ABSTRACT
Oxyresveratrol (OXY) has been reported for its anti-inflammatory activity; however, the pharmaceutical applications of this compound are limited by its physicochemical properties and poor pharmacokinetic profiles. The use of an ester prodrug is a promising strategy to overcome these obstacles. In previous researches, several carboxylate esters of OXY were synthesized and oxyresveratrol tetraacetate (OXY-TAc) was reported to possess anti-melanogenic and anti-skin-aging properties. In this study, in addition to OXY-TAc, two novel ester prodrugs of OXY, oxyresveratrol tetrapropionate (OXY-TPr), and oxyresveratrol tetrabutyrate (OXY-TBu), were synthesized. Results from the Caco-2-permeation assay suggested that synthesized ester prodrugs can improve the membrane-permeation ability of OXY. The OXY-TAc exhibited the most significant profile, then this prodrug was chosen to observe anti-inflammatory activities with lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Our results showed that OXY-Tac significantly alleviated secretion of several pro-inflammatory mediators (nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α)), mitigated expression of enzyme-regulated inflammation (inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2)), and suppressed the MAPK cascades. Interestingly, the observed anti-inflammatory activities of OXY-TAc were more remarkable than those of its parent compound OXY. Taken together, we demonstrated that OXY-TAc improved physicochemical and pharmacokinetic profiles and enhanced the pharmacological effects of OXY. Hence, the results in the present study would strongly support the clinical utilities of OXY-TAc for the treatment of inflammation-related disorders.
Subject(s)
Lipopolysaccharides , Prodrugs , Animals , Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/pharmacology , Caco-2 Cells , Cyclooxygenase 2/metabolism , Esters/metabolism , Esters/pharmacology , Humans , Inflammation/drug therapy , Inflammation/metabolism , Lipopolysaccharides/metabolism , Lipopolysaccharides/pharmacology , Macrophages , Mice , NF-kappa B/metabolism , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/metabolism , Plant Extracts , Prodrugs/metabolism , Prodrugs/pharmacology , RAW 264.7 Cells , StilbenesABSTRACT
Oxyresveratrol (ORV) is a naturally extracted compound with many pharmacological activities. However, information about the crystalline form is not known when considering the development of a form for oral dosage. Cocrystal engineering offers drug molecular understanding and drug solubility improvements. Thus, we attempted cocrystallization of ORV using 10 carboxylic acids as a coformer at a 1:1 M ratio. Each combination was processed with liquid-assisted grinding, solvent evaporation and a slurry method, then characterized by powder X-ray powder diffraction (PXRD), conventional and low-frequency Raman spectroscopy and thermal analysis. The solubility, dissolution and permeation studies across Caco-2 cell monolayers were conducted to evaluate the ORV samples. A screening study revealed that an ORV and citric acid (CTA) cocrystal formed by ethyl acetate-assisted grinding had characteristic PXRD peaks (14.0 and 16.5°) compared to those of ORV dihydrate used as a starting material. Low-frequency Raman measurements, with peaks at 100 cm-1, distinguished potential cocrystals among three processing methods while conventional Raman could not. An endothermic melt (142.2°C) confirmed the formation of the novel crystalline complex. The solubility of the cocrystal in the dissolution media of pH 1.2 and 6.8 was approximately 1000 µg/mL, a 1.3-fold increase compared to ORV alone. In vitro cytotoxicity studies showed that the cocrystal and physical blend were not toxic at concentrations of 25 and 12.5 µM ORV, respectively. The ORV-CTA cocrystal enhanced the cellular transport of ORV across Caco-2 monolayers. Therefore, cocrystallization could be used to improve aqueous solubility and permeability, leading to better oral bioavailability of ORV.
Subject(s)
Plant Extracts/chemistry , Plant Extracts/pharmacology , Stilbenes/chemistry , Stilbenes/pharmacology , Biological Transport , Caco-2 Cells , Cell Survival/drug effects , Crystallization , Humans , Permeability , SolubilityABSTRACT
A new phenanthrene dimer, namely dendropalpebrone (1), was isolated from the whole plant of Dendrobium palpebre, along with nine known compounds (2-10). All of the isolates were evaluated for their hydroxyl radical scavenging effects using a deoxyribose assay. Dendroflorin (10) showed an appreciable activity, and therefore was selected for further studied in RAW264.7 cells. Compound 10 significantly decreased ROS in H2O2-stimulated RAW264.7 cells in a dose-dependent manner, and improved activity of SOD, GPx, and CAT enzymes.
Subject(s)
Dendrobium/chemistry , Free Radical Scavengers/isolation & purification , Phenanthrenes/isolation & purification , Animals , Free Radical Scavengers/chemistry , Free Radical Scavengers/pharmacology , Mice , Phenanthrenes/chemistry , Phenanthrenes/pharmacology , RAW 264.7 Cells , Reactive Oxygen Species/metabolismABSTRACT
Curcumin diglutaric acid-loaded polyethylene glycol-chitosan oligosaccharide-coated superparamagnetic iron oxide nanoparticles (CG-PEG-CSO-SPIONs) were fabricated by co-precipitation and optimized using a Box-Behnken statistical design in order to achieve the minimum size, optimal zeta potential (≥ ±20 mV), and maximum loading efficiency and capacity. The results demonstrated that CG-PEG-CSO-SPIONs prepared under the optimal condition were almost spherical in shape with a smooth surface, a diameter of 130 nm, zeta potential of 30.6 mV, loading efficiency of 83.3%, and loading capacity of 8.3%. The vibrating sample magnetometer results of the optimized CG-PEG-CSO-SPIONs showed a superparamagnetic behavior. Fourier transform infrared spectroscopy and X-ray diffraction analyses indicated that the CG physically interacted with PEG-CSO-SPIONs. In addition, the CG-PEG-CSO-SPIONs could be stored dry for up to 12 weeks or in aqueous solution for up to 4 days at either 4 °C or 25 °C with no loss of stability. The CG-PEG-CSO-SPIONs exhibited a sustained release profile up to 72 h under simulated physiological (pH 7.4) and tumor extracellular (pH 5.5) environments. Furthermore, the CG-PEG-CSO-SPIONs showed little non-specific protein binding in the simulated physiological environment. The CG-PEG-CSO-SPIONs enhanced the cellular uptake and cytotoxicity of CG against human colorectal adenocarcinoma HT-29 cells compared to free CG, and more CG was delivered to the cells after applying an external magnetic field. The overall results suggest that PEG-CSO-SPIONs have potential to be used as a novel drug delivery system for CG.
Subject(s)
Chitosan/chemistry , Drug Delivery Systems/methods , Polyethylene Glycols/chemistry , Cell Line, Tumor , Curcumin/chemistry , Curcumin/pharmacology , Humans , Magnetic Iron Oxide Nanoparticles/chemistry , Magnetite Nanoparticles/chemistry , Nanoparticles/chemistry , Particle Size , Spectroscopy, Fourier Transform Infrared/methodsABSTRACT
Mycophenolic acid (MPA), an immunosuppressant drug, possesses antimicrobial, anticancer, and antipsoriatic activities. However, the use of MPA in therapeutic applications is limited to its poor oral bioavailability, low aqueous solubility, and undesired gastrointestinal side effects. Polymeric micelles are a drug delivery system that has been used to enhance the water solubility of pharmaceuticals. In this work, poloxamer 407 (P407) and MPA were conjugated via an ester linkage resulting in a P407-MPA conjugate. The P407-MPA conjugate was investigated for micellization, particle size, size distribution, MPA release in phosphate buffer (pH 7.4) and human plasma, and antipsoriatic activity. 1H-nuclear magnetic resonance suggested that polymeric micelles formed from the P407-MPA conjugate exposed its polyethylene oxide chain to the aqueous environment while restricting the conjugated MPA within the inner core. The P407-MPA conjugate has an improved micellization property with the over 12-fold lower critical micelle concentration compared to P407. The conjugate exhibited an enzyme-dependent sustained-release property in human plasma. Finally, the conjugate exhibited an improved antiproliferation activity in tumor necrosis factor-α-induced HaCaT cells, which is an in vitro psoriasis model. Therefore, the prepared P407-MPA conjugate, with an improved aqueous solubility and biological activity of MPA, has the potential to be further developed for psoriasis treatment.