Therapeutic effects of dendrimer-based Nano-Fluconazole/Nano-Chitosan in murine cutaneous leishmaniasis: lesion size reduction and mechanistic insights from NMR-based metabolomics

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Abstract Cutaneous leishmaniasis (CL) remains a therapeutic challenge due to drug resistance and the toxicity of conventional treatments. This study developed a dendrimer-based nanostructure conjugating fluconazole with chitosan to enhance therapeutic efficacy. We employed Nuclear Magnetic Resonance (NMR) - based metabolomics to elucidate the underlying mechanism of action. The dendrimer-chitosan-fluconazole nanostructure was characterized using Dynamic Light Scattering (DLS) , Scanning Electron Microscopy (SEM) , and Fourier-Transform Infrared (FTIR) spectroscopy. We evaluated drug loading, release kinetics, and in vitro/in vivo efficacy against Leishmania major . Safety was assessed through cytotoxicity, hematological, biochemical, and histopathological analyses. The nanostructure exhibited uniform morphology with drug-loading efficiencies of 49% (chitosan) and 56% (fluconazole), enabling enhanced solubility and sustained release. The formulation (NFLZ/Chi) displayed potent in vitro activity (IC₅₀ = 13 µg/mL; CI = 0.61) and a 97% reduction in lesion size in a murine model. Metabolomic profiling revealed significant disruptions in amino acid, carbohydrate, and lipid pathways—specifically branched-chain amino acid and glycine/serine/threonine metabolism. Toxicity assays indicated favorable preliminary biocompatibility. This dendrimer-based system shows promising potential for CL management. Metabolomic insights suggest treatment-associated metabolic alterations, warranting further investigation into their biological significance and clinical potential.

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