Abstract
The development of an effective oral therapeutics is an immediate need for the control and elimination of visceral leishmaniasis (VL). We exemplify the preparation and optimization of 2-hydroxypropyl-β-cyclodextrin (HPCD) modified solid lipid nanoparticles (SLNs) based oral combinational cargo system of Amphotericin B (AmB) and Paromomycin (PM) against murine VL. The emulsion solvent evaporation method was employed to prepare HPCD modified dual drug-loaded solid lipid nanoparticles (m-DDSLNs). The optimized formulations have a mean particle size of 141 ± 3.2 nm, a polydispersity index of 0.248 ± 0.11 and entrapment efficiency for AmB and PM was found to be 96% and 90% respectively. The morphology of m-DDSLNs was confirmed by scanning electron microscopy and transmission electron microscopy. The developed formulations revealed a sustained drug release profile upto 57% (AmB) and 21.5% (PM) within 72 h and were stable at both 4 °C and 25 °C during short term stability studies performed for 2 months. Confocal laser scanning microscopy confirmed complete cellular internalization of SLNs within 24 h of incubation. In vitro cytotoxicity study against J774A.1 macrophage cells confirmed the safety and biocompatibility of the developed formulations. Further, m-DDSLNs did not induce any hepatic/renal toxicities in Swiss albino mice. The in vitro simulated study was performed to check the stability in simulated gastric fluids and simulated intestinal fluids and the release was found almost negligible. The in vitro anti-leishmanial activity of m-DDSLNs (1 µg/ml) has shown a maximum percentage of inhibition (96.22%) on intra-cellular amastigote growth of L. donovani. m-DDSLNs (20 mg/kg × 5 days, p.o.) has significantly (P < 0.01) reduced the liver parasite burden as compared to miltefosine (3 mg/kg × 5 days, p.o.) in L. donovani-infected BALB/c mice. This work suggests that the superiority of as-prepared m-DDSLNs as a promising approach towards the oral delivery of anti-leishmanial drugs.
Highlights
Visceral leishmaniasis (VL), known as Kala-Azar is the most severe form of leishmaniasis, a neglected tropical disease caused by the protozoan parasite Leishmania donovani, The disease is transmitted to human host by the bite of an infected female haemo-flagellate sand fly[1]
Antimonial chemotherapy was the mainstay for visceral leishmaniasis (VL) treatment in the past, parasite resistance against these drugs, especially in the Indian subcontinent, led to the introduction of other drugs such as Amphotericin B (AmB), AmBisome, Miltefosine, and Paromomycin (PM) to treat VL in areas of antimonial drug resistance
Employing a combination of in vitro and in vivo experiments, we have shown that HPCD modified solid lipid nanoparticles (SLNs) can demonstrate the enhanced anti-leishmanial activity with reduced toxicity when administered orally
Summary
Visceral leishmaniasis (VL), known as Kala-Azar is the most severe form of leishmaniasis, a neglected tropical disease caused by the protozoan parasite Leishmania donovani, The disease is transmitted to human host by the bite of an infected female haemo-flagellate sand fly[1]. Antimonial chemotherapy was the mainstay for VL treatment in the past, parasite resistance against these drugs, especially in the Indian subcontinent, led to the introduction of other drugs such as Amphotericin B (AmB), AmBisome, Miltefosine, and Paromomycin (PM) to treat VL in areas of antimonial drug resistance These drugs are associated with problems, such as toxicity, high cost, potential development of parasite drug resistance, and prolonged treatment r egime[5,6,7]. This property has been attributed to the increased thermodynamic activity of the drug in the vehicle and/or to enhance the rate of drug d issolution[29,30,31,32,33] In this current study, we exemplify the preparation and characterization of HPCD modified SLNs based combinational cargo system of AmB and PM. Employing a combination of in vitro and in vivo experiments, we have shown that HPCD modified SLNs can demonstrate the enhanced anti-leishmanial activity with reduced toxicity when administered orally
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