WHEN NANOMEDICINE MEETS NEGLECTED TROPICAL DISEASES

Neglected tropical diseases (NTDs) are a diverse group of conditions caused by a variety of pathogens and associated with devastating health, social and economic consequences. NTDs are mainly prevalent among impoverished communities in tropical areas, with often limited access to available treatments. Existing medications are generally scarce, old, and toxic, often requiring prolonged and parenteral treatments. Enhancing existing drugs through novel drug delivery approaches, particularly those based on nanotechnology, can address the urgent need for new treatments. A good example is AmBisome, a liposomal formulation of amphotericin B (AmB), which showed improved pharmacokinetic and toxicity profiles compared to deoxycholate-AmB formulation. However, the high cost of AmBisome and its low bioavailability via oral and topical routes still limit its use against NTDs. To overcome these limitations, our group recently developed new processes and lipid compositions for incorporation of AmB into liposomes, aiming to manipulate the drug aggregation state, obtain a simple and scalable process, and achieve nanoformulations with high stability and enhanced bioavailability via oral and topical routes. Three different liposomal AmB formulations for parenteral, oral and topical administrations have been obtained and characterized by DLS, cryo-TEM, SAXS, circular dichroism, HPLC and LC-MS. The pharmacokinetic of the parenteral formulation was determined following intravenous administration in mice. These formulations were finally evaluated for their therapeutic efficacy in rodent models of cutaneous (CL) and visceral leishmaniasis (VL), as well as in a murine model of sporotrichosis (EPT). In the three formulations, liposomes were essentially unilamellar and monodisperse, with mean diameter below 150 nm, and AmB encapsulation efficiencies exceeding 90%. All formulations showed less aggregated AmB and faster drug release, compared to AmBisome. The parenteral liposomal formulation demonstrated more prolonged plasma drug levels than AmBisome and greater efficacy than AmBisome in CL and VL, although it exhibited higher toxicity. The oral formulation demonstrated efficacy equivalent to that of parenteral AmBisome in reducing parasite burden in the liver and spleen in the VL model, as well as good efficacies against CL and EPT, with no signs of toxicity. The topical liposomal formulation also showed high efficacy in reducing parasite load and lesion size in CL.