Long-Circulating Liposomes Codelivering Amphotericin B and Retinoic Acid for Cutaneous Leishmaniasis Treatment

Area of Science:

• Pharmacology
• Drug Delivery Systems
• Immunology

Background:

• Leishmaniasis is a neglected tropical disease with limited treatment options, particularly for cutaneous leishmaniasis (CL).
• Conventional amphotericin B formulations like AmBisome have efficacy limitations in CL and immunocompromised patients.
• Retinoic acid (RA) can act as an immunomodulator, potentially enhancing treatment outcomes.

Purpose of the Study:

• To evaluate a novel PEGylated liposomal formulation (LAmB-RA) co-encapsulating amphotericin B (AmB) and retinoic acid (RA) for cutaneous leishmaniasis (CL) treatment.
• To assess the physicochemical properties, pharmacokinetics, in vivo efficacy, and immunomodulatory effects of LAmB-RA.

Main Methods:

• Characterization of LAmB-RA liposomes (size, polydispersity, encapsulation efficiency).
• Analysis of AmB aggregation state and hemolytic activity.
• Pharmacokinetic studies in mice comparing LAmB-RA with AmBisome.
• In vivo efficacy assessment in Leishmania major and Leishmania amazonensis infected mouse models.
• Evaluation of immune response (IFN-γ/IL-10 ratio) in splenocytes.

Main Results:

• LAmB-RA exhibited favorable physicochemical properties with high encapsulation efficiencies for AmB and RA.
• LAmB-RA demonstrated reduced hemolytic activity and superior pharmacokinetic profile (higher Cmax, prolonged exposure) compared to AmBisome.
• Significant reduction in lesion size and parasite burden (up to 99%) was observed in L. major infected mice.
• Marked inhibition of lesion progression and significant reduction in splenic parasite load (60%) occurred in L. amazonensis infected mice.
• LAmB-RA promoted a Th1-skewed immune response, indicated by an increased IFN-γ/IL-10 ratio.

Conclusions:

• LAmB-RA represents a promising therapeutic strategy for cutaneous leishmaniasis.
• The formulation combines prolonged drug circulation with enhanced efficacy and immunomodulatory properties.
• Further investigation is warranted to explore its clinical potential for leishmaniasis treatment.