Miltefosine Lipid Nanocapsules for Single Dose Oral Treatment of Schistosomiasis Mansoni: A Preclinical Study (original) (raw)
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International Journal of Nanomedicine, 2018
Purpose: Lipid nanocapsules (LNCs) have shown potential to increase the bioavailability and efficacy of orally administered drugs. However, their intestinal translocation to distal target sites and their implication in pharmacokinetic (PK)-pharmacodynamic (PD) relationships are yet to be elucidated. In this study, the effect of LNCs on the PD activity and pharmacokinetics of praziquantel (PZQ), the mainstay of schistosomiasis chemotherapy, was investigated. Materials and methods: The composition of LNCs was modified to increase PZQ payload and to enhance membrane permeability. PZQ-LNCs were characterized in vitro for colloidal properties, entrapment efficiency (EE%), and drug release. PD activity of the test formulations was assessed in Schistosoma mansoni-infected mice 7 days post-oral administration of a single 250 mg/kg oral dose. Pharmacokinetics of the test formulations and their stability in simulated gastrointestinal (GI) fluids were investigated to substantiate in vivo data. Results: PZQ-LNCs exhibited good pharmaceutical attributes in terms of size (46-62 nm), polydispersity index (0.01-0.08), EE% (.95%), and sustained release profiles. Results indicated significant efficacy enhancement by reduction in worm burden, amelioration of liver pathology, and extensive damage to the fluke suckers and tegument. This was partly explained by PK data determined in rats. In addition, oral targeting of the worms was supported by the stability of PZQ-LNCs in simulated GI fluids and scanning electron microscopy (SEM) visualization of nanostructures on the tegument of worms recovered from mesenteric/hepatic veins. Cytotoxicity data indicated tolerability of PZQ-LNCs. Conclusion: Data obtained provide evidence for the ability of oral LNCs to target distal postabsorption sites, leading to enhanced drug efficacy. From a practical standpoint, PZQ-LNCs could be suggested as a potential tolerable single lower dose oral nanomedicine for more effective PZQ mass chemotherapy.
International Journal of Progressive Sciences and Technologies (IJPSAT), 2022
The poor rate of drug discovery for the control of Neglected tropical diseases (NTDs) including schistosomiasis has necessitated effective management of existing drugs by modulating their delivery. Nanotechnology-based colloidal drug carriers have been explored to improve the activity and safety profile of drugs for NTDs including parasitic diseases. In developing new drug delivery systems for schistosomiasis, research efforts have focused mainly on Praziquantel (PZQ) as the sole antischistosomal agent in current clinical practice. Carrier systems of the polymer, inorganic and lipid-based type have been investigated for the delivery of PZQ. However, promising results were obtained using lipid-based delivery systems including liposomes, solid lipid nanoparticles, nanostructured lipid carriers and nanoemulsions. Selection of these lipid carrier systems has been based on the lipophilicity of PZQ, controlled drug release, potential increase in its bioavailability by promoting lymphatic absorption to bypass the extensive first pass effect biodistribution to the host liver and enhancement of PZQ interaction with the worm tegument of a similar phospholipid nature.
Pharmaceutics
This study employed nanotechnological techniques to design and develop a praziquantel nanoliposomal (NLP) system and surface-functionalized the NLP with anti-calpain antibody (anti-calpain-NLP) for targeted praziquantel (PZQ) delivery in the treatment of schistosomiasis. Anti-calpain-NLPs were prepared and validated for their physicochemical parameters, in vitro and in vivo toxicity, drug entrapment efficiency (DEE), drug loading capacity (DLC), 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 functionalization of the nanoliposome surface was stable, uniform, and spherical. Fourier-transform infrared (FTIR), thermal behavior and X-ray powder diffraction (XRPD) analysis confirmed that the anti-calpain antibody and PZQ were attached to the surface and the nanolipo...
International journal of nanomedicine, 2018
Lipid nanocapsules (LNCs) have shown potential to increase the bioavailability and efficacy of orally administered drugs. However, their intestinal translocation to distal target sites and their implication in pharmacokinetic (PK)-pharmacodynamic (PD) relationships are yet to be elucidated. In this study, the effect of LNCs on the PD activity and pharmacokinetics of praziquantel (PZQ), the mainstay of schistosomiasis chemotherapy, was investigated. The composition of LNCs was modified to increase PZQ payload and to enhance membrane permeability. PZQ-LNCs were characterized in vitro for colloidal properties, entrapment efficiency (EE%), and drug release. PD activity of the test formulations was assessed in -infected mice 7 days post-oral administration of a single 250 mg/kg oral dose. Pharmacokinetics of the test formulations and their stability in simulated gastrointestinal (GI) fluids were investigated to substantiate in vivo data. PZQ-LNCs exhibited good pharmaceutical attributes ...
Journal of Drug Delivery Science and Technology, 2020
Praziquantel (PZQ) is an anthelmintic drug, being the first choice for the treatment of schistosomiasis. Its high hydrophobic character and its low water solubility are the main limitations to the development of liquid formulations for the oral administration of the drug. The aim of this work was to develop Solid Lipid Nanoparticles (SLN) for the loading of PZQ for the treatment of S. mansoni infections. PZQ-SLN were produced by hot high shear homogenization. The obtained SLN exhibited a mean size of~300 nm, with a polydispersity index of 0.20, zeta potential of~-28 mV and encapsulation efficiency of 92.31%. Thermal analysis demonstrated that the production process reduced the lipid crystallinity of the SLN matrices, which displayed a spherical morphology by scanning electron microscopy (SEM). The mathematical fitting of the release profile demonstrated that PZQ followed the Weibull model whereas PZQ-loaded SLN the Peppas model. PZQ-loaded SLN were more effective in inducing S. mansoni death than PZQ alone. The increased drug solubility did not exhibit toxicity against human fibroblast cell lines (L929). PZQ-loaded SLN demonstrated great parasiticidal properties, being an improved alternative to the classical treatment of schistosomiasis.
Journal of Nanoscience and Nanotechnology, 2014
Schistosomiasis is a neglected tropical disease caused by blood flukes of the genus Schistosoma. This disease control has been widely made by praziquantel-reference drug, but resistance to this drug has already been found. There has been the finding of an imidazole alkaloid in jaborandi leaves-epiisopiloturine, which has known activity against adult, young and egg forms of Schistosoma mansoni. This alkaloid is an apolar molecule with difficult solubility; therefore, the liposomal structure of epiisopiloturine was proposed. Liposomes are carrying structures of drugs that may enhance solubility of compounds such as epiisopiloturine. In this work, we report in vitro epiisopiloturine-loaded liposomes effect formed by different concentrations of lipids 9:1 (weight ratio) dipalmitoylphosphatidylcholine:cholesterol and 8:2 (weight ratio) dipalmitoylphosphatidylcholine:cholesterol. Results have showed that epiisopiloturine extraction and isolation have been successful through high-performance liquid chromatography-HPLC and its purity confirmed through mass spectrometry has showed 287 Da molecular mass. Formulations from 9:1 DPPC:cholesterol and 8:2 DPPC:cholesterol with loaded EPI (300 g/ml) have killed parasites at 100% after incubation 96 h and 120 h, respectively. Confocal microscopy employed to observe morphological alterations in the tegument of adult form of Schistosoma mansoni. Details from interaction, between epiisopiloturine and liposome, have been achieved by semi-empirical AM1 calculations, which have showed that epiisopiloturine inside is more stable than the outside form, at least 10 k cal. This is first time that schistosomicidal activity has been reported for epiisopiloturine-loaded into liposome.
Therapeutic Efficacy of Carvacrol-Loaded Nanoemulsion in a Mouse Model of Schistosomiasis
Frontiers in Pharmacology
Since praziquantel is the only drug available to treat schistosomiasis, a neglected parasitic disease that affects more than 240 million people worldwide, there is an urgent demand for new antischistosomal agents. Natural compound-loaded nanoparticles have recently emerged as a promising alternative for the treatment of schistosomiasis. Carvacrol is an antimicrobial monoterpene present in the essential oil extracted from several plants, especially oregano (Origanum vulgare). In this study, a carvacrol nanoemulsion (CVNE) was prepared, characterized, and administered orally (200 mg/kg) in a mouse infected with either immature (prepatent infection) or adult (patent infection) Schistosoma mansoni. For comparison, data obtained with an unloaded nanoemulsion (blank formulation), free carvacrol, and the drug of reference praziquantel are also presented. CVNE was more effective than free carvacrol in reducing the worm burden and egg production in both patent and prepatent infections. Favor...
Parasites & Vectors
Background: Schistosomiasis is responsible for a considerable global disease burden. This work aimed to improve the therapeutic outcome of the only available antischistosomal drug worldwide, praziquantel (PZQ), by incorporating it into a novel carrier, "solid lipid nanoparticles (SLNs)", to enhance its solubility, bioavailability and efficacy. A simple, cost-effective method was used to prepare SLN-PZQ. Results: Compared to market PZQ (M-PZQ), SLN-PZQ was more bioavailable, as denoted by higher serum concentrations in both normal and infected mice where elevated K a , AUC 0-24 , C max , and t 1/2e with a decrease in k el were demonstrated. The AUC 0-24 for SLN-PZQ in normal and Schistosoma mansoni-infected groups was almost nine-and eight-fold higher, respectively, than that for M-PZQ in corresponding groups. In normal and S. mansoni-infected mice, SLN-PZQ was detectable in serum at 24 h, while M-PZQ completely vanished 8 h post-treatment. Additionally, enhanced absorption with extended residence time was recorded for SLN-PZQ. Compared to M-PZQ, SLN-PZQ revealed superior antischistosomal activity coupled with enhanced bioavailability in all treated groups where higher percentages of worm reduction were recorded with all dosages tested. This effect was especially evident at the lower dose levels. The ED 95 of SLN-PZQ was 5.29-fold lower than that of M-PZQ, with a significantly higher reduction in both the hepatic and intestinal tissue egg loads of all treated groups and almost complete disappearance of immature deposited eggs (clearly evident at the low dose levels). Conclusions: SLN-PZQ demonstrated enhanced PZQ bioavailability and antischistosomal efficacy with a safe profile despite the prolonged residence in the systemic circulation.
A Review of Nanotechnology for Targeted Anti-schistosomal Therapy
Frontiers in Bioengineering and Biotechnology
Schistosomiasis is one of the major parasitic diseases and second most prevalent among the group of neglected diseases. The prevalence of schistosomiasis may be due to environmental and socioeconomic factors, as well as the unavailability of vaccines for schistosomiasis. To date, current treatment; mainly the drug praziquantel (PZQ), has not been effective in treating the early forms of schistosome species. The development of drug resistance has been documented in several regions globally, due to the overuse of PZQ, rate of parasitic mutation, poor treatment compliance, co-infection with different strains of schistosomes and the overall parasite load. Hence, exploring the schistosome tegument may be a potential focus for the design and development of targeted anti-schistosomal therapy, with higher bioavailability as molecular targets using nanotechnology. This review aims to provide a concise incursion on the use of various advance approaches to achieve targeted anti-schistosomal therapy, mainly through the use of nano-enabled drug delivery systems. It also assimilates the molecular structure and function of the schistosome tegument and highlights the potential molecular targets found on the tegument, for effective specific interaction with receptors for more efficacious anti-schistosomal therapy.
The control and treatment of Leishmaniasis, a neglected and infectious disease affecting approximately 12 million people worldwide, are challenging. Leishmania parasites multiply intracellularly within macrophages located in deep skin and in visceral tissues, and the currently employed treatments for this disease are subject to significant drawbacks, such as resistance and toxicity. Thus, the search for new Leishmaniasis treatments is compulsory, and Ocotea duckei Vattimo, a plant-derived product from the biodiverse Brazilian flora, may be a promising new treatment for this disease. In this regard, the aim of this work was to develop and characterize a delivery system based on solid lipid nanoparticles (SLN) that contain the liposoluble lignan fraction (LF) of Ocotea duckei Vattimo, which targets the Leishma-nia phagolysosome of infected macrophages. LF-loaded SLNs were obtained via the hot microemulsion method, and their physical and chemical properties were comprehensively assessed using PCS, AFM, SEM, FT-IR, DSC, HPLC, kinetic drug release studies, and biological assays. The size of the developed delivery system was 218.85 ± 14.2 nm, its zeta potential was −30 mV and its entrapment efficiency (EE%) was high (the EEs% of YAN [yangambin] and EPI-YAN [epi-yangambin] markers were 94.21 ± 0.40% and 94.20 ± 0.00%, respectively). Microscopy, FT-IR and DSC assays confirmed that the delivery system was nanosized and indicated a core–shell encapsulation model, which corroborated the measured kinetics of drug release. The total in vitro release rates of YAN and EPI-YAN in buffer (with sink conditions attained) were 29.6 ± 8.3% and 34.3 ± 8.9%, respectively, via diffusion through the cellulose acetate membrane of the SLN over a period of 4 h. After 24 h, the release rates of both markers reached approximately 45%, suggesting a sustained pattern of release. Mathematical modeling indicated that both markers, YAN and EPI-YAN, followed matrix diffusion-based release kinetics (Higuchi's model) with an estimated diffusion coefficient (D) of 1.3.10 −6 cm 2 /s. The LF-loaded SLNs were non-toxic to murine macrophages (20–80 g mL −1 range) and exerted a prominent anti-leishmanial effect (20 g mL −1). These data suggest this new and well-characterized lipid nanoparticle delivery system safely and effectively kills Leishmania and warrants further clinical investigation.