMM-DS LNP caused higher peripheral blood mononuclear cells (PBMC) infiltration with diminished toxicity and inflammation. Therefore, the in vitro and in vivo studies predicted enhanced safety and efficacy of LA ISMM-DS LNP compared with free ISMM. To conclude, successfully developed LA ISMM-DS LNP would elicit a tremendous clinical potential for treatment and prevention against trypanosomiasis.