ABSTRACT
The purpose of this study was to investigate the impact of different functional stabilizers on in vitro/in vivo drug performances after oral administration of drug nanocrystals. Quercetin nanocrystals (QT-NCs) respectively stabilized by five types of functional stabilizers, including hydroxypropyl methyl cellulose E15 (HPMC E15), poloxamer 407 (P407), poloxamer 188 (P188), D-α-tocopherol polyethylene glycol succinate (TPGS), and glycyrrhizin acid (GL), were fabricated by wet media milling technique. The particle size, morphology, physical state, drug solubility, drug dissolution in vitro, and orally pharmacokinetic behaviors of all QT-NCs were investigated. All QT-NCs with similar particle size about 200 nm were obtained by controlling milling speed and milling time. No significant differences in particles shape and crystalline nature were found for QT-NCs stabilized by different functional stabilizers. But the solubility and dissolution of QT-NCs were significantly influenced by the different functional stabilizers. The AUC0â¼t of all QT-NCs after oral administration was in the following order: QT-NCs/P188 ≈ QT-NCs/HPMC E15 > QT-NCs/GL > QT-NCs/P407 ≈ QT-NCs/TPGS, and the Cmax showed an order of QT-NCs/P407 > QT-NCs/P188 ≈ QT-NCs/GL > QT-NCs/HPMC E15 > QT-NCs/TPGS. Both of QT-NCs/P407 and QT-NCs/TPGS exhibited faster oral absorption with Tmax at 0.5 h and 0.83 h, respectively, while the other three QT-NCs (QT-NCs/P188, QT-NCs/GL and QT-NCs/HPMC E15) showed a relatively slow absorption with same Tmax at 5.33 h. The longest MRT0â¼t (11.72 h) and t1/2z (32.22 h) were observed for QT-NCs/HPMC E15. These results suggested that the different functional stabilizers could significantly influence on drug solubility, drug dissolution in vitro and orally pharmacokinetic behavior of QT-NCs, and it is possible to alter the drug dissolution in vitro, oral absorption and drug retention in vivo by changing the type of functional stabilizers in NCs preparation.
Subject(s)
Biological Availability , Nanoparticles , Quercetin , Solubility , Quercetin/pharmacokinetics , Quercetin/administration & dosage , Quercetin/chemistry , Quercetin/pharmacology , Nanoparticles/chemistry , Animals , Administration, Oral , Male , Particle Size , Rats, Sprague-Dawley , Drug Liberation , Rats , Excipients/chemistry , Poloxamer/chemistry , Glycyrrhizic Acid/chemistry , Glycyrrhizic Acid/pharmacokinetics , Glycyrrhizic Acid/administration & dosage , Vitamin E/chemistry , Vitamin E/pharmacokineticsABSTRACT
SCOPE: Tocomonoenols (T1) are little-known vitamin E derivatives naturally occurring in foods. Limited knowledge exists regarding the cellular uptake and metabolism of α-tocomonoenol (αT1) and none about that of γ-tocomonoenol (γT1). METHODS AND RESULTS: The study investigates the cytotoxicity, uptake, and metabolism of αT1 and γT1 in HepG2 cells compared to the α- and γ-tocopherols (T) and -tocotrienols (T3). None of the studied tocochromanols are cytotoxic up to 100 µmol L-1. The uptake of the γ-congeners is significantly higher than that of the corresponding α-forms, whereas no significant differences are observed based on the degree of saturation of the sidechain. Carboxymethylbutyl-hydroxychromans (CMBHC) are the predominant short-chain metabolites of all tocochromanols and conversion is higher for γT1 than αT1 as well as for the γ-congeners of T and T3. The rate of metabolism increases with the number of double bonds in the sidechain. The rate of metabolic conversion of the T1 is more similar to tocopherols than to that of the tocotrienols. CONCLUSION: This is the first evidence that both αT1 and γT1 follow the same sidechain degradation pathway and exert similar rates of metabolism than tocopherols. Therefore, investigation into the biological activities of tocomonoenols is warranted.
Subject(s)
Chromans , Vitamin E , Humans , Hep G2 Cells , Chromans/pharmacology , Vitamin E/pharmacology , Vitamin E/analogs & derivatives , Vitamin E/metabolism , Vitamin E/pharmacokinetics , gamma-Tocopherol/metabolism , gamma-Tocopherol/pharmacology , Tocotrienols/pharmacology , Tocotrienols/metabolism , Tocotrienols/pharmacokinetics , Cell Survival/drug effects , alpha-Tocopherol/pharmacology , alpha-Tocopherol/metabolism , alpha-Tocopherol/analogs & derivativesABSTRACT
Vitamin E (VE) is a potent nutritional antioxidant that is critical in alleviating poultry oxidative stress. However, the hydrophobic nature and limited stability of VE restrict its effective utilization. Nanotechnology offers a promising approach to enhance the bioavailability of lipophilic vitamins. The objective of this experiment was to investigate the effects of different sources and addition levels of VE on the growth performance, antioxidant capacity, VE absorption site, and pharmacokinetics of Arbor Acres (AA) broilers. Three hundred and eighty-four 1-d-old AA chicks were randomly allocated into four groups supplemented with 30 and 75 IU/kg VE as regular or nano. The results showed that dietary VE sources had no significant impact on broiler growth performance. However, chickens fed 30 IU/kg VE had a higher average daily gain at 22 to 42 d and 1 to 42 d, and lower feed conversion ratio at 22 to 42 d than 75 IU/kg VE (Pâ <â 0.05). Under normal feeding conditions, broilers fed nano VE (NVE) displayed significantly higher superoxide dismutase (SOD) activity and glutathione peroxidase (GSH-Px) enzyme activities and lower malonic dialdehyde (MDA) concentration (Pâ <â 0.05). Similarly, NVE had a higher antioxidant effect in the dexamethasone-constructed oxidative stress model. It was found that nanosizing technology had no significant effect on the absorption of VE in the intestinal tract by examining the concentration of VE in the intestinal tract (Pâ >â 0.05). However, compared to broilers perfused with regular VE (RVE), the NVE group displayed notably higher absorption rates at 11.5 and 14.5 h (Pâ <â 0.05). Additionally, broilers perfused with NVE showed a significant increase in the area under the concentration versus time curve from zero to infinity (AUC0-∞), mean residence time (MRT0-∞), elimination half-life (t1/2z), and peak concentration (Cmax) of VE in plasma (Pâ <â 0.05). In summary, nanotechnology provides more effective absorption and persistence of VE in the blood circulation for broilers, which is conducive to the function of VE and further improves the antioxidant performance of broilers.
With the rapid development of intensive farming, factors such as high temperature, harmful gases, high-fat and high-protein diets, and changes in feeding methods have become causes of oxidative stress in animals. Studies have shown that oxidative stress decreases livestock feed intake and slows growth in animals, thereby affecting the quality of livestock products. Antioxidants and micronutrients are commonly added to animal feed to reduce the effects of oxidative stress. Since the progress in nanotechnology, nanovitamins have gained extensive recognition due to their novel qualities, including a high level of adsorption capacity and low toxicity. Therefore, the present study compared the effects of dietary supplementation with different sources of vitamin E (regular, RVE vs. nano, NVE) and varying inclusion levels on the growth performance, antioxidant capacity, VE absorption sites, and pharmacokinetics in AA broilers. The results indicated that supplementing broiler diets with NVE provides superior antioxidant benefits compared to RVE. This improvement is attributed to the enhanced absorption efficiency and extended half-life of NVE, both contributing to increased antioxidant performance of broilers.
Subject(s)
Animal Feed , Antioxidants , Chickens , Diet , Dietary Supplements , Vitamin E , Animals , Antioxidants/metabolism , Antioxidants/pharmacology , Animal Feed/analysis , Diet/veterinary , Vitamin E/administration & dosage , Vitamin E/pharmacokinetics , Vitamin E/pharmacology , Dietary Supplements/analysis , Oxidative Stress/drug effects , Nanoparticles/chemistry , Nanoparticles/administration & dosage , Animal Nutritional Physiological Phenomena , Male , Random AllocationABSTRACT
This study aimed to synthesize a nano-structure between selenium, Vit. C, and Vit. E (Vit-E/C@SeNPs) as a promising protective and therapeutic agent for hepatocellular carcinoma. Vit-E/C@SeNPs were characterized using TEM and DLS and its zetapotential was measured to evaluate its stability. DPPH assay and SRB test were performed to estimate its antioxidant capacity and cytotoxicity, respectively. A radiosynthesis of 99mTc-Vit-E/C@SeNPs was done for further in-vivo pharmacokinetic studies on normal and solid tumor induced mice. Further, in-vivo studies were conducted to investigate Vit-E/C@SeNPs efficacy against hepatocellular damage in Wistar albino rats induced by diethylnitrosamine (DEN) / Carbon Tetra chloride (CCl4). The synthesis results showed spherical Vit-E/C@SeNPs with core size of 50 nm, radical scavenging activity (%RSC) of 75.9%, and IC50 of 27.9 µg/ml. The biochemical analysis results showed that the lower liver function biomarker values (ALT, AST, ALP, total bilirubin and GGT) has gone for the Vit-E/C@SeNPs prevention and treated group, which also showed significant depletion of liver tissue l-MDA, and obvious increase in GSH concentration and CAT activity and marked improvement in the histological feature of liver tissue. Additionally, a significant up-regulation of mRNA gene expression levels of inflammatory gene (TGFß1, NFκB, iNOS, PPAR-γ and TNFα) and Apoptotic gene (P53) were determined by using Quantitative real-time PCR (qPCR). The values down regulate and tend to normal in prevention and control group. All of these introduce Vit-E/C@SeNPs as a promising agent as protective and therapeutic agent against DEN/ CCl4-induced hepatocellular damage (Hepatocellular carcinoma).
Subject(s)
Antioxidants/pharmacology , Ascorbic Acid/pharmacology , Liver/drug effects , Selenium/pharmacology , Vitamin E/pharmacology , Animals , Antioxidants/administration & dosage , Antioxidants/pharmacokinetics , Ascorbic Acid/administration & dosage , Ascorbic Acid/pharmacokinetics , Carcinoma, Hepatocellular/drug therapy , Cell Line , Humans , Liver/metabolism , Liver Neoplasms/drug therapy , Male , Nanoparticles/administration & dosage , Nanoparticles/analysis , Rats , Rats, Wistar , Selenium/administration & dosage , Selenium/pharmacokinetics , Vitamin E/administration & dosage , Vitamin E/pharmacokineticsABSTRACT
In vitro human digestion models are widely used to determine the digestibility of bioactive substances and to perform drug delivery analyses. To develop the most accurate in vitro human digestion model reported to date, we simulated all digestion conditions, including pH and digestion time, with changes in the amount of digestive enzymes, motility, and proportion of human gut microbiota in adult and elderly individuals. Using this newly developed model, the digestibility of vitamin E emulsified by lard was found to be significantly different between adults and the elderly. Therefore, this model can accurately simulate oral, gastric, and intestinal (with gut microbiota effects) digestion of bioactive substances and can aid in analyzing drug delivery in adults and elderly individuals.
Subject(s)
Digestion/physiology , Gastrointestinal Microbiome , Vitamin E/pharmacokinetics , Adult , Age Factors , Aged , Female , Gastric Juice , Humans , Intestine, Large/metabolism , Male , Peristalsis , Time FactorsABSTRACT
Whether dietary antioxidants are effective for alleviating oxidative costs associated with energy-demanding life events first requires they are successfully absorbed in the digestive tract and transported to sites associated with reactive species production (e.g. the mitochondria). Flying birds are under high energy and oxidative demands, and although birds commonly ingest dietary antioxidants in the wild, the bioavailability of these consumed antioxidants is poorly understood. We show for the first time that an ingested lipophilic antioxidant, α-tocopherol, reached the mitochondria in the flight muscles of a songbird but only if they regularly exercise (60 min of perch-to-perch flights two times in a day or 8.5 km day-1). Deuterated α-tocopherol was found in the blood of exercise-trained zebra finches within 6.5 hrs and in isolated mitochondria from pectoral muscle within 22.5 hrs, but never reached the mitochondria in caged sedentary control birds. This rapid pace (within a day) and extent of metabolic routing of a dietary antioxidant to muscle mitochondria means that daily consumption of such dietary sources can help to pay the inevitable oxidative costs of flight muscle metabolism, but only when combined with regular exercise.
Subject(s)
Mitochondria, Muscle/metabolism , Muscle, Skeletal/metabolism , Physical Conditioning, Animal , Vitamin E/pharmacokinetics , Animals , Female , Finches , Male , Vitamin E/pharmacologyABSTRACT
The oral bioavailability of curcumin is limited, attributed to its low solubility or dissolution and poor absorption. Herein, the study describes formulation of curcumin-loaded mixed micelles of Gelucire® 48/16 and TPGS for its dissolution rate enhancement. Curcumin was dispersed in these molten lipidic surfactants which was then adsorbed on carrier and formulated as pellets by extrusion spheronization. Critical micelle concentration (CMC) of binary mixture of Gelucire® 48/16 and TPGS was lower than their individual CMC demonstrating the synergistic behavior of mixture. Thermodynamic parameters like partition coefficient and Gibbs free energy of solubilization indicated that mixed micelles were more efficient than micelles of its individual components in curcumin solubilization. Dynamic light scattering (DLS) suggested slight increase in micellar size of mixed micelles than its components suggesting curcumin loading in mixed micelles. Fourier transform infrared spectroscopy (FTIR) revealed that phenolic hydroxyl group interacts with lipids which contribute to its enhanced solubility. Furthermore, the differential scanning calorimetry (DSC) and X-ray diffraction (XRD) study indicated the conversion of crystalline curcumin into amorphous form. In the pellet formulation, Gelucire® 48/16 acted as a binder and eliminated the requirement of additional binder. Microcrystalline cellulose (MCC) forms wet mass and retards the release of curcumin from pellets. Increase in concentration of water-soluble diluent increased drug release. The optimized formulation released more than 90% drug and maintains supersaturation level of curcumin for 2 h. Thus, mixed micellar system was effective delivery system for curcumin while pellet formulation is an interesting formulation strategy consisting semi-solid lipids.
Subject(s)
Curcumin/chemical synthesis , Micelles , Polyethylene Glycols/chemical synthesis , Polymethacrylic Acids/chemical synthesis , Vitamin E/chemical synthesis , Biological Availability , Curcumin/pharmacokinetics , Drug Carriers/chemical synthesis , Drug Carriers/pharmacokinetics , Drug Liberation , Excipients/chemical synthesis , Excipients/pharmacokinetics , Polyethylene Glycols/pharmacokinetics , Polymethacrylic Acids/pharmacokinetics , Solubility , Vitamin E/pharmacokinetics , X-Ray Diffraction/methodsABSTRACT
We systematically investigated the impact of oil droplet diameter (≈0.15, 1.6, and 11 µm) on the bioaccessibility of three oil-soluble vitamins (vitamin A palmitate, vitamin D, and vitamin E acetate) encapsulated within soybean oil-in-water emulsions stabilized by quillaja saponin. Lipid digestion kinetics decreased with increasing droplet size due to the reduction in oil-water interfacial area. Vitamin bioaccessibility decreased with increasing droplet size from 0.15 to 11 µm: 87 to 39% for vitamin A; 76 to 44% for vitamin D; 77 to 21% for vitamin E. Vitamin bioaccessibility also decreased as their hydrophobicity and molecular weight increased, probably because their tendency to remain inside the oil droplets and/or be poorly solubilized by the mixed micelles increased. Hydrolysis of the esterified vitamins also occurred under gastrointestinal conditions: vitamin A palmitate (â¼90%) and vitamin E acetate (â¼3%). Consequently, the composition and structure of emulsion-based delivery systems should be carefully designed when creating vitamin-fortified functional food products.
Subject(s)
Diterpenes/pharmacokinetics , Gastrointestinal Tract/physiology , Retinyl Esters/pharmacokinetics , Vitamin D/pharmacokinetics , Vitamin E/pharmacokinetics , Biological Availability , Capsules , Digestion , Diterpenes/chemistry , Drug Carriers/chemistry , Drug Liberation , Emulsions , Hydrophobic and Hydrophilic Interactions , In Vitro Techniques , Lipid Metabolism , Micelles , Particle Size , Retinyl Esters/chemistry , Solubility , Soybean Oil/chemistry , Vitamin D/chemistry , Vitamin E/chemistryABSTRACT
An increasing body of evidence has shown that gut microbiota imbalances are linked to diseases. Currently, the possibility of regulating gut microbiota to reverse these perturbations by developing novel therapeutic and preventive strategies is being extensively investigated. The modulatory effect of vitamins on the gut microbiome and related host health benefits remain largely unclear. We investigated the effects of colon-delivered vitamins A, B2, C, D, and E on the gut microbiota using a human clinical study and batch fermentation experiments, in combination with cell models for the assessment of barrier and immune functions. Vitamins C, B2, and D may modulate the human gut microbiome in terms of metabolic activity and bacterial composition. The most distinct effect was that of vitamin C, which significantly increased microbial alpha diversity and fecal short-chain fatty acids compared to the placebo. The remaining vitamins tested showed similar effects on microbial diversity, composition, and/or metabolic activity in vitro, but in varying degrees. Here, we showed that vitamins may modulate the human gut microbiome. Follow-up studies investigating targeted delivery of vitamins to the colon may help clarify the clinical significance of this novel concept for treating and preventing dysbiotic microbiota-related human diseases. Trial registration: ClinicalTrials.gov, NCT03668964. Registered 13 September 2018 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03668964.
Subject(s)
Bacteria/growth & development , Colon/metabolism , Dietary Supplements , Gastrointestinal Microbiome/physiology , Vitamins/administration & dosage , Ascorbic Acid/administration & dosage , Ascorbic Acid/pharmacokinetics , Bacteria/classification , Bacteria/metabolism , Caco-2 Cells , Colon/microbiology , Cytokines/metabolism , Double-Blind Method , Drug Delivery Systems , Fatty Acids, Volatile/metabolism , Feces/microbiology , Fermentation , HT29 Cells , Humans , Pilot Projects , Riboflavin/administration & dosage , Riboflavin/pharmacokinetics , Vitamin A/administration & dosage , Vitamin A/pharmacokinetics , Vitamin D/administration & dosage , Vitamin D/pharmacokinetics , Vitamin E/administration & dosage , Vitamin E/pharmacokinetics , Vitamins/pharmacokineticsABSTRACT
Pharmacokinetic (PK) profiles of a range of bedaquiline (BDQ) long-acting injectable (LAI) microsuspensions in rats after parenteral (i.e., intramuscular and subcutaneous) administration were correlated with the in vitro intrinsic dissolution rate (IDR) and thermodynamic solubility of BDQ in media varying in surfactant type and concentration to better understand the impact of different nonionic surfactants on the in vivo performance of BDQ LAI microsuspensions. All LAI formulations had a similar particle size distribution. The investigated surfactants were d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), poloxamer 338, and poloxamer 188. Furthermore, the relevance of medium complexity by using a biorelevant setup to perform in vitro measurements was assessed by comparing IDR and thermodynamic solubility results obtained in biorelevant media and formulation vehicle containing different surfactants in varying concentrations. In the presence of a surfactant, both media could be applied to obtain in vivo representative dissolution and solubility data because the difference between the biorelevant medium and formulation vehicle was predominantly nonsignificant. Therefore, a more simplistic medium in the presence of a surfactant was preferred to obtain in vitro measurements to predict the in vivo PK performance of LAI aqueous suspensions. The type of surfactant influenced the PK profiles of BDQ microsuspensions in rats, which could be the result of a surfactant effect on the IDR and/or thermodynamic solubility of BDQ. Overall, two surfactant groups could be differentiated: TPGS and poloxamers. Most differences between the PK profiles (i.e., maximum concentration observed, time of maximum concentration observed, and area under the curve) were observed during the first 21 days postdose, the time period during which particles in the aqueous suspension are expected to dissolve.
Subject(s)
Diarylquinolines/chemistry , Diarylquinolines/pharmacokinetics , Suspensions/chemistry , Suspensions/pharmacokinetics , Water/chemistry , Animals , Chemistry, Pharmaceutical/methods , Excipients/chemistry , Excipients/pharmacokinetics , Male , Poloxamer/chemistry , Poloxamer/pharmacokinetics , Polyethylene Glycols/chemistry , Rats , Rats, Sprague-Dawley , Solubility , Surface-Active Agents/chemistry , Surface-Active Agents/pharmacokinetics , Thermodynamics , Vitamin E/chemistry , Vitamin E/pharmacokineticsABSTRACT
With the successful development and increased use of targeted radionuclide therapy for treating cancer comes the increased risk of radiation injury to bone marrow-both direct suppression and stochastic effects, leading to neoplasia. Herein, we report a novel radioprotector drug, a liposomal formulation of γ-tocotrienol (GT3), or GT3-Nano for short, to mitigate bone marrow radiation damage during targeted radionuclide therapy. Methods: GT3 was loaded into liposomes using passive loading. 64Cu-GT3-Nano and 3H-GT3-Nano were synthesized to study the in vivo biodistribution profile of the liposome and GT3 individually. The radioprotection efficacy of GT3-Nano was assessed after acute 137Cs whole-body irradiation at a sublethal (4 Gy), a lethal (9 Gy), or a single high-dose administration of 153Sm-ethylenediamine-N,N,N',N'-tetrakis(methylene phosphonic acid) (EDTMP). Flow cytometry and fluorescence microscopy were used to analyze hematopoietic cell population dynamics and the cellular site of GT3-Nano localization in the spleen and bone marrow, respectively. Results: Bone marrow uptake and retention (percentage injected dose per gram of tissue) at 24 h was 6.98 ± 2.34 for 64Cu-GT3-Nano and 7.44 ± 2.52 for 3H-GT3-Nano. GT3-Nano administered 24 h before or after 4 Gy of total-body irradiation (TBI) promoted rapid and complete hematopoietic recovery, whereas recovery of controls stalled at 60%. GT3-Nano demonstrated dose-dependent radioprotection, achieving 90% survival at 50 mg/kg against lethal 9-Gy TBI. Flow cytometry of the bone marrow indicated that progenitor bone marrow cells MPP2 and CMP were upregulated in GT3-Nano-treated mice. Immunohistochemistry showed that GT3-Nano accumulates in CD105-positive sinusoid epithelial cells. Conclusion: GT3-Nano is highly effective in mitigating the marrow-suppressive effects of sublethal and lethal TBI in mice. GT3-Nano can facilitate rapid recovery of hematopoietic components in mice treated with the endoradiotherapeutic agent 153Sm-EDTMP.
Subject(s)
Chromans/administration & dosage , Chromans/pharmacology , Hematopoiesis/drug effects , Hematopoiesis/radiation effects , Radiation-Protective Agents/administration & dosage , Radiation-Protective Agents/pharmacology , Radiotherapy/adverse effects , Vitamin E/analogs & derivatives , Animals , Chromans/pharmacokinetics , Liposomes , Mice , Radiation-Protective Agents/pharmacokinetics , Tissue Distribution , Vitamin E/administration & dosage , Vitamin E/pharmacokinetics , Vitamin E/pharmacologyABSTRACT
Background and purpose - Vitamin E-infused polyethylene is a relatively new material in joint arthroplasty; there are no long-term reports, and only few mid-term results. Using radiostereometric analysis (RSA), we primarily determined whether vitamin E-infused highly cross-linked polyethylene (HXLPE/VitE) acetabular cups show less wear than ultra-high molecular weight polyethylene (UHMWPE) acetabular cups at 5 years after total hip arthroplasty (THA). We also assessed whether wear rates correlate with increasing cup inclination angles or cup sizes.Patients and methods - This is a 5-year follow-up of our previously reported randomized controlled trial of 62 patients with 3 years' follow-up, who received THA with either an HXLPE/VitE or a UHMWPE acetabular cup. At 5 years, 40 patients were analyzed (22 in the HXLPE/VitE and 18 in the UHMWPE group).Results - HXLPE/VitE cups continued to show less cumulative femoral head penetration than UHMWPE cups (HXLPE/VitE: 0.24 mm, UHMWPE: 0.45 mm; p < 0.001). Distribution of wear was also more even with HXLPE/VitE cups than with UHMWPE cups (p = 0.002). Moreover, the difference in PE wear between 1 and 5 years in both groups showed no statistically significant correlation with increasing cup inclination angles or cup sizes. Finally, no osteolysis and implant loosening occurred, and no revision surgeries were required.Interpretation - Wear rates continue to be lower in HXLPE/VitE cups than in UHMWPE cups at 5 years of follow-up without correlation with increasing cup inclination angles or cup sizes. Finally, HXLPE/VitE cups may have the potential to prevent osteolysis and implant loosening.
Subject(s)
Arthroplasty, Replacement, Hip , Hip Prosthesis , Polyethylene , Prosthesis Design , Prosthesis Failure , Vitamin E/pharmacokinetics , Aged , Female , Humans , Male , Middle Aged , Polyethylenes , Radiostereometric AnalysisABSTRACT
Potential benefit of microencapsulation is its ability to deliver and protect incorporated ingredients such as vitamin E. Microcapsule wall properties can be changed by adding of coss-linking agents that are usually considered toxic for application. The microcapsules were prepared by a spray-drying technique using coacervation method, by depositing the coacervate formed in the mixture of chitosan and sodium lauryl ether sulfate to the oil/water interface. All obtained microcapsules suspensions had slightly lower mean diameter compared to the starting emulsion (6.85 ± 0.213 µm), which shows their good stability during the drying process. The choice and absence of cross-linking agents had influence on kinetics of vitamin E release. Encapsulation efficiency of microcapsules without cross-linking agent was 73.17 ± 0.64 %. This study avoided the use of aldehydes as cross-linking agents and found that chitosan/SLES complex can be used as wall material for the microencapsulation of hydrophobic active molecules in cosmetic industry.
Subject(s)
Drug Compounding/methods , Vitamin E/administration & dosage , Capsules/chemistry , Chitosan/chemistry , Cosmetics/administration & dosage , Cosmetics/pharmacokinetics , Cross-Linking Reagents , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/chemistry , Delayed-Action Preparations/pharmacokinetics , Dermatologic Agents/administration & dosage , Dermatologic Agents/pharmacokinetics , Desiccation , Emulsions , Humans , Hydrophobic and Hydrophilic Interactions , In Vitro Techniques , Kinetics , Microscopy, Electron, Scanning , Particle Size , Polyethylene Glycols/chemistry , Vitamin E/pharmacokineticsABSTRACT
Vitamin E belongs to the family of lipid-soluble vitamins and can be divided into two groups, tocopherols and tocotrienols, with four isomers (alpha, beta, gamma and delta). Although vitamin E is widely known as a potent antioxidant, studies have also revealed that vitamin E possesses anti-inflammatory properties. These crucial properties of vitamin E are beneficial in various aspects of health, especially in neuroprotection and cardiovascular, skin and bone health. However, the poor bioavailability of vitamin E, especially tocotrienols, remains a great limitation for clinical applications. Recently, nanoformulations that include nanovesicles, solid-lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, and polymeric nanoparticles have shown promising outcomes in improving the efficacy and bioavailability of vitamin E. This review focuses on the pharmacological properties and pharmacokinetics of vitamin E and current advances in vitamin E nanoformulations for future clinical applications. The limitations and future recommendations are also discussed in this review.
Subject(s)
Nanostructures/chemistry , Vitamin E/pharmacology , Vitamin E/pharmacokinetics , Biological Availability , Drug Compounding , Humans , Vitamin E/chemistryABSTRACT
Vitamin E, a natural antioxidant, is of interest to scientists, health care pundits and faddists; its nutritional and biomedical attributes may be validated, anecdotal or fantasy. Vitamin E is a mixture of tocopherols (TPs) and tocotrienols (T-3s), each class having four substitutional isomers (α-, ß-, γ-, δ-). Vitamin E analogues attain only low concentrations in most tissues, necessitating exacting invasive techniques for analytical research. Quantitative positron emission tomography (PET) with an F-18-labeled molecular probe would expedite access to Vitamin E's biodistributions and pharmacokinetics via non-invasive temporal imaging. (R)-6-(3-[18F]Fluoropropoxy)-2,7,8-trimethyl-2-(4,8,12-trimethyltrideca-3,7,11-trien-1-yl)-chromane ([18F]F-γ-T-3) was prepared for this purpose. [18F]F-γ-T-3 was synthesized from γ-T-3 in two steps: (i) 1,3-di-O-tosylpropane was introduced at C6-O to form TsO-γ-T-3, and (ii) reaction of this tosylate with [18F]fluoride in DMF/K222. Non-radioactive F-γ-T-3 was synthesized by reaction of γ-T-3 with 3-fluoropropyl methanesulfonate. [18F]F-γ-T-3 biodistribution in a murine tumor model was imaged using a small-animal PET scanner. F-γ-T-3 was prepared in 61% chemical yield. [18F]F-γ-T-3 was synthesized in acceptable radiochemical yield (RCY 12%) with high radiochemical purity (>99% RCP) in 45 min. Preliminary F-18 PET images in mice showed upper abdominal accumulation with evidence of renal clearance, only low concentrations in the thorax (lung/heart) and head, and rapid clearance from blood. [18F]F-γ-T-3 shows promise as an F-18 PET tracer for detailed in vivo studies of Vitamin E. The labeling procedure provides acceptable RCY, high RCP and pertinence to all eight Vitamin E analogues.
Subject(s)
Fluorides/chemistry , Fluorine Radioisotopes/chemistry , Tissue Distribution/physiology , Tocotrienols/chemistry , Tocotrienols/pharmacokinetics , Vitamin E/chemistry , Vitamin E/pharmacokinetics , Animals , Antioxidants/chemistry , Antioxidants/pharmacokinetics , Cell Line, Tumor , Female , Fluorides/pharmacokinetics , Fluorine Radioisotopes/pharmacokinetics , Humans , Isotope Labeling/methods , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Probes/chemistry , Molecular Probes/pharmacokinetics , Oxidation-Reduction , Positron-Emission Tomography/methods , Radiochemistry/methods , Radiopharmaceuticals/metabolism , gamma-Tocopherol/chemistry , gamma-Tocopherol/pharmacokineticsABSTRACT
CoQ10 and Vitamin E are used in medicinal applications, but they are both lipophilic molecules and the poor solubility in aqueous media results in an inefficient administration, poor bioavailability and potential toxicity. A mixed conjugate Ubiquinol-Polyethylene glycol-Vitamin E was synthesized and characterized to improve the bioavailability of CoQ10 and Vitamin E. The synthesized mixed PEG conjugate was characterized by 1H NMR spectroscopy and MALDI spectrometry. The in vitro release of the conjugate was measured at various pH conditions and in human plasma and the evaluation of free CoQ10 and Vitamin E were also conducted. The obtained results demonstrated that more CoQ10 and Vitamin E were released from PEG conjugate at pH 7.4 and in plasma within the 24 h. The antioxidant activity evaluation was carried out by DPPH assay. Our results indicated that the chemical modification after esterification with PEG of the two drugs Ubiquinol and Vitamin E doesn't significantly affected their antioxidant potential.
Subject(s)
Antioxidants/chemistry , Drug Carriers/chemistry , Polyethylene Glycols/chemistry , Ubiquinone/analogs & derivatives , Vitamin E/chemistry , Antioxidants/pharmacology , Biological Availability , Drug Compounding , Drug Liberation , Drug Therapy, Combination , Humans , Solubility , Succinic Acid/chemistry , Ubiquinone/chemistry , Ubiquinone/pharmacokinetics , Vitamin E/pharmacokineticsABSTRACT
Efficient delivery of chemotherapeutic agents into tumor cells and reversal of chemoresistance are crucially important to enhance cancer therapy. We fabricated pH/redox dual responsive nanocarriers based on cell penetrating peptides (TAT) functionalized TPGS (cTAT-TPGS) and polypeptide (PEG-b-poly(aspartic-lipoic acid), PPAL) to reduce the permanent drug release and overcome multidrug resistance. TAT was used to functionalize TPGS and shielded by pH-responsive fatty acids, and polypeptides with lipoic acid side chains (PPAL) were synthesized. Reversibly crosslinked hybrid micelles (RCMs) were fabricated based on cTAT-TPGS and PPAL. RCMs nanocarriers exhibited acid-responsive charge reversal and redox-responsive drug release. The in vitro results showed that the RCMs could be efficiently internalized by the MCF-7/ADR cells in an acidic microenvironment and inhibited the DOX efflux, causing a higher cytotoxicity than non-crosslinked nanocarriers. Furthermore, the dual-responsive structure effectively prolonged the circulation time of RCM nanocarriers and achieved a high level of accumulation in cancer cells in vivo, leading to much more effective inhibition of tumor growth. The DOX-loaded RCMs also showed excellent biosafety, especially for the myocardium tissue. This novel strategy provided an effective platform for drug target delivery and reversal of MDR.
Subject(s)
Antineoplastic Agents/therapeutic use , Doxorubicin/therapeutic use , Drug Carriers/chemistry , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Neoplasms/drug therapy , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Apoptosis/drug effects , Cell-Penetrating Peptides/chemistry , Cell-Penetrating Peptides/pharmacokinetics , Doxorubicin/chemistry , Doxorubicin/pharmacokinetics , Drug Carriers/pharmacokinetics , Drug Liberation , Female , Fluorescence , Humans , MCF-7 Cells , Mice, Inbred BALB C , Micelles , Polyethylene Glycols/chemistry , Polyethylene Glycols/pharmacokinetics , Vitamin E/pharmacokinetics , Vitamin E/therapeutic useABSTRACT
Garcinoic acid (GA or δ-T3-13'COOH), is a natural vitamin E metabolite that has preliminarily been identified as a modulator of nuclear receptors involved in ß-amyloid (Aß) metabolism and progression of Alzheimer's disease (AD). In this study, we investigated GA's effects on Aß oligomer formation and deposition. Specifically, we compared them with those of other vitamin E analogs and the soy isoflavone genistein, a natural agonist of peroxisome proliferator-activated receptor γ (PPARγ) that has therapeutic potential for managing AD. GA significantly reduced Aß aggregation and accumulation in mouse cortical astrocytes. Similarly to genistein, GA up-regulated PPARγ expression and apolipoprotein E (ApoE) efflux in these cells with an efficacy that was comparable with that of its metabolic precursor δ-tocotrienol and higher than those of α-tocopherol metabolites. Unlike for genistein and the other vitamin E compounds, the GA-induced restoration of ApoE efflux was not affected by pharmacological inhibition of PPARγ activity, and specific activation of pregnane X receptor (PXR) was observed together with ApoE and multidrug resistance protein 1 (MDR1) membrane transporter up-regulation in both the mouse astrocytes and brain tissue. These effects of GA were associated with reduced Aß deposition in the brain of TgCRND8 mice, a transgenic AD model. In conclusion, GA holds potential for preventing Aß oligomerization and deposition in the brain. The mechanistic aspects of GA's properties appear to be distinct from those of other vitamin E metabolites and of genistein.
Subject(s)
Amyloid beta-Peptides/metabolism , Benzopyrans/pharmacology , Brain/drug effects , Protein Aggregation, Pathological/prevention & control , Vitamin E/analogs & derivatives , Amyloid beta-Peptides/ultrastructure , Animals , Benzopyrans/pharmacokinetics , Brain/metabolism , Brain/pathology , Male , Mice , Protein Aggregates/drug effects , Protein Aggregation, Pathological/pathology , Vitamin E/pharmacokinetics , Vitamin E/pharmacologyABSTRACT
Hepatocellular carcinoma (HCC) is a foremost type of cancer problem in which asialoglycoprotein receptors are overexpressed. In this study, asialoglycoprotein receptor-targeted nanoformulation (galactose-conjugated TPGS micelles) loaded with docetaxel (DTX) was developed to achieve its site-specific delivery for HCC therapy. The pharmaceutical characteristics like shape morphology, average particle size and zeta potential, drug entrapment efficiency, and in vitro release kinetics of developed system were evaluated. DTX-loaded galactosylated TPGS (DTX-TPGS-Gal) micelles and TPGS micelles (DTX-TPGS) were having 58.76 ± 1.82% and 54.76 ± 1.42% entrapment of the DTX, respectively. In vitro drug release behavior from micelles was controlled release. Cytotoxicitiy (IC50) of DTX-TPGS-Gal formulation on HepG2 cell lines was significantly (p ≤ 0.01) lower (6.3 ± 0.86 µg/ml) than DTX-TPGS (9.06 ± 0.82 µg/ml) and plain DTX (16.06 ± 0.98 µg/ml) indicating higher efficacy of targeted formulation. Further, in vivo biodistribution studies in animal model showed maximum drug accumulation at target site, i.e., the liver in the case of DTX-TPGS-Gal as compared with non-targeted one. It is concluded from the findings that TPGS-Gal micelles can be utilized for targeted drug delivery of cytotoxic drugs towards HCC with minimized side effects. Graphical abstract.
Subject(s)
Carcinoma, Hepatocellular/metabolism , Docetaxel/chemistry , Drug Delivery Systems/methods , Galactose/chemistry , Liver Neoplasms/metabolism , Vitamin E/chemistry , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Carcinoma, Hepatocellular/drug therapy , Cell Line, Tumor , Docetaxel/administration & dosage , Docetaxel/pharmacokinetics , Drug Development/methods , Female , Galactose/administration & dosage , Galactose/pharmacokinetics , Hep G2 Cells , Humans , Liver Neoplasms/drug therapy , Male , Random Allocation , Rats , Tissue Distribution/drug effects , Tissue Distribution/physiology , Vitamin E/administration & dosage , Vitamin E/pharmacokineticsABSTRACT
Novel vitamin E chelate derivatives and their VIV/V complexes have been synthesized and characterized, and their anticancer properties have been evaluated. The new complexes have been designed to exhibit enhanced cytotoxicity by combining high lipophilicity with the properties of vanadium to induce the formation of reactive oxygen species (ROS). In particular, the ß-tocopherol derivatives with iminodiethanol (ß-tocDEA) and dipicolylamine (ß-tocDPA) as well their VV and VIV complexes, [VVO(ß-tocDEA] and [VIVO(ß-tocDPA] have been synthesized and characterized by Nuclear Magnetic Resonance (NMR), Ultra Violet-Visible (UV-Vis) and Electron Paramagnetic Resonance (EPR) spectroscopies. Although the ß-tocopherol compounds exhibit antioxidant activity their complexes induce formation of radicals. In addition, two vanadium amphiphilic complexes of 2,2'-((2-hydroxyoctadecyl)azanediyl)bis(ethan-1-ol) (C18DEA) and 1-(bis(pyridin-2-ylmethyl)amino)octadecan-2-ol (C18DPA) known to activate O2 and produce ROS were synthesized and characterized (C. Drouza, A. Dieronitou, I. Hadjiadamou, M. Stylianou, J. Agric. Food. Chem., vol. 65, 2017, pp. 4942-4951). The four amphiphilic vanadium complexes exhibit enhanced hydrolytic stability. All compounds found to be cytotoxic for cancer cells exhibiting activity similar or higher to cis-platin.