Stearylamine enriched lipid-polymer hybrid nanoparticles of ursolic acid for targeting Leishmania donovani: In-vitro studies

Visceral leishmaniasis (VL) is a systemic parasitic infection resulting from Leishmania species that primarily targets macrophages and leads to fatal organ damage if left untreated. Ursolic acid (UA), a pentacyclic triterpene of natural origin, exhibits potent antileishmanial properties. However, poor aqueous solubility and low bioavailability restrict its clinical potential. Therefore, UA was formulated into stearylamine-enriched lipid polymer hybrid nanoparticles (UA-LPHNPs) composed of polycaprolactone (PCL) as a polymeric core and lipid shell by the nanoprecipitation method. Further, UA-LPHNPs were optimised by the Quality-by- Design (QBD) approach using Box-Behnken Design (BBD). UA-LPHNPs with nanosize and a positive surface charge, provided high colloidal stability, favouring macrophage interaction and intracellular accumulation. Physicochemical characterisation confirmed successful encapsulation of UA and its transformation into an amorphous state. UA-LPHNPs demonstrated sustained drug release and markedly improved in vitro antileishmanial efficacy compared with standard paromomycin in in vitro studies. Molecular docking further demonstrated stable interactions of UA with mannosyl-oligosaccharide glucosidase (MOGS), a key enzyme in Leishmania glycoprotein processing, validating the proposed mechanism of action. In conclusion, UA-LPHNPs warrant further testing in a validated experimental model of VL under robust in vivo parameters for clinical translation.