In Vitro Evaluation of Aerosol Therapy with Pentamidine-Loaded Liposomes Coated with Chondroitin Sulfate or Heparin for the Treatment of Leishmaniasis.
Lucía Román-ÁlamoMohamad AllawYunuen Avalos-PadillaMaria Letizia MancaMaria ManconiFederica FulgheriJorge Fernández-LajoLuis RivasJosé Antonio VázquezJosé Esteban PerisXavier Roca-GeronèsSrisupaph PoonlaphdechaMaria Magdalena AlcoverRoser FisaCristina RieraXavier Fernàndez-BusquetsPublished in: Pharmaceutics (2023)
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.
Keyphrases
- optic nerve
- drug delivery
- endothelial cells
- type diabetes
- cancer therapy
- cystic fibrosis
- drug release
- venous thromboembolism
- case report
- stem cells
- low dose
- cardiovascular disease
- growth factor
- early onset
- signaling pathway
- combination therapy
- risk assessment
- emergency department
- glycemic control
- adipose tissue
- climate change
- skeletal muscle
- high glucose
- insulin resistance
- induced pluripotent stem cells