Targeting Leishmania amazonensis amastigotes through macrophage internalisation of a hydroxymethylnitrofurazone nanostructured polymeric system

Abstract

Dextran-coated poly (n-butyl cyanoacrylate) nanoparticles (PBCA-NPs) were prepared and were evaluated for enhanced delivery of a promising anti-Leishmania drug candidate, hydroxymethylnitrofurazone (NFOH), to phagocytic cells. Currently available chemotherapy for leishmaniasis, such as pentavalent antimonials, presents low safety and efficacy. Furthermore, widespread drug resistance in leishmaniasis is rapidly emerging. To overcome these drawbacks, the use of nanosized delivery systems can reduce systemic drug toxicity and increase the drug concentration in infected macrophages, therefore improving treatment of leishmaniasis. PBCA-NPs containing NFOH (PBCA-NFOH-NPs) were prepared by an anionic emulsion polymerisation method. The z-average and polydispersity index (PDI) were determined by photon correlation spectroscopy, the zeta potential by microelectrophoresis and the entrapment efficiency by HPLC. Cytotoxicity was determined using macrophages from BALB/c mice. Efficacy tests were performed using Leishmania amazonensis promastigotes and amastigotes. The z-average of PBCA-NFOH-NPs was 151.5 ± 61.97 nm, with a PDI of 0.104 ± 0.01, a zeta potential of -10.1 ± 6.49 mV and an entrapment efficiency of 64.47 ± 0.43%. Efficacy in amastigotes revealed IC values of 0.33 µM and 31.2 µM for the nanostructured and free NFOH, respectively (95-fold increase). The cytotoxicity study indicated low toxicity of the PBCA-NFOH-NPs to macrophages. The selectivity index was 370.6, which is 49-fold higher than free NFOH (7.6). Such findings indicated that improved efficacy could be due to NP internalisation following site-specific drug delivery and reactivation of immune protective reactions by the NP components. Thus, PBCA-NFOH-NPs have the potential to significantly improve the treatment of leishmaniasis, with reduced systemic side effects.

Biodegradable nanocarriers coated with polymyxin B: Evaluation of leishmanicidal and antibacterial potential

“…However, PBCAnp also killed protozoa, (dilution of NP at IC50 = 1: 620) and was largely responsible for the leishmanicidal effect of PBCAnp-polB. In accordance with our results, control PBCAnp were described as active against promastigotes of Leishmania amazonensis [34], but the related paper did not evaluate coated NPs, like ours. Leishmanicidal activity of NPs tailored with a similar polymer (poly isohexylcyanoacrylate) was also described in infected macrophages with amastigotes from Leishmania donovani [35].…”

Promising nanotherapy in treating leishmaniasis

“…Different methods have been employed to load antileishmanial drug substances into polymeric nanoparticles such as emulsion or microemulsion polymerization (Monteiro et al, 2017b), interfacial polymerization (Chaubey and Mishra, 2014) and precipitation polymerization (Kumar et al, 2015). Their major drawbacks refer to inadequate biodegradability and/or the possible presence of organic solvent toxic residues (Ahlin Grabnar and Kristl, 2011).…”

“…The selectivity index was 370.6 for PBCA-NFOH-NPs, which was a 49-fold increase than free NFOH. The activity of PBCA-NFOH-NPs presented great efficacy for delivery aimed at macrophages (Monteiro et al, 2017b). The authors have filed a patent application for this invention (BR 10 2014 007923-8).…”

Nanostructured lipid carrier containing hydroxymethylnitrofurazone: preparation, characterization and in vitro and in vivo evaluation of leishmanicidal activity

“…It can be achieved using design of experiments (DoE). The applicability of DoE has increased due to its ease in overcoming limitations and time-consuming methodologies (MONTEIRO et al, 2017b;VALICHERLA et al, 2016;YUKUYAMA et al, 2019). Therefore, this work is focused on developing a novel NFOH-loaded NLC for oral administration to treat leishmaniasis, using a design space approach.…”

“…Additionally, drug solubility and crystallization behavior in solid lipids were carried out by using differential scanning calorimetry (DSC), according to Monteiro et al (MONTEIRO et al, 2017b). The NFOH, solid lipids, 1:1 physical mixtures (PM) and the mixtures of selected lipids thermal behavior were characterized in a DSC 4,000…”