Targeted, lipoidal nanosystem for the treatment of schistosomiasis

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2022

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Adekiya, Tayo Alex

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Schistosomiasis, also known as snail fever, is tagged by the World Health Organization (WHO) as Neglected Tropical Diseases (NTDs). This NTDs, is a chronic and acute disease initiated by blood flukes (parasitic worms) which belongs to the class of trematode (flatworm) and Schistosoma as its genus. In the region where this disease is prevalent, the lifestyles of both pregnant women and school children encounter detrimental effects because of the parasitizing of the flukes. Likewise, the endemic of this disease has a great consequential impact on reducing the agricultural produces. Thus, retarding the socio-economics developments of the area(s) afflicted by the disease. Over the past four decades, the Schistosoma disease treatment has been based on an oral single dose of praziquantel (PZQ). This is due to the following factors: it is inexpensive and readily available; its effectiveness against all forms of Schistosomes and it is well tolerated by patients of all ages. Sadly, the use of praziquantel has been faced with several challenges with regard to the treatment of schistosome-based infections. Such challenges include low aqueous solubility, the short plasma half-life of about 1 to 2 hours and extensive hepatic first-pass metabolism. In addition to this, other challenges that are encountered in the treatment of the disease include the ineffectiveness of praziquantel against young schistosome worms, and drug tolerance and resistance in some parts of the world, which is attributed to poor treatment compliance, rate of mutation of the parasite, overall parasite load and the co-infection of different strains of Schistosoma parasites. This novel study employed nanotechnological techniques to designed and developed praziquantel nanoliposomal (NLP) nanosystem and surface-functionalized the NLP with anticalpain antibody (anticalpain-NLP) for targeted PZQ delivery in the treatment of Schistosomiasis. Anticalpain-NLP were prepared and validated for their physicochemical properties, in vitro and in vivo toxicity, drug loading capacity (DLC), drug entrapment efficiency (DEE), drug release and parasitological cure rate. The particle sizes for the formulated nanoliposomes ranged from 88.3 to 92.7 nm (PdI = 0.17-0.35), and zeta potential ranged from - 20.2 to -31.9 mV. The DLC and DEE ranged from 9.03% to 14.16% and 92.07% to 94.63%, respectively. The surface functionalization of the nanoliposomes was stable, uniform, and spherical in shape. Fourier transform infrared (FTIR), thermal behaviour and X-ray powder diffraction (XRPD) analysis confirmed that anticalpain antibody and PZQ were incorporated into the surface and inner core of the nanoliposomes, respectively. The sustained drug release was showed to be 93.2 and 91.1% of PZQ within 24 h for NLP and anticalpain-NLP, respectively. In the in vitro analysis study, the concentrations range of 30 to 120 g/ml employed revealed acceptable levels of cell viability, with no significant cytotoxic effects on RAW 264.7 murine macrophage cells and 3T3 human fibroblast cells. More so, the study developed and evaluated the long-term stability of drug-loaded solid lipid nanoparticles (SLNs) which can extend drug release and overcome the problem of bioavailability and solubility as well as investigated its toxicity and efficacy. Solvent injection-co-homogenization techniques was used to fabricated SLNs in which compritol ATO 888 and lecithin were used as lipids, and Pluronic F127 (PF127) was used as a stabilizer. The long-term stability effect of the PF127 as a stabilizer on the SLNs was evaluated thoroughly. The particle size, stability and polydispersity were determined by a dynamic light scattering (DLS) technique. The morphological analysis of the SLNs was investigated by Transmission and Scanning Electron Microscopy (TEM) and (SEM), respectively. The chemical properties, mechanical, thermal, and crystal behaviours of SLNs were evaluated using FTIR, ElastoSens Bio2, XRPD, DSC and TGA, respectively. SLNs with PF127 depicted an encapsulation efficiency of 71.63% and a drug loading capacity of 11.46%. The in vitro drug release study for SLNs with PF127 showed a cumulative release of 48.08% for the PZQ within 24 h, with a similar release profile for SLNs suspension after 120 days. DLS, ELS, and optical characterization and stability profiling data indicate that the addition of PF127 as the surfactants provided long-term stability for SLNs. RAW 264.7 macrophages showed acceptable, dose-dependent levels of viability following treatment with SLNs in an in vitro toxicity study. Biochemical markers and histopathological analysis showed that the formulated nanoliposomes and SLNs present no or minimal oxidative stress and confer hepatoprotective effects on the animals. The cure rate of the anticalpain-NLP, SLNs and PZQ was assessed by parasitological analysis. It was discovered that, with treatment using the 250 mg/kg anticalpain-NLP and PF127 stabilized SLNs showed greater activity on the total worm burden, ova count in both the intestine and the liver of juvenile and adult schistosomes. From the findings obtained, the study supports the ability of oral anticalpain-NLP and SLNs to target young and adult schistosomes in the liver and portomesenteric locations, resulting in improved the overall effectiveness of PZQ.

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A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Faculty of Health Sciences, School of Therapeutic Sciences, University of the Witwatersrand, Johannesburg, 2021

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