Nanonization Increases the Antileishmanial Efficacy of Amphotericin B: An Ex Vivo Approach

Abstract

With widespread resistance to pentavalent antimonial in the endemic eastern terai belt of Nepal and Bihar, India, Amphotericin B deoxycholate is now the first-line antileishmanial drug for the treatment of visceral leishmaniasis (VL). However, universal occurrence of infusion-related fever and rigors with amphotericin B (AmB), occasional serious life-threatening toxicities like cardiotoxicity, anaphylaxis, hypokalemia, and nephrotoxicity are major barriers to its use in areas with limited medical facilities. Liposomal amphotericins, however, are devoid of adverse effects, high cost makes it unaffordable. We had formulated nanoparticles (10-20 nm) from amphotericin B deoxycholate (1-2 μm) applying high pressure (150 atm) milling homogenization in argon atmosphere and tested its ex vivo efficacy in Leishmania infected J774A cell line and peritoneal macrophage. The ex vivo ED50 for intracellular amastigotes in peritoneal macrophage by nano-amphotericin was 0.0027 ± 0.001 μg/mL which was significantly less (p = 0.0029) than the required dose of amphotericin B (0.0426 ± 0.003 μg/mL). Similarly, in J774A cell line, 50 % of intracellular amastigotes were cleared by 0.0038 ± 0.001 μg/mL of nano-amphotericin while the dose was a bit more for AmB (0.0196 ± 0.001 μg/mL) illustrating the significant difference (p value, 0.0122). The nanoformulation has also shown high efficacy (ED50, 0.0028-0.0035 μg/mL) in inhibition of infected macrophage count. The new formulation accumulated to spleen, the targeted organ, 7 days after inoculation of drug to the infected hamster as traced in vivo by TEM convincing it as potential drug. Given a favorable safety profile and very low cost of production contemplated, it may prove to be a feasible alternative for conventional amphotericin B.

Promising therapeutic effect of thapsigargin nanoparticles on chronic kidney disease through the activation of Nrf2 and FoxO1

“…NPs supply potentially efficient and safe selective drug delivery as well as specific biomarker and/or imaging probe binding [23]. Furthermore, NP drug delivery systems not only enhance targeting ability, but also control drug release [24, 25]. Thus, NPs can deliver drugs very effectively to a target site to enhance efficacy and reduce side effects [26].…”

Review of the effects of manufactured nanoparticles on mammalian target organs

“…NPs offer potentially safe and efficient selective drug delivery, as well as specific biomarker and/or imaging probe binding (Dellinger et al, 2013). Furthermore, novel NPs drug delivery systems not only enhance the targeting capability of transitional drugs (Bao et al, 2015;Broz et al, 2008), but also improve the drug efficacy through slow and sustained release (Botella et al, 2011;Das Manandhar et al, 2014).…”

High-throughput virtual screening and quantum mechanics approach to develop imipramine analogues as leads against trypanothione reductase of leishmania

“…However, the major disadvantage associated with all these drugs are high resistance, dose dependent toxicity, high cost and their storage in cooling condition make them stumbling block. Nanonization of amphotericin-B has also shown increased efficacy [24,25] and its carbon nanotube attached form made it suitable for targeted killing of leishmania parasite in both in vitro and in vivo experiments [26,27]. Recently, Pandey RK et al have reported imidazole and febrifugine analogues as an antileishmanial drug candidate against TR of L. donovani against their native use to treat human african trypanosomiasis and malaria respectively [4,28].…”