Abstract
Chitosan nanoparticles have gained attention as drug delivery systems (DDS) in the medical field as they are both biodegradable and biocompatible with reported antimicrobial and anti-leishmanial activities. We investigated the application of chitosan nanoparticles as a DDS for the treatment of cutaneous leishmaniasis (CL) by preparing two types of chitosan nanoparticles: positively charged with tripolyphosphate sodium (TPP) and negatively charged with dextran sulphate. Amphotericin B (AmB) was incorporated into these nanoparticles. Both types of AmB-loaded nanoparticles demonstrated in vitro activity against Leishmania major intracellular amastigotes, with similar activity to unencapsulated AmB, but with a significant lower toxicity to KB-cells and red blood cells. In murine models of CL caused by L. major, intravenous administration of AmB-loaded chitosan-TPP nanoparticles (Size = 69 ± 8 nm, Zeta potential = 25.5 ± 1 mV, 5 mg/kg/for 10 days on alternate days) showed a significantly higher efficacy than AmBisome® (10 mg/kg/for 10 days on alternate days) in terms of reduction of lesion size and parasite load (measured by both bioluminescence and qPCR). Poor drug permeation into and through mouse skin, using Franz diffusion cells, showed that AmB-loaded chitosan nanoparticles are not appropriate candidates for topical treatment of CL.
Highlights
Cutaneous leishmaniasis (CL) is a neglected tropical disease (NTD), caused by intracellular parasites belonging to the genus Leishmania, which are transmitted among mammals through the bite of female sand flies [1,2]
To translate this activity into an in vivo model of L. major infection, we used chitosan nanoparticles prepared by the ionotropic gelation method as a drug delivery vehicle for amphotericin B (AmB) because chitosan nanoparticles: (i) potentially reduce the toxicity of AmB, improve its efficacy, modulate AmB pharmacokinetics, permit sustainable AmB release at the site of infection and protect the drug from degradation [15,33,38], (ii) have promising features for drug delivery systems (DDS) due to their biocompatibility, biodegradability, controlled drug release, mucoadhesiveness, wound healing and antimicrobial properties [11,12,39] and (iii) have high stability at different temperatures and a simple preparation process [40,41] while other drug carriers, such as liposomal formulations, need the cold chain for stability, have a complex preparation process and can be costly which limits their use [22,27,29]
For the synthesis of chitosan nanoparticles, we selected two crosslinkers: tripolyphosphate sodium (TPP) which resulted in positively charged nanoparticles and dextran sulphate which resulted in negatively charged nanoparticles
Summary
Cutaneous leishmaniasis (CL) is a neglected tropical disease (NTD), caused by intracellular parasites belonging to the genus Leishmania, which are transmitted among mammals through the bite of female sand flies [1,2]. All of the currently available drugs for CL-pentavalent antimonials, the aminoglycoside paromomycin, the alkylphospholipid miltefosine and the polyene antifungal amphotericin B (AmB)—have drawbacks such as, variable cure rates, toxicity and high costs. These limitations highlight the need for novel drugs or formulations that can provide a short, safe, efficacious, affordable and field-adapted treatment for all forms of cutaneous leishmaniasis [5]. The process of developing and discovering new drugs is long (more than 10 years), slow, expensive
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