Leishmanicidal Activity of a Hydrazone Derivative Loaded into Nanocarrier Systems.

Abstract

Visceral leishmaniasis (VL) is a neglected parasitic disease whose treatment is limited by parasite resistance, drug toxicity, and high costs. Seeking safer and more effective therapies, we evaluated the hydrazone derivative LASSBio-1736, a cysteine protease inhibitor hydrazone derivative, which demonstrated plasma stability and low initial hepatic and renal toxicity, focusing on its oral delivery in bovine serum albumin nanoparticles (LASSBio-1736n). An HPLC-UV method was validated for quantitative analysis in biological samples, showing high sensitivity, precision, and linearity. Standardized in vitro digestion (INFOGEST) and Caco-2 assays demonstrated enhanced bioaccessibility and intestinal permeability of the nanoformulation. In the INFOGEST model, LASSBio-1736n maintained structural integrity and drug content, with a 239.7% increase between gastric and intestinal phases compared to the free compound (LASSBio-1736f). Caco-2 assays further confirmed higher apparent permeability, supporting improved oral absorption. In vivo efficacy was evaluated in golden hamsters ( Mesocricetus auratus ) infected with Leishmania (L.) infantum chagasi . Animals treated orally with LASSBio-1736n (12.5 mg/kg/day for 10 days) showed a significant reduction (85.48%) in splenic parasite burden compared to Glucantime. This effect was associated with cytokine modulation (increased IL-10 and reduced IFN-γ) and histopathological improvement, including reduced granuloma area, balanced parenchyma/interstitium ratio, and normalized hepatocyte glycogen distribution. LASSBio-1736f showed milder effects, whereas Glucantime induced a stronger pro-inflammatory response. Overall, these findings demonstrate that albumin-based nanocarriers enhance the in vivo efficacy of LASSBio-1736 and support its development as a promising orally deliverable therapy for VL.