Leishmanicidal Activity of a Hydrazone Derivative Loaded into Nanocarrier Systems

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.