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Abstract
Visceral leishmaniasis (VL) has been a major health concern in the developing world, primarily affecting impoverished people. It is caused by a protozoan parasite Leishmania donovani and is characterized by immune dysfunction that can lead to deadly secondary infections. Several adverse side effects limit the existing treatment options; hence, the need of the hour is some drug option with high efficacy and no toxicity. To make targeted delivery of Amphotericin B (AmB), we have used amine-functionalized versions of carbon nanostructures, namely f-CNT and f-Graphene (f-Grap). The results with f-Grap-AmB, because of a much larger surface area, were expected to be better. However, the results obtained by us showed only marginal improvement (IC50 f-Grap-AmB; 0.0038 ± 0.00119 μg/mL). This is, in all likelihood, due to the agglomeration effect of f-Grap-AmB, which is invariably obtained with graphene. To resolve this issue, we have synthesized a graphene-CNT composite (graphene 70% and CNT 30% by weight). Because CNT is dispersed in between graphene sheets, the agglomeration effect is avoided, and our study suggests that the f-Composite-AmB (f-Comp-AmB) showed no toxicity against the murine J774A.1 macrophage cell line and did not induce any hepatic or renal toxicity in Swiss albino mice. The f-Comp-AmB also showed a remarkable elevation in the in vitro and in vivo antileishmanial efficacy in comparison to AmB and f-CNT-AmB or f-Grap-AmB in J774A.1 and Golden Syrian hamsters, respectively. Additionally, we have also observed that the percentage suppression of parasite replication in the spleen of the hamster was significantly higher in the f-Comp-AmB (97.79 ± 0.2375) treated group in comparison with the AmB (85.66 ± 1.164) treated group of hamsters. To conclude, f-Comp-AmB could be a safe and reliable therapeutic option over the other carbon-based nanoparticles (NPs), i.e., f-CNT-AmB, f-Grap-AmB, and conventional AmB.
Highlights
Visceral leishmaniasis (VL) is a fatal protozoan disease caused by the intramacrophagic amastigote form of the Leishmania donovani parasite and is transmitted through the bite of the sand fly vector belonging to the genus Phlebotomus (Tiwari et al, 2018; Gedda et al, 2019b)
X-ray diffraction (XRD) patterns of graphene sheets (GS) and CNT composite are shown in Figure 1C, which suggests that the peak corresponding to the plane (00.2) shifts toward the lower angle side (2θ = 24.995) and becomes broad, which is due to the combined size effects of GS and CNT
The other functionalized carbon nanomaterials, i.e., f-GrapAmB and f-CNT-Amphotericin B (AmB), have shown only 7.98- and 6.71-fold improvement in the in vitro antileishmanial activity over the conventional AmB, which has been in corroboration with our previous in vitro results (Prajapati et al, 2011a,b; Mudavath et al, 2014)
Summary
Visceral leishmaniasis (VL) is a fatal protozoan disease caused by the intramacrophagic amastigote form of the Leishmania donovani parasite and is transmitted through the bite of the sand fly vector belonging to the genus Phlebotomus (Tiwari et al, 2018; Gedda et al, 2019b). A single dose of liposomal amphotericin-B formulation (AmBisome) has minimal toxicity and enhanced efficacy when compared to AmB (Sundar et al, 2010), the high cost of the drug and its subsequent lack of access by the people most commonly affected (from lower economic strata in the endemic regions of the Indian and African subcontinent) has been a major concern (Sinha et al, 2010) New drugs, such as oxaboroles (DNDI6148) and nitroimidazole (DNDI-0690) by DNDi, are in the pipeline for preclinical development against VL and CL for an optimized pharmacological profile. Many research groups have employed several NP-based AmB formulations against the infected macrophage both at the in vitro and in vivo levels for the treatment of experimental leishmaniasis (Khatik et al, 2014; Asthana et al, 2015; Shahnaz et al, 2017)
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