Nanoliposomal Buparvaquone Immunomodulates Leishmania infantum-Infected Macrophages and Is Highly Effective in a Murine Model

Autor(es)

da Costa-Silva, Thais Alves ; Galisteo, Jr., Andres Jimenez ; Lauletta Lindoso, Jose Angelo ; Barbosa, Leandro R. S. ; Tempone, Andre Gustavo

• Tipo de documento: Artigo Científico
• Fonte: Antimicrobial Agents and Chemotherapy; v. 61, n. 4 APR 2017.
• Citações Web of Science: 8

Resumo

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 the in vitro immunomodulatory potential of buparvaquone (BPQ) and to establish a safe regimen to evaluate the in vivo efficacy of BPQ entrapped by negatively charged nanoliposomes (BPQ-LP) in Leishmania infantum-infected hamsters. Small-angle X-ray scattering, dynamic light scattering, and the zeta-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 in Leishmania-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. (AU)

• Processo FAPESP: 15/15822-1 - Estudo das propriedades físico-químicas e estruturais de fármacos e líquidos iônicos com sistemas de relevância biológica
• Beneficiário: Leandro Ramos Souza Barbosa
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/23403-9 - Estudo Pré-Clínico Racional de Novos Candidatos a Fármacos em Protozooses Negligenciadas Utilizando Abordagens Farmacocinéticas
• Beneficiário: André Gustavo Tempone Cardoso
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/07275-5 - Estudo da resposta imune celular in vitro frente a ação de fármacos anti-Leishmania (L.) infantum
• Beneficiário: Thaís Alves da Costa Silva
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 13/50228-8 - Componentes da biodiversidade, e seus caracteres metabólicos, de ilhas do Brasil: uma abordagem integrada
• Beneficiário: Roberto Gomes de Souza Berlinck
• Modalidade de apoio: Auxílio à Pesquisa - Programa BIOTA - Temático