Nanoliposomal Buparvaquone Immunomodulates Leishmania infantum-Infected Macrophages and Is Highly Effective in a Murine Model.
Visceral leishmaniasis is a fatal parasitic neglected disease affecting 1.5 million people worldwide. Based on a drug repositioning approach, the aim of this work was to investigate thein vitroimmunomodulatory potential of buparvaquone (BPQ) and to establish a safe regimen to evaluate thein vivoefficacy of BPQ entrapped by negatively charged nanoliposomes (BPQ-LP) inLeishmania infantum-infected hamsters. Small-angle X-ray scattering, dynamic light scattering, and the ζ-potential were applied in order to study the influence of BPQ on the liposome structure. Our data revealed that BPQ was located in the polar-apolar interface, snorkeling the polar region, and protected against aggregation inside the lipophilic region. The presence of BPQ also decreased the Z-average hydrodynamic diameter and increased the surface charge. Compared to intravenous and intramuscular administration, a subcutaneous route was a more effective route for BPQ-LP; at 0.4 mg/kg, BPQ-LP reduced infection in the spleen and liver by 98 and 96%, respectively. Treatment for 5 days resulted in limited efficacy, but 10 days of treatment resulted in an efficacy similar to that of a 15-day regimen. The nanoliposomal drug was highly effective, with a mean 50% effective dose of 0.25 mg/kg, reducing the parasite load in bone marrow by 80%, as detected using quantitative PCR analysis. In addition, flow cytometry studies showed that BPQ upregulated cytokines as tumor necrosis factor, monocyte chemoattractant protein 1, interleukin-10 (IL-10), and IL-6 inLeishmania-infected macrophages, eliminating the parasites via a nitric oxide-independent mechanism. This new formulation proved to be a safe and effective treatment for murine leishmaniasis that could be a useful candidate against visceral leishmaniasis.
Centre for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo, Brazil.
Thais Alves
TA
da Costa-Silva
Instituto de Medicina Tropical, São Paulo, Brazil.
Andrés Jimenez
AJ
Galisteo
Instituto de Medicina Tropical, São Paulo, Brazil.|Instituto de Infectologia Emilio Ribas, São Paulo, Brazil.
José Angelo Lauletta
JA
Lindoso
Instituto de Física da Universidade de São Paulo, São Paulo, Brazil.
Leandro R S
LR
Barbosa
Centre for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo, Brazil atempone@usp.br.
Andre Gustavo
AG
Tempone
D000279:Administration, Cutaneous; D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D018932:Chemokine CCL2 / Q000819:agonists / Q000096:biosynthesis; D006224:Cricetinae; D004195:Disease Models, Animal; D004339:Drug Compounding / Q000379:methods; D007155:Immunologic Factors / Q000737:chemistry / Q000494:pharmacology*; D016753:Interleukin-10 / Q000819:agonists / Q000096:biosynthesis; D015850:Interleukin-6 / Q000819:agonists / Q000096:biosynthesis; D018314:Leishmania infantum / Q000187:drug effects* / Q000254:growth & development; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000276:immunology / Q000469:parasitology; D008081:Liposomes / Q000737:chemistry* / Q000493:pharmacokinetics; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000469:parasitology; D008297:Male; D051379:Mice; D049329:Nanostructures / Q000008:administration & dosage / Q000737:chemistry; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D059208:Parasite Load; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D055672:Static Electricity; D014409:Tumor Necrosis Factor-alpha / Q000819:agonists / Q000096:biosynthesis
D000981:Antiprotozoal Agents; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C556062:IL10 protein, mouse; D007155:Immunologic Factors; D015850:Interleukin-6; D008081:Liposomes; D009285:Naphthoquinones; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; C046326:buparvaquone; D016753:Interleukin-10
Leishmania; drug delivery; liposomes; therapy