Accelerated healing of cutaneous leishmaniasis in non-healing BALB/c mice using water soluble amphotericin B-polymethacrylic acid

Abstract

Cutaneous leishmaniasis (CL) is a neglected tropical disease that causes prominent skin scaring. No water soluble, non-toxic, short course and low cost treatment exists. We developed a new water soluble amphotericin B-polymethacrylic acid (AmB-PMA) using established and scalable chemistries. AmB-PMA was stable for 9 months during storage. In vitro, it was effective against Leishmania spp. promastigotes and amastigote infected macrophages. It was also less toxic and more effective than deoxycholate-AmB, and similar to liposomal AmB. Its in vivo activity was determined in both early and established CL lesion models of Leishmania major infection in genetically susceptible non-healing BALB/c mice. Intradermal AmB-PMA at a total dose of 18 mg of AmB/kg body weight led to rapid parasite killing and lesion healing. No toxicity was seen. No parasite relapse occurred after 80 days follow-up. Histological studies confirmed rapid parasite clearance from macrophages followed by accelerated fibroblast mediated tissue repair, regeneration and cure of the infection. Quantitative mRNA studies of the CL lesions showed that accelerated healing was associated with increased Tumor Necrosis Factor-α and Interferon-γ, and reduced Interleukin-10. These results suggest that a cost-effective AmB-PMA could be used to pharmacologically treat and immunotherapeutically accelerate the healing of CL lesions.

Surface-Engineered Dendrimeric Nanoconjugates for Macrophage-Targeted Delivery of Amphotericin B: Formulation Development andIn VitroandIn VivoEvaluation

“…In general, the surface-conjugated dendrimers displayed more biocompatible behavior than the plain PPI dendrimers, probably due to the shielding/masking of cationic charge at the surfaces of PPI dendrimers by the attached mannose ligands. Our results for hematological toxicity of AmB are in accordance with previous reports in which AmB elicited dose-dependent toxicity toward the hematopoietic system (29,36,37).…”

“…It was proposed that AmB may bind to low-density lipoproteins (LDL), and there are large numbers of renal LDL receptors that mediate the cellular uptake of AmB. This interaction of AmB, LDL, and renal receptors is believed to be a major contributor to the dose-limiting nephrotoxicity of AmB (5,37). The low renal toxicity of the MPPIA formulation can possibly be attributed to selective delivery of AmB to macrophages, with a reduced distribution of AmB to the kidneys of mice treated with surface-engineered dendrimeric formulations of AmB (28,36).…”

Self-assembled amphotericin B-loaded polyglutamic acid nanoparticles: preparation, characterization and in vitro potential against Candida albicans

“…[40][41][42][43][44][45][46][47][48] In some of the earlier efforts, polymers synergized the toxicity of AmB, 49 while in others the AmB was unable to retain the beneficial physicochemical properties associated with its liposomal form (AmB-L). 50 Although, AmB-cyclodextrin complexes showed improved water solubility, 49,51 they were found to be toxic to human red blood cells. 52,53 On the other hand, polyvinylpyrrolidone has been shown to complex AmB, but suffers from very low (0.249% w/w) AmB loading.…”

Perspective: Dendrimer drugs for infection and inflammation

“…This has not proven to be the case because the cost of new drug delivery dendrimer platforms has not been commercially viable when compared to the low cost of the generic small molecule antiinfective drugs being delivered [21]. In this specific context, we have recently shown, in two in vivo mouse model systems, that very small MWt and very well characterised and low cost polymethacrylic acid of MWt 3.52 kDa can be used to effectively deliver amphotericin B to the site of infection for the cure of parasitic (cutaneous leishmaniasis) and fungal (invasive aspergillosis) infections [22,23]. Our approach has been progressed into a clinical trial of a cost-effective medicine (Anfoleish) for cutaneous leishmaniasis in South America by the Geneva based Drugs for Neglected Diseases Initiative (DNDi) [24,25].…”