In vitro evaluation of bisnaphthalimidopropyl derivatives loaded into pegylated nanoparticles against Leishmania infantum protozoa

Abstract

Bisnaphthalimidopropyl (BNIP) derivatives have recently been shown to have potential as antileishmanial agents. However, these compounds have some drawbacks, including their low aqueous solubility and some toxic effects. In this study, we designed a drug delivery system for enhanced delivery of BNIP derivative compounds whilst reducing adverse toxic effects, and hence increasing their biological efficacy. A coated drug delivery system based on polymeric nanoparticles of pegylated poly(lactic acid) (PLA), a biodegradable polymer, was successfully achieved. The pegylated PLA nanoformulations loaded with BNIP derivatives were evaluated in an in vitro model of intracellular amastigotes in murine J774 and human THP-1 cells for visceral leishmaniasis using luciferase-expressing Leishmania infantum parasites. Pegylation of PLA nanoparticles significantly reduced the capacity of empty nanoparticles in inhibiting intracellular parasite growth. The BNIP derivatives BNIPDadec and BNIPDaoct exhibited EC50 values (concentration of compound necessary to decrease cell viability to 50% of the untreated control) of ca. 4.5μM for THP-1 and J774 cells and ca. 9.0μM for mouse bone marrow-derived macrophages. Nanoparticle encapsulation of the BNIP derivative compounds decreased their toxicity towards macrophages by ≥10-fold as evaluated by the MTT assay. The antileishmanial activity of free BNIPDadec was 1.02±0.41μM and 0.73±0.06μM for THP-1 and J774 macrophages, respectively. Pegylation of PLA nanoparticles loaded with BNIPDadec resulted in EC50 values of 1.43±0.63μM and 1.79±0.77μM for THP-1 and J774 macrophages, respectively. A similar trend was observed for free BNIPDaoct and pegylated BNIPDaoct PLA nanoparticles (2.43±0.19μM and 1.23±0.40μM for THP-1 macrophages and 1.36±0.17μM and 1.52±0.57μM for J774 macrophages). The nanoformulations were more efficient in reducing parasitic growth inside human macrophages than in murine cells, suggesting host cell-dependent metabolism.