Lymphatic-targeted amphotericin B nanocrystals delivered using microarray patches applied to cutaneous leishmaniasis

Abstract

Leishmaniasis, a parasitic disease transmitted by female sandflies, primarily affects impoverished populations in tropical and subtropical regions. Cutaneous leishmaniasis (CL) is the most prevalent form, with over 600,000 new cases annually. Leishmania parasites spread via the lymphatic system, leading to disease progression. Amphotericin B (AmB) has shown efficacy against Leishmania spp, yet causes renal toxicity and requires intravenous administration, posing challenges in resource-limited settings. This study explores intradermal delivery of AmB nanocrystals (NCs) via dissolving microarray patches (MAPs) to enhance lymphatic uptake. AmB-NCs were formulated using media milling, achieving a mean particle size of 108 ± 4 nm. In vitro studies showed faster dissolution and potent antileishmanial activity with lower host cell toxicity. Ex vivo studies demonstrated MAP-mediated intradermal drug deposition of 247 ± 25 μg/0.49 cm². In vivo rat studies revealed MAPs achieved 3.2-fold and 2.8-fold higher AmB accumulation in axillary and lumbar lymph nodes, respectively, compared to the commercial formulation IV AmBisome® (p < 0.05). Reduced liver, spleen and kidney accumulation suggests lower organ toxicity. AmB-NCs MAPs present a promising, minimally invasive alternative for CL treatment, enhancing lymphatic targeting while reducing healthcare burdens, addressing key barriers to effective treatment.

Keywords: Intradermal; Media milling; Nanocrystals-in-microneedles; Nanosuspensions; Neglected diseases; Poorly soluble drugs.