In Vitro Evaluation of Aerosol Therapy with Pentamidine-Loaded Liposomes Coated with Chondroitin Sulfate or Heparin for the Treatment of Leishmaniasis

Abstract

The second-line antileishmanial compound pentamidine is administered intramuscularly or, preferably, by intravenous infusion, with its use limited by severe adverse effects, including diabetes, severe hypoglycemia, myocarditis and renal toxicity. We sought to test the potential of phospholipid vesicles to improve the patient compliance and efficacy of this drug for the treatment of leishmaniasis by means of aerosol therapy. The targeting to macrophages of pentamidine-loaded liposomes coated with chondroitin sulfate or heparin increased about twofold (up to ca. 90%) relative to noncoated liposomes. The encapsulation of pentamidine in liposomes ameliorated its activity on the amastigote and promastigote forms of Leishmania infantum and Leishmania pifanoi, and it significantly reduced cytotoxicity on human umbilical endothelial cells, for which the concentration inhibiting 50% of cell viability was 144.2 ± 12.7 µM for pentamidine-containing heparin-coated liposomes vs. 59.3 ± 4.9 µM for free pentamidine. The deposition of liposome dispersions after nebulization was evaluated with the Next Generation Impactor, which mimics human airways. Approximately 53% of total initial pentamidine in solution reached the deeper stages of the impactor, with a median aerodynamic diameter of ~2.8 µm, supporting a partial deposition on the lung alveoli. Upon loading pentamidine in phospholipid vesicles, its deposition in the deeper stages significantly increased up to ~68%, and the median aerodynamic diameter decreased to a range between 1.4 and 1.8 µm, suggesting a better aptitude to reach the deeper lung airways in higher amounts. In all, nebulization of liposome-encapsulated pentamidine improved the bioavailability of this neglected drug by a patient-friendly delivery route amenable to self-administration, paving the way for the treatment of leishmaniasis and other infections where pentamidine is active.

Effect of the aggregated protein dye YAT2150 on Leishmania parasite viability

“…One of these compounds, YAT2150, stood out with an in vitro IC 50 of around 0.52 µM against both promastigotes and amastigotes, which was ca. 54-, 20-, and 542-fold lower than that reported in promastigotes for the commonly used antileishmanial agents pentamidine ( 34 ), miltefosine ( 35 ), and paromomycin ( 36 ), respectively. Amphotericin B has a lower IC 50 (0.04 µM in promastigotes) ( 37 ), but frequently associated nephrotoxicity has limited its clinical use, a drawback absent in its liposomal formulations ( 38 ).…”

Pathogen‐binding nanoparticles to inhibit host cell infection by heparan sulfate and sialic acid dependent viruses and protozoan parasites

“…156 Heparin in the context of nanomedicine for Leishmania was evaluated recently as an inhalable heparin/chitosan NP for drug delivery. 157 In this example, heparin increased macrophage uptake of drug-loaded NPs. Hence, it remains to be seen whether HS mimetic polymers or NPs have a therapeutic potential for leishmaniasis.…”

The Future of Leishmaniasis Treatment: Protein Targets and Beyond

“…Currently, standard active compounds used against Leishmania parasites include Amphotericin B, Miltefosine, Pentamidine, Antimonials, Paromomycin, Sitamaquine, Pamidronate, Azoles, and 3 of 29 Nucleoside analogues. [30][31][32][33][34][35][36], However, these drugs often demonstrate inefficiency and high toxicity in patients undergoing clinical treatments. The effectiveness and toxicity of these drugs depend on various factors, such as the immunological state of the infected host and the pharmacokinetic properties of the drugs themselves.…”