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

Author(s)

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

• Document type: Journal article
• Source: Antimicrobial Agents and Chemotherapy; v. 61, n. 4 APR 2017.
• Web of Science Citations: 8

Abstract

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)

• FAPESP's process: 15/15822-1 - Physicochemical and structural properties of Ionic Liquids and drugs interacting with biologicaly relevant systems.
• Grantee: Leandro Ramos Souza Barbosa
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/23403-9 - Rational Pre-Clinical Study of New Drug Candidates Against Neglected Protozoan Diseases Using Pharmacokinetic Approaches
• Grantee: André Gustavo Tempone Cardoso
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/07275-5 - In vitro study of cellular immune response against synthetic drugs with antileishmanial activities
• Grantee: Thaís Alves da Costa Silva
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 13/50228-8 - Biodiversity components, and their metabolic characters, of Brazilian Islands: an integrated approach
• Grantee: Roberto Gomes de Souza Berlinck
• Support Opportunities: BIOTA-FAPESP Program - Thematic Grants