QbD-based formulation development of resveratrol nanocrystal incorporated into soluble mesoporous material: Pharmacokinetic proof of concept study.

Resveratrol (RSV) has powerful antioxidant activities. However, the bioavailability is still limited due to low solubility and transport issues. Nanocrystal technology has been introduced to address these issues; however, the bulky formulation of the nanocrystal process through nanosuspension faces a big challenge in terms of stability and scale-up ability. This work aimed to enhance the bioavailability of RSV through nanocrystal formulation incorporated into soluble mesoporous carriers for superior solid-state stability and feasibility. This formulation was designed and developed rationally through scientific justification in the nanocrystal formulation along with quality by design paradigm. Box-Behnken design was applied to determine the optimized formulation based on the particle size and distribution, drug loading, zeta potential, and supersaturation parameters. The nanocrystal was formed through evaporation of drug, polymer, and surfactant in the solvent incorporated into mesoporous material. The nanocrystal was evaluated by vibrational spectroscopy, thermal analyses, and SEM and TEM photographs, followed by crystallinity evaluation. The results indicated that the factors only affected the particle size variation, zeta potential, drug loading, and the time to reach the supersaturation peak level. The optimized formulation was achieved by 68 % desirability value, producing 133.3 ± 1.2 nm particle size and -24.6 mV zeta potential. The physical and chemical evaluation characterization indicated no interaction between RSV and carrier. In addition, there was no difference in crystallinity between the RSV nanocrystal and native RSV. Moreover, the RSV nanocrystal improved the bioavailability nearly twice compared to the RSV suspension.

Intestinal Targeted Nanogel with Broad-Spectrum Autonomous ROS Scavenging Performance for Enhancing the Bioactivity of trans-Resveratrol.

Introduction: To improve the bioavailability of trans-resveratrol (trans-Res), it is commonly co-delivered with antioxidant bioactives using a complex synthetic intestinal targeted carrier, however, which makes practical application challenging. Methods: A nanogel (Ngel), as broad-spectrum autonomous ROS scavenger, was prepared using selenized thiolated sodium alginate (TSA-Se) and crosslinked with calcium lactate (CL) for loading trans-Res to obtain Ngel@Res, which maintained spherical morphology in the upper digestive tract but broke down in the lower digestive tract, resulting in trans-Res release. Results: Under protection of Ngel, trans-Res showed enhanced stability and broad-spectrum ROS scavenging activity. The synergistic mucoadhesion of Ngel prolonged the retention time of trans-Res in the intestine. Ngel and Ngel@Res increased the lifespan of Caenorhabditis elegans to 26.00 ± 2.17 and 26.00 ± 4.27 days by enhancing the activity of antioxidases, upregulating the expression of daf-16, sod-5 and skn-1, while downregulating the expression of daf-2 and age-1. Conclusion: This readily available, intestinal targeted selenized alginate-based nanogel effectively improves the bioactivity of trans-Res.

In vivo modification of the enamel pellicle and saliva resveratrol levels after use of resveratrol-containing orodispersible capsules.

OBJECTIVES: To evaluate in vivo 1) the bioavailability of trans-resveratrol when administered through sublingual capsules; 2) the effect of resveratrol on the protein composition of the acquired enamel pellicle (AEP). DESIGN: Ten volunteers received a sublingual capsule containing 50 mg of trans-resveratrol. Unstimulated saliva was then collected after 0, 30, 60, and 120 min and AEP was collected after 120 min following administration of the capsule. In the next week, the volunteers received a placebo sublingual capsule, and saliva and AEP were collected again. Saliva samples were analyzed for free trans-resveratrol using high-performance liquid chromatopgraphy (HPLC), and AEP samples were subjected to proteomic analysis (nLC-ESI-MS/MS). RESULTS: Trans-resveratrol was detected in saliva at all the time points evaluated, with the peak at 30 min. A total of 242 proteins were identified in both groups. Ninety-six proteins were increased and 23 proteins were decreased in the Resveratrol group. Among the up-regulated proteins, isoforms of cystatins, PRPs, Mucin-7, Histatin-1, Lactotrasnferrin and Lysozyme-C were increased and the isoforms of Protein S100, Neutrophil defensins, Albumin, PRPs, and, Statherin were decreased in Resveratrol group. CONCLUSION: The sublingual capsule is effective at increasing the bioavailability of trans-resveratrol in saliva. Several proteins involved in important processes to maintain systemic and oral health homeostasis were identified. These proteins differently expressed due to the presence of trans-resveratrol deserve attention for future studies, since they have important functions, mainly related to antimicrobial action.

Hyaluronic acid-poly(glyceryl)10-stearate nanoemulsion for co-delivery of fish oil and resveratrol: Enhancing bioaccessibility and antioxidant potency.

Hyaluronic acid (HA), an endogenous polysaccharide comprising alternating D-glucuronic acid and N-acetylglucosamine units, is renowned for its high hydrophilicity, biocompatibility, and biodegradability. These attributes have rendered HA invaluable across medical and drug delivery fields. HA can be altered through physical, chemical, or enzymatic methods to improve the properties of the modified substances. In this work, we synthesized a derivative via the esterification of HA with poly(glyceryl)10-stearate (PG10-C18), designated as HA-PG10-C18. This novel derivative was employed to fabricate a nano co-delivery system (HA-PG10-C18@Res-NE) for fish oil and resveratrol (Res), aiming to enhance their stability and bioaccessibility. An exhaustive investigation of HA-PG10-C18@Res-NE revealed that the HA-modified system displayed superior physicochemical stability, notably in withstanding oxidation and neutralizing free radicals. Moreover, in vitro simulated digestion underscored the system's enhanced bioaccessibility of Res and more efficient release of free fatty acids. These outcomes underscore the strategic advantage of HA in modifying PG10-C18 for nanoemulsion formulation. Consequently, HA-PG10-C18 stands as a promising emulsifier for encapsulating lipophilic bioactives in functional foods, nutraceuticals, and pharmaceuticals.

Resveratrol-Ampicillin Dual-Drug Loaded Polyvinylpyrrolidone/Polyvinyl Alcohol Biomimic Electrospun Nanofiber Enriched with Collagen for Efficient Burn Wound Repair.

Background: The healing of burn wounds is a complicated physiological process that involves several stages, including haemostasis, inflammation, proliferation, and remodelling to rebuild the skin and subcutaneous tissue integrity. Recent advancements in nanomaterials, especially nanofibers, have opened a new way for efficient healing of wounds due to burning or other injuries. Methods: This study aims to develop and characterize collagen-decorated, bilayered electrospun nanofibrous mats composed of PVP and PVA loaded with Resveratrol (RSV) and Ampicillin (AMP) to accelerate burn wound healing and tissue repair. Results: Nanofibers with smooth surfaces and web-like structures with diameters ranging from 200 to 400 nm were successfully produced by electrospinning. These fibres exhibited excellent in vitro properties, including the ability to absorb wound exudates and undergo biodegradation over a two-week period. Additionally, these nanofibers demonstrated sustained and controlled release of encapsulated Resveratrol (RSV) and Ampicillin (AMP) through in vitro release studies. The zone of inhibition (ZOI) of PVP-PVA-RSV-AMP nanofibers against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) was found 31±0.09 mm and 12±0.03, respectively, which was significantly higher as compared to positive control. Similarly, the biofilm study confirmed the significant reduction in the formation of biofilms in nanofiber-treated group against both S. aureus and E. coli. X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) analysis proved the encapsulation of RSV and AMP successfully into nanofibers and their compatibility. Haemolysis assay (%) showed no significant haemolysis (less than 5%) in nanofiber-treated groups, confirmed their cytocompatibility with red blood cells (RBCs). Cell viability assay and cell adhesion on HaCaT cells showed increased cell proliferation, indicating its biocompatibility as well as non-toxic properties. Results of the in-vivo experiments on a burn wound model demonstrated potential burn wound healing in rats confirmed by H&E-stained images and also improved the collagen synthesis in nanofibers-treated groups evidenced by Masson-trichrome staining. The ELISA assay clearly indicated the efficient downregulation of TNF-alpha and IL-6 inflammatory biomarkers after treatment with nanofibers on day 10. Conclusion: The RSV and AMP-loaded nanofiber mats, developed in this study, expedite burn wound healing through their multifaceted approach.

Preparation of Eudragit S100-pullulan/hydroxypropyl-ß-cyclodextrin complex-Eudragit S100 multilayer nanofiber film for resveratrol colon delivery.

Cyclodextrin-based electrospun nanofibers are promising for encapsulating and preserving unstable compounds, but quick dissolution of certain nanofibers hinders their delivery application. In this study, hydroxypropyl-ß-cyclodextrin (HPßCD) was used as an effective carrier of resveratrol (RSV) to obtain the RSV/HPßCD inclusion complex (HPIC), which was then incorporated into pullulan nanofibers. For enhancement of RSV release toward colon target, multilayer structure with a pullulan/HPIC film sandwiched between two layers of hydrophobic Eudragit S100 (ES100) nanofibers was employed. The relationship between the superiority of the ES100-pullulan/HPIC-ES100 film and its multilayer structure was verified. The intimate interactions of hydrogen bonds between two adjacent layers enhanced thermal stability, and the hydrophobic outer layers improved water contact resistance. According to release results, multilayer films also showed excellent colon-targeted delivery property and approximately 78.58 % of RSV was observed to release in colon stage. In terms of release mechanism, complex mechanism best described RSV colonic release. Additionally, ES100-pullulan/HPIC-ES100 multilayer films performed higher encapsulation efficiency when compared to the structures without HPIC, which further increased the antioxidant activity and total release amount of RSV. These results suggest a promising strategy for designing safe colonic delivery systems based on multilayer and HPIC structures with superior preservation for RSV.

Fabrication and characterization of novel prolamin nanoparticle-filled starch gels incorporating resveratrol.

This study aimed to improve the mechanical properties of wheat starch gels (WSG) and the stability and bioaccessibility of resveratrol (Res) in prolamin nanoparticles. Res-loaded gliadin (Gli), zein, deamidated gliadin (DG) and deamidated zein (DZ) nanoparticles were filled in WSG. The hardness, G' and G'' of WSG were notably increased. It can be attributed to the more ordered and stable structure induced by the interaction of prolamin nanoparticles and starch. The Res retention of nanoparticles and nanoparticle-filled starch gels was at least 24.6 % and 36.0 % higher than free Res upon heating. When exposed to ultraviolet, the Res retention was enhanced by over 6.1 % and 37.5 %. The in-vitro digestion demonstrated that the Res releasing percentage for nanoparticle-filled starch gels was 25.8 %-38.7 % lower than nanoparticles in the simulated stomach, and more Res was released in the simulated intestine. This resulted in a higher bioaccessibility of 82.1 %-93.2 %. The bioaccessibility of Res in Gli/Res/WSG and DG/Res/WSG was greater than that of Zein/Res/WSG and DZ/Res/WSG. More hydrophobic interactions occurred between Res and Gli, DG. The interactions between Res and zein, DZ were mainly hydrogen bonding. The microstructure showed that nanoparticles exhibited dense spherical structures and were uniformly embedded in the pores of starch gels.

Enhanced in vitro bioavailability of resveratrol-loaded emulsion stabilized by ß-lactoglobulin-catechin with excellent antioxidant activity.

The study aimed to fabricate ß-Lactoglobulin-catechin (ß-La-Ca) conjugates as a natural designed antioxidant emulsifier to improve the physicochemical stability of resveratrol emulsion delivery system. Fourier transform infrared (FT-IR) and fluorescence spectroscopy analysis confirmed the formation of conjugates using free radical grafting. The antioxidant ability of emulsion was evaluated by DPPH scavenging activities and ORAC experiments. The emulsion stabilized by ß-La-Ca conjugates exhibited strong antioxidant activity with ORAC value of 2541.39 ± 29.58 µmol TE/g, which was significantly higher than that by ß-Lactoglobulin alone with 387.96 ± 23.45 µmol TE/g or their mixture with 948.23 ± 32.77 µmol TE/g. During the whole simulated gastrointestinal digestion, emulsion stabilized by ß-La-Ca conjugates exhibited excellent oxidative stability that the lipid was mainly digested in the small intestine. This behavior attributed to the greater stability of resveratrol to chemical transformation leading to a higher overall bioavailability in vivo. These results suggested that the ß-La-Ca conjugates could be used to fabricate the emulsion-based delivery system to improve the oxidative stability and bioavailability of chemically labile hydrophobic bioactive compounds.

An exosomal approach for oral delivery of resveratrol: Implications for inflammatory bowel disease treatment in rat model.

AIMS: Resveratrol (RSV) is a polyphenolic substance found in numerous natural products. Despite the wide range of therapeutic activities, including antioxidant and anti-inflammatory effects, the poor pharmacokinetic characteristics decrease the RSV bioavailability following oral administration. Milk-derived exosomes (MEXOs), as a class of natural nanocarriers, are promising candidates for oral drug delivery approaches. MAIN METHODS: The current study developed RSV-loaded MEXOs to enhance the RSV oral bioavailability, introducing a suitable exosomal formulation for suppressing colon inflammation in acetic acid-induced rat models. KEY FINDINGS: The results showed a remarkable encapsulation efficiency of 83.33 %. The in vitro release profile demonstrated a good retaining capability in acidic conditions (pH 1.2) and a considerable release in a simulated duodenal environment (pH 6.8). According to the permeability study, encapsulation of RSV improved its transportation across the Caco-2 monolayer. Moreover, the in vivo and histological analysis results proved that the RSV-MEXOs formulation successfully alleviates the inflammation in colitis rat models and effectively relieves the colitis. SIGNIFICANCE: Our findings suggest that MEXOs should be of great attention as promising oral drug delivery vehicles for further clinical evaluations.

The science of resveratrol, formulation, pharmacokinetic barriers and its chemotherapeutic potential.

Chemopreventive properties of resveratrol has been studied for decades. Despite its potential for chemotherapeutic advancement, the compound has pharmaceutical limitations, such as, the drug has a poor pharmacokinetic profile and low bioavailability. Studies have comforting results that that the nano-formulations may aid the future resveratrol drug development. Resveratrol can also be encapsulated as co-drug with an anticipation of gaining improved targeting and pharmacokinetic parameters, as well as achieving desired therapeutic plasma levels. It has been envisaged that the nanoformulations can also address the issue of drug accumulation, which may lead to hepatotoxicity. Nanoformulations can bring a major improvement in the bioavailability of resveratrol but still the formulation still suffers with pharmacokinetics issues clinically. This review encompasses the pharmacokinetics barriers associated with resveratrol and a possible suggestion to overcome those barriers for improving absorbance, reducing toxicity andimproving the drug releaseand encapsulation efficiency. The article also suggest that co-administration of resveratrol with chemotherapeutic drugsmust be tested in vivo on a wide range of cancers to avoid accidental proliferation exacerbation. The review's focusses on the resveratrol formulation and make suggestions for improvements in order to overcome the pharmacokinetic and toxicity issues.

GSH-responsive poly-resveratrol based nanoparticles for effective drug delivery and reversing multidrug resistance.

Cancer poses a serious threat to human health and is the most common cause of human death. Polymer-based nanomedicines are presently used to enhance the treatment effectiveness and decrease the systemic toxicity of chemotherapeutic agents. However, the disadvantage of currently polymeric carriers is without therapy procedure. Herein, for the first time, glutathione (GSH)-responsive polymer (PRES) with anti-cancer effect was synthesized following the condensation-polymerization method using resveratrol (RES) and 3,3'-dithiodipropionic acid. PRES can not only suppress the tumor cells growth but can also self-assemble into nanoparticles (∼93 nm) for delivering antitumor drugs, such as paclitaxel (PTX@PRES NPs). The system could achieve high drug loading (∼7%) and overcome multidrug resistance (MDR). The results from the in vitro studies revealed that the NPs formed of PRES were stable in the systemic circulation, while could be efficiently degraded in tumor cells high GSH environment. Results from cytotoxicity tests confirmed that PTX@PRES NPs could effectively suppress the growth of cancer cells (A549) and drug-resistant cells (A549/PTX). The NPs could also be used to significantly increase the therapeutic efficacy of the drugs in A549/PTX tumor-bearing mice. In vivo investigations also demonstrated that the PRES-based NPs exhibited tumor inhibition effects. In summary, we report that the GSH-responsive polymer synthesized by us exhibited multiple interesting functions and could be used for effective drug delivery. The polymer exhibited good therapeutic effects and could be used to overcome MDR. Thus, the synthesized system can be used to develop a new strategy for treating cancer.

A rapid HPLC-MS/MS method for the simultaneous determination of luteolin, resveratrol and their metabolites in rat plasma and its application to pharmacokinetic interaction studies.

Both luteolin (LUT) and resveratrol (RES) are natural polyphenols that exert therapeutic effects on liver injuries. Extensive glucuronidation by uridine diphosphate-glucuronosyltransferases 1As (UGT1As) results in poor bioavailability of LUT, which limits its clinical application. As an inhibitor of UGT1A1 and UGT1A9, RES may affect the bioavailability of LUT. The purpose of this study was to develop and validate an HPLC-MS/MS method for the simultaneous determination of LUT, luteolin-3'-O-glucuronide (LUT-3'-G), RES and resveratrol-3-O-glucuronide (RES-3-G) in rat plasma to investigate the effects of RES on the bioavailability and metabolism of LUT after coadministration. The samples were extracted by protein precipitation with methanol using daidzein and naringenin as the internal standards. Separation was achieved on an XBridgeTM C18 column by isocratic elution using 88% methanol-12% water with 2 mM ammonium acetate and 0.01% formic acid. Multiple reaction monitoring mode with a negative electrospray ionization interface was used for quantification of the analytes. The calibration curves were linear over the concentration ranges of 1-1000 (r > 0.995), 2-2000 (r > 0.999), 5-5000 (r > 0.998) and 10-40000 ng/mL (r > 0.996) for LUT, LUT-3'-G, RES and RES-3-G, respectively. The method was fully validated in terms of accuracy, precision, matrix effect, recovery and stability. The validated data met the acceptance criteria in FDA guidelines. The method was successfully applied in a pharmacokinetic interaction study of LUT and RES. The results indicated that RES had a significant effect on the enhanced bioavailability of LUT by reducing the major glucuronidation metabolite in rats, which provides a reference for the combination of LUT and RES in liver diseases.

Impact of calcium ions and degree of oxidation on the structural, physicochemical, and in-vitro release properties of resveratrol-loaded oxidized gellan gum hydrogel beads.

Oxidized gellan gum (OGG) hydrogel beads as delivery systems for resveratrol were fabricated by ionic cross-linking with calcium chloride (CaCl2). The degree of oxidation (DO) and CaCl2 concentration had significant influences on the formation and functional properties of hydrogel beads. The resveratrol encapsulation efficiency (66.43%-79.84%) and loading capacity (4.15%-5.05%) of OGG hydrogel beads were enhanced as DO increased. The hydrogel beads exhibited a uniform spherical shape as observed by scanning electron microscope. Fourier transform infrared spectroscopy analysis confirmed that hydrogen bonds and ionic interaction participated in the formation of hydrogel beads. X-ray diffraction analysis revealed that the physical state of resveratrol was changed from crystalline to amorphous form after encapsulation. Furthermore, the physical stability and antioxidant capacity evaluation demonstrated that the hydrogel bead fabricated with DO80 OGG and CaCl2 concentration of 1.0 M could provide high protection for resveratrol against degradation by environmental stresses and maintain its antioxidant capacity. The DO and CaCl2 concentrations could modulate the in-vitro release behaviors of hydrogel beads and obtain a good small intestinal-targeted release of resveratrol at high DO and medium CaCl2 concentration. These findings suggested that a promising delivery system for encapsulating bioactive ingredients can be fabricated by rational design.

Bare Metal Stents on Resveratrol-Coated Balloons in Porcine Coronary and Peripheral Arteries.

Balloon angioplasty and stent implantation are standard techniques to reopen stenotic vessels. Often, balloons or stents coated with cytostatic drugs are used to prevent re-occlusion of the arteries. Resveratrol, which is known for its numerous beneficial effects on cardiovascular health, is used as an antioxidant additive on paclitaxel-coated balloon catheters. What is still unclear is whether resveratrol-only balloon coating in combination with a bare metal stent (BMS) also has positive effects on vascular healing. Here, we analyzed neointimal thickening, fibrin deposition, inflammation, vasa vasorum density, and reendothelialization after implantation of BMS via a resveratrol coated balloon approach in a porcine model. In general, resveratrol treatment did not result in significantly altered responses compared to the control group in peripheral arteries. In coronary arteries, an increase in vasa vasorum density became evident three days after resveratrol treatment compared to the control group and abolished up to day 7. Significant effects of the resveratrol treatment on the fibrin score or intima-media area were transient and restricted to either peripheral or coronary arteries. In conclusion, local single-dose resveratrol treatment via a resveratrol-only coated balloon and BMS approach did not lead to adverse systemic or local effects, but also no significant beneficial effects on vascular healing were detected in the current study.

Resveratrol and Colorectal Cancer: A Molecular Approach to Clinical Researches.

Phytochemicals are the most valuable and comprehensive structures, which may have a broad range of protective benefits, from reducing inflammation and speeding healing to preventing infection and fighting cancer. Resveratrol (RSV) is a natural phenolic compound from the oligomeric stilbenoids group, which is usually found in daily human diet, such as grape, peanut, berries and grains. It exhibits anti-inflammatory, neuroprotective, antioxidant, and cancer prevention and treatment effects. RSV is thought to have an impressive outcome in colorectal cancer (CRC) treatment through the vital molecules and cancer signaling pathways, including SIRT1, P53, P21, AMPK, ROS, BMP7, COX-2, NO, caspases, Wnt, TNFs, NF-κB, EMT, and pentose phosphate pathway. Therefore, this paper reviews the current researches on the pharmacological effects and pharmacokinetics of resveratrol and its drug delivery system, as well as clinical studies involving CRC.

Resveratrol (RV): A pharmacological review and call for further research.

Resveratrol (RV) is a well-known polyphenolic compound in various plants, including grape, peanut, and berry fruits, which is quite famous for its association with several health benefits such as anti-obesity, cardioprotective neuroprotective, antitumor, antidiabetic, antioxidants, anti-age effects, and glucose metabolism. Significantly, promising therapeutic properties have been reported in various cancer, neurodegeneration, and atherosclerosis and are regulated by several synergistic pathways that control oxidative stress, cell death, and inflammation. Similarly, RV possesses a strong anti-adipogenic effect by inhibiting fat accumulation processes and activating oxidative and lipolytic pathways, exhibiting their cardioprotective effects by inhibiting platelet aggregation. The RV also shows significant antibacterial effects against various food-borne pathogens (Listeria, Campylobacter, Staphylococcus aureus, and E. coli) by inhibiting an electron transport chain (ETC) and F0F1-ATPase, which decreases the production of cellular energy that leads to the spread of pathogens. After collecting and analyzing scientific literature, it may be concluded that RV is well tolerated and favorably affects cardiovascular, neurological, and diabetic disorders. As such, it is possible that RV can be considered the best nutritional additive and a complementary drug, especially a therapeutic candidate. Therefore, this review would increase knowledge about the blend of RV as well as inspire researchers around the world to consider RV as a pharmaceutical drug to combat future health crises against various inhumane diseases. In the future, this article will be aware of discoveries about the potential of this promising natural compound as the best nutraceuticals and therapeutic drugs in medicine.

Effect of Scomberomorus niphonius peptide on the characteristics of resveratrol.

Resveratrol has a variety of physiological activities, but its bioavailability in the body is low. In this study, the interaction between the peptide SH, prepared from Scomberomorus niphonius, and resveratrol was judged by fluorescence spectroscopy. Then, SHa1 was obtained by the purification of SH, and its effect on the characteristics of resveratrol was studied. SHa1 interacted with resveratrol at 37 °C for 30 min to obtain the complex SHa1-R, which then showed an obviously stronger inhibition on B16 cells than resveratrol using the MTT assay after in vitro gastrointestinal digestion. The solubility and digestive stability of SHa1-R were higher than that of free resveratrol. The intestinal absorption rate of SHa1-R was also increased compared with resveratrol according to the non-inverted rat intestinal sac model. The structure of SHa1 was analyzed by UPLC, auto amino acid analysis, and UPLC-MS/MS. The molecular weight of SHa1 was mainly concentrated under 1000 Da, and it was rich in glutamic acid, aspartic acid, lysine, and leucine. Eighteen possible peptides were identified from SHa1. The results suggested that the peptide SHa-1 may help to increase the bioavailability of resveratrol by increasing the solubility, digestive stability and intestinal absorption of resveratrol, thereby promoting its inhibitory effect on B16 cells.

Development of a novel UPLC-MS/MS method for the simultaneously quantification of polydatin and resveratrol in plasma: Application to a pharmacokinetic study in rats.

The purpose of this study is to develop a sensitive LC-MS-MS method to simultaneously quantify polydatin and its metabolite, resveratrol, for its application in a pharmacokinetic (PK) study and to determine polydatin hydrolysis by microflora. A Shimadzu UHPLC system coupled to an AB Sciex QTrap 4000 mass spectrometer was used for the analysis. Separation was achieved using an Acquity BEH C18 column (2.1 × 50 mm) with acetonitrile and 0.1% formic acid as the mobile phases. Analysis was performed under negative ionization mode using the multiple reaction monitoring (MRM) approach. The method was linear in the range of 9.77-1250 nM for both resveratrol and polydatin with correlation coefficient values >0.99. Themethodhas been shown to be reproducible, with intra- and inter-day accuracy and precision ±10.4% of nominal values, for both analytes. The average extraction recovery rates were 81.78-98.3% for polydatin and 86.4-103.2% for resveratrol, respectively. Matrix effect was in the acceptable range (<15%). The analytes in plasma were found to be stable under bench-top, freeze-thaw, and storage (-4 °C) conditions. The metabolic studies showed that polydatin can be rapidly hydrolyzed by rat fecal S9 fractions and PK studies showed that both polydatin and resveratrol were exposed in the plasma and variable tissues. This novel UPLC-MS-MS method can quantify the levels of both polydatin and its major metabolite resveratrol in biological samples.

Co-Crystals of Resveratrol and Polydatin with L-Proline: Crystal Structures, Dissolution Properties, and In Vitro Cytotoxicities.

Resveratrol (RSV) and polydatin (PD) have been widely used to treat several chronic diseases, such as atherosclerosis, pulmonary fibrosis, and diabetes, among several others. However, their low solubility hinders their further applications. In this work, we show that the solubility of PD can be boosted via its co-crystallization with L-proline (L-Pro). Two different phases of co-crystals, namely the RSV-L-Pro (RSV:L-Pro = 1:2) and PD-L-Pro (PD:L-Pro = 1: 3), have been prepared and characterized. As compared to the pristine RSV and PD, the solubility and dissolution rates of PD-L-Pro in water (pH 7.0) exhibited a 15.8% increase, whereas those of RSV-L-Pro exhibited a 13.8% decrease. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of pristine RSV, PD, RSV-L-Pro, and PD-L-Pro against lung cancer cell line A549 and human embryonic kidney cell line HEK-293 indicated that both compounds showed obvious cytotoxicity against A549, but significantly reduced cytotoxicity against HEK-293, with PD/PD-L-Pro further exhibiting better biological safety than that of RSV/RSV-L-Pro. This work demonstrated that the readily available and biocompatible L-Pro can be a promising adjuvant to optimize the physical and chemical properties of RSV and PD to improve their pharmacokinetics.

Rationalizing the Design of Hyaluronic Acid-Decorated Liposomes for Targeting Epidermal Layers: A Combination of Molecular Dynamics and Experimental Evidence.

This work provides information on the features of low molecular weight hyaluronic acid (HA)-decorated liposomes to target resveratrol (RSV) in the skin. Deformable liposomes were made of soy-phosphatidylcholine with Tween 80 as the fluidizing agent. For HA conjugation, three different phosphoethanolamines were tested: 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). The different phosphoethanolamine-HA conjugates were inserted into the liposome bilayer by hydration (HA on both faces of the bilayer) or by the postinsertion method (HA only on the external face of the bilayer). The effect of these variables on deformability was experimentally assessed by an in-house method (K value, the lower the value, the higher the deformability) and molecular dynamics (MD) simulations. The results showed that the K values of HA-liposomes obtained by hydration were higher than the K values of HA-liposomes prepared by postinsertion, and both were at least 10-fold higher than the K values of the corresponding plain liposomes. The nature of the lipid anchor played a key role in deformability (DMPE > DOPE > DPPE) with high variability in the case of DOPE formulations. These data were justified by the trends found in silico for the bilayer bending modulus and the HA end-to-end distance. In addition to liposome flexibility, the HA extent seems to be the key factor governing the skin penetration of RSV. When the extent is higher, the amount of the drug retained in the skin is larger. Regarding skin permeation, a parabolic trend was recorded, and the optimal amount to favor skin permeation was an approximately 30 HA/phospholipid (µg/mmol) ratio. This study reports the first piece of evidence that it is possible to control drug delivery in the skin by tuning the amount of HA on the vesicle surface.