In Vivo Evaluation of an Antibody-Functionalized Lipoidal Nanosystem for Schistosomiasis Intervention (original) (raw)
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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.
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.
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 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 ...
Miltefosine (MFS) is an alkylphosphocholine used for the local treatment of cutaneous metastases of breast cancer and oral therapy of visceral leishmaniasis. Recently, the drug was reported in in vitro and preclinical studies to exert significant activity against different developmental stages of schistosomiasis mansoni, a widespread chronic neglected tropical disease (NTD). This justified MFS repurposing as a potential antischistosomal drug. However, five consecutive daily 20 mg/kg doses were needed for the treatment of schistosomiasis mansoni in mice. The present study aims at enhancing MFS efficacy to allow for a single 20mg/kg oral dose therapy using a nanotechnological approach based on lipid nanocapsules (LNCs) as oral nanovectors. MFS was incorporated in LNCs both as membraneactive structural alkylphospholipid component and active antischistosomal agent. MFS-LNC formulations showed high entrapment efficiency (EE%), good colloidal properties, sustained release pattern and physical stability. Further, LNCs generally decreased MFSinduced erythrocyte hemolytic activity used as surrogate indicator of membrane activity. While MFS-free LNCs exerted no antischistosomal effect, statistically significant enhancement was observed with all MFS-LNC formulations. A maximum effect was achieved with MFS-LNCs incorporating CTAB as positive charge imparting agent or oleic acid as membrane permeabilizer. Reduction of worm load, ameliorated liver pathology and extensive damage of the worm tegument provided evidence for formulation-related efficacy enhancement. Non-compartmental analysis of pharmacokinetic data obtained in rats indicated independence of antischistosomal activity on systemic drug exposure, suggesting possible gut uptake of the stable LNCs and targeting of the fluke tegument which was verified by SEM. The study findings put forward MFS-LNCs as unique oral nanovectors combining the bioactivity of MFS and biopharmaceutical advantages of LNCs, allowing targeting via the oral route. From a clinical point of view, data suggest MFS-LNCs as a potential single dose oral nanomedicine for enhanced therapy of schistosomiasis mansoni and possibly other diseases.
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.
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.
Biomédica
Introduction: Praziquantel (PZQ) is the only commercially available drug for schistosomiasis. The current shortage of alternative effective drugs and the lack of successful preventive measures enhance its value. The increase in the prevalence of PZQ resistance under sustained drug pressure is, therefore, an upcoming issue.Objective: To overcome the tolerance to PZQ using nanotechnology after laboratory induction of a Schistosoma mansoni isolate with reduced sensitivity to the drug during the intramolluscan phase.Materials and methods: Shedding snails were treated with PZQ doses of 200 mg/kg twice/ week followed by an interval of one week and then repeated twice in the same manner. The success of inducing reduced sensitivity was confirmed in vitro via the reduction of cercarial response to PZQ regarding their swimming activity and death percentage at different examination times.Results: Oral treatment with a single PZQ dose of 500 mg/kg in mice infected with cercariae with reduced se...
Keywords Abbreviations www.IJVST.um.ac.ir Despite the development of novel drugs and technologies in combating the infectious diseases, they remain as a global health challenge. The use of conventional antimicrobial drugs are always associated with problems such as antimicrobial resistance, adverse effects, and inefficient drug delivery. In this regard, the unique physiochemical properties of the nanoparticles have led to increase in the researches on nanoparticles and their application as promising antimicrobial products. Lipid nanoparticles (LNPs) are new carrier systems developed as an alternative to traditional nanoparticle vehicles. The solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLCs), lipid-drug conjugates (LDCs), Lipid-core nanocapsules (LNCs) and lipid-polymer nanoparticles (LPNs) are carriers with a lipid matrix showing advantages for different applications due to the use of biodegradable, and biocompatible lipids. LNPs have exclusive properties owing to their ultra-small size and high surface area, thereby, they are able to increase drug targeting, treatment efficiency and reduce the toxicity of antimicrobial drugs. LNPs are often used as sustained release systems, and they also used for improving drug bio-availability. It has been found that the composition and structure of LNPs are two critical factors that may influence their pharmaceutical performance in different body organs. This review focuses on the development of LNP systems for antimicrobial drugs delivery and gives an overview on the modern LNP-based therapeutic strategies against the infections. The mechanism of action and advantages of these nanoparticles as antibacterial, antifungal, antiviral and anti-parasitic agents are highlighted in this review.
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.