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Preparation, Physical Characterization, Pharmacokinetics and Anti-Hyperglycemic Activity of Esculetin-Loaded Mixed Micelles
Abstract
Despite its low water solubility, esculetin (EC) have been described to demonstrate various health benefits. Thus, we sought to develop esculetin-loaded mixed micelles (EC-M) delivery system to purposively improve biological availability and anti-hyperglycemia activity of EC. Thin-film hydration method was employed to fabricate EC-M, amid characterization with transmission electron microscopic analysis (TEM), coupled with physical properties such as particle size (PS), poly-dispersity index (PDI), zeta-potential (ZP) and stability testing. We analyzed in-vitro release and studied EC-M pharmacokinetics in rats. The hyperglycemic mice model was established with streptozotocin (STZ) to evaluate anti-hyperglycemic activity of EC-M. The PS, PDI and ZP of EC-M were 47.97 ± 0.41 nm, 0.189 ± 0.005 and -25.55 ± 0.28 mV, respectively. The release rate of EC-M increased comparable to free EC in the three media. The oral biological availability and half-life of EC-M increased respectively by 3.06 and 1.45 folds compared to free EC. Besides, we observed 46.21% decrease in blood glucose of mice in EC-M group comparable to the model control, wherein, the anti-hyperglycemic effect of EC-M was better compared to free EC. Conclusively, EC-M may ideally serve as a novel approach to enhance biological availability and increased anti-hyperglycemic activity of EC.
... Due to their very good biocompatibility (Chen et al. 2016, Verma et al. 2016, liposomes can increase intestinal permeability (Porter et al. 2007, Liu et al. 2017, reduce chemical and biological degradation (Feng et al. 2016, Song et al. 2017, as well as non-specific side effects of drugs (Moosavian et al. 2021). According to a previous literature survey (Zuo et al. 2020, Li et al. 2023), there are not many types of nano-formulations related to esculetin (Karatug Kacar et al. 2020). Therefore, in this study, the nano-structured lipid carrier composed of DSPE-MPEG2000 was used to prepare the nanopreparation of esculetin. ...
... The dialysis method (Li et al. 2023) was used to conduct the in-vitro drug release studies to simulate the in-vivo biological conditions in different release media, including HCl (pH 1.2), DDW (pH 7.0), and PBS (pH 6,8 and 7.4). Briefly, esculetin solution (1 mg/ml, 1 ml) and Esc-NLC (1 mg/mL, 1 ml) were put into dialysis bags separately, then placed in a conical flask, prior to the addition of 50 ml different release medium, accordingly. ...
Unlabelled:
Objective Encapsulation of esculetin into DSPE-MPEG2000 carrier was performed to improve its water solubility and oral bioavailability, as well as enhance its anti-inflammatory effect on mouse model of ulcerative colitis that was induced with dextran sulfate sodium (DSS).
Methods:
We determined the in-vitro and in-vivo high performance liquid chromatographic (HPLC) analysis method of esculetin; Esculetin-loaded nanostructure lipid carrier (Esc-NLC) was prepared using a thin-film dispersion method, wherein a particle size analyzer was used to measure the particle size (PS) and zeta potential (ZP) of the Esc-NLC, while a transmission electron microscope (TEM) was employed to observe its morphology. Also, HPLC was used to measure its drug loading (DL), encapsulation efficiency (EE) and the in-vitro release of the preparation, as well as investigate the pharmacokinetic parameters. In addition, its anti-colitis effect was evaluated via histopathological examination of HE-stained sections and detection of the concentrations of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1 beta (β), and IL-6 in serum with ELISA kits.
Results:
The PS of Esc-NLC was 102.29 ± 0.63 nm with relative standard deviation (RSD) of 1.08% (with poly-dispersity index-PDI of 0.197 ± 0.023), while the ZP was -15.67 ± 1.39 mV with RSD of 1.24%. Solubility of esculetin was improved coupled with prolonged release time. Its pharmacokinetic parameters were compared with that of free esculetin, wherein the maximum concentration of the drug in plasma was increased by 5.5 times. Of note, bioavailability of the drug was increased by 1.7 times, while the half-life was prolonged by 2.4 times. In the anti-colitis efficacy experiment, the mice in Esc and Esc-NLC groups exhibited significantly reduced levels of TNF-α, IL-1β, and IL-6 in their sera comparable to the DSS group. Colon histopathological examination revealed that mice with ulcerative colitis in both Esc and Esc-NLC groups displayed improved inflammation, amid the Esc-NLC groups having the best prophylactic treatment effect.
Conclusion:
Esc-NLC could ameliorate DSS-induced ulcerative colitis by improving bioavailability, prolonging drug release time and regulating cytokine release. This observation confirmed the potential of Esc-NLC to reduce inflammation in ulcerative colitis, albeit the need for follow-up research to verify the application of this strategy to clinical treatment of ulcerative colitis.
... To evaluate the stability of MYR liposomes during storage, we kept them at a constant temperature of 4 °C for 7 days. On the 1, 3, 5, 7, 10, 14, and 21 days (Li et al. 2023), a small amount of liposomal film was scraped off and its PS, PDI, and ZP were measured after hydration. ...
Aims
Myricetin (MYR) was incorporated into pH-sensitive liposomes in order to improve its bioavailability and anti-hyperuricemic activity.
Methods
The MYR pH-sensitive liposomes (MYR liposomes) were prepared using thin film dispersion method, and assessed by particle size (PS), polydispersed index (PDI), zeta potential (ZP), encapsulation efficiency, drug loading, and in vitro release rate. Pharmacokinetics and anti-hyperuricemic activities were also evaluated.
Results
The PS, PDI, ZP, encapsulation efficiency, and drug loading of MYR liposomes were 184.34 ± 1.05 nm, 0.215 ± 0.005, −38.46 ± 0.30 mV, 83.42 ± 1.07%w/w, and 6.20 ± 0.31%w/w, respectively. The release rate of MYR liposomes was higher than free MYR, wherein the cumulative value responded to pH. Besides, the Cmax of MYR liposomes was 4.92 ± 0.20 μg/mL. The level of uric acid in the M-L-H group (200 mg/kg) was reduced by 54.74%w/v in comparison with the model group.
Conclusion
MYR liposomes exhibited pH sensitivity and could potentially enhance the oral bioavailability and anti-hyperuricemic efficacy of MYR.
... The micellar solution was then hydrated with phosphate buffered saline (PBS, pH 7.4, 5 mL) . 29 In Vitro Evaluation of the Micelles ...
... The highest readings, at pH 6.8, indicate increased bioavailability in the intestinal environment. Moreover, drug stability was increased, and the mixed micelles were superior to free EC in treating mice with hyperglycemia [44]. ...
Mixed micelles from copolymers in aqueous media have emerged as a valuable tool for producing functional polymer nanostructures with applications in nanomedicine, including drug delivery and bioimaging. In this review, we discuss the basics of mixed copolymer micelles’ design, structure, and physicochemical properties. We also focus on their utilization in biomedical applications using examples from recent literature.
... The samples were diluted with double-distilled water to obtain the appropriate light intensity for the measurement. Each sample was measured three times in parallel and the results were recorded [33]. ...
Purpose In this regard, we developed vitexin (Vi)-loaded D-ɑ-tocopherol polyethylene glycol succinate, polyvinylpyrrolidone K30 and sodium cholate mixed micelles (Vi-MMs) mainly for improving oral bioavailability and enhancing anti-osteoporotic effect of Vi.
Methods Thin layer dispersion method was employed to prepare Vi-MMs, and then the optimal prescription was optimized by the orthogonal design-response surface method, wherein encapsulation efficiency (EE) was used as optimizing index. The physical properties of Vi-MMs such as appearance morphology, particle size, and zeta potential were also characterized. We further analyzed the in-vitro release of Vi and Vi-MMs in three media and investigated the pharmacokinetics of Vi and Vi-MMs in rats. Anti-osteoporotic activity of Vi and Vi-MMs was assessed by establishing a zebrafish osteoporosis model with prednisone.
Results Drug loading, encapsulation efficiency, particle size and zeta potential of the optimized Vi-MMs were 8.58 ± 0.13%, 93.86 ± 1.79%, 20.41 ± 0.64 nm and -10 ± 0.56 mV, respectively. The optimized Vi-MMs were shaped spherically as exhibited by transmission electron microscopic technique, with evident core shell nano-structure, well dispersed. In all three media, the release rate of Vi-MMs was significantly higher than that of free Vi. The oral bioavailability of Vi-MMs was increased by 5.6-fold compared to free Vi. In addition, alleviation of prednisone induced osteoporosis in zebrafish by Vi-MMs further demonstrated good anti-osteoporotic effect.
Formononetin is a flavonoid compound with anti-tumor and anti-inflammatory properties. However, its low solubility limits its clinical use. We employed microfluidic technology to prepare formononetin-loaded PLGA-PEGDA microspheres (Degradable polymer PLGA, Crosslinking agent PEGDA), which can encapsulate and release drugs in a controlled manner. We optimized and characterized the microspheres, and evaluated their antitumor effects. The microspheres had uniform size, high drug loading efficiency, high encapsulation efficiency, and stable release for 35 days. They also inhibited the proliferation, migration, and apoptosis. The antitumor mechanism involved the induction of reactive oxygen species and modulation of Bcl-2 family proteins. These findings suggested that formononetin-loaded PLGA-PEGDA microspheres, created using microfluidic technology, could be a novel drug delivery system that can overcome the limitations of formononetin and enhance its antitumor activity.
At present, ulcerative colitis (UC) has become a global disease due to its high incidence. Hyperoside (HYP) is a naturally occurring flavonoid compound with many pharmacological effects. This study aimed to develop HYP-loaded mixed micelles (HYP-M) to improve oral bioavailability of HYP and to evaluate its therapeutic effect on UC. The prepared HYP-M exhibited stable physical and chemical properties, smaller particle size (PS) (21.48 ± 1.37 nm), good polydispersity index (PDI = 0.178 ± 0.013), negative Zeta potential (ZP) (− 20.00 ± 0.48 mV) and high entrapment rate (EE) (89.59 ± 2.03%). In vitro release and in vivo pharmacokinetic results showed that HYP-M significantly increased the releasing rate of HYP, wherein its oral bioavailability was 4.15 times higher than that of free HYP. In addition, HYP-M was more effective in the treatment of UC than free HYP. In conclusion, HYP-M could serve as a novel approach to improve bioavailability and increase anti-UC activity of HYP.
Emodin is applied as an antitumor drug in many tumor therapies. However, its pharmacology performances are limited due to its low solubility. Herein, we fused erythrocyte and macrophage to form a hybrid membrane (EMHM) and encapsulated emodin to form hybrid membrane-coated nanoparticles. We employed glycyrrhizin to increase the solubility of emodin first and prepared the hybrid membrane nanoparticle-coated emodin and glycyrrhizin (EG@EMHM NPs) which exhibited an average particle size of 170 ± 20 nm and encapsulation efficiency of 98.13 ± 0.67%. The half-inhibitory concentrations (IC50) of EG@EMHM NPs were 1.166 μg/mL, which is half of the free emodin. Based on the photosensitivity of emodin, the reactive oxygen species (ROS) results disclosed that ROS levels of the photodynamic therapy (PDT) section were higher than the normal section (P < 0.05). Compared to the normal section, PDT-mediated EG@EMHM NPs could induce an early stage of apoptosis of B16. The western blot and flow cytometry results verified that PDT-mediated EG@EMHM NPs can significantly improve the solubility of emodin and perform a remarkably antitumor effect on melanoma via BAX and BCL-2 pathway. The application of the combined chemical and PDT therapy could provide an improving target therapy for cutaneous melanoma and also may offer an idea for other insoluble components sources of traditional Chinese medicine.Graphical abstract
Schematic of EG@EMHM NPs formulation
Betulinic acid (3β-Hydroxy-20(29)-lupaene-28-oic acid, BA) has excellent anti-cancer activity but poor solubility and low bioavailability. To improve the antitumor activity of BA, a polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol (PVCL–PVA–PEG) graft copolymer (Soluplus) encapsulated BA micelle (Soluplus-BA) was fabricated. The Soluplus-BA micelles presented a mean size of 54.77 ± 1.26 nm and a polydispersity index (PDI) of 0.083. The MTT assay results showed that Soluplus-BA micelles increased the inhibitory effect of BA on MDA-MB-231 cells, mainly due to the enhanced accumulation of reactive oxygen species (ROS) and the destruction of mitochondrial membrane potential (MMP). Soluplus-BA micelles induced the DNA double-strand breaks (DSBs) as the γH2AX foci increased. Moreover, Soluplus-BA also inhibited the tube formation and migration of human umbilical vein endothelial cells (HUVECs), and inhibited the neovascularization of the chicken chorioallantoic membrane (CAM). This angiogenesis inhibitory effect may be accomplished by regulating the HIF-1/VEGF-FAK signaling pathway. The in vivo study confirmed the improved anti-tumor effect of Soluplus-BA and its inhibitory effect on angiogenesis, demonstrating the possibility of Soluplus-BA as an effective anti-breast cancer drug delivery system.
Seaweeds are an important ingredient of functional foods recommended for daily food, due to their unique compositions and nutritional value. Padina tetrastromatica is a brown edible seaweed that is commonly found along the coastal regions of Peninsular Malaysia and consumed as food by some coastal communities. This study investigates the nutritional and antihyperglycaemic potential of P. tetrastromatica extracts, which is generally accepted as an important functional food. In our methodology, we induced diabetes intraperitoneally in experimental animals with a dose of 65 mg kg−1 body weight of streptozotocin. Oral treatment with 200 and 400 mg kg−1 of P. tetrastromatica ethanolic and ethyl acetate extracts were initiated, respectively, to experimental rats once daily for 18 days. Metformin was used as the positive control. Biochemical estimations and histopathological analysis were included in this study. Treatment with P. tetrastromatica extracts significantly lowered the plasma glucose levels in Streptozotocin-induced diabetic rats. In addition, P. tetrastromatica extract treatment also showed a significant reduction in serum alanine transaminase levels. However, no significant changes were observed in serum aspartate transaminase levels. The ethyl acetate extract of P. tetrastromatica at 400 mg kg−1 dose shows some nephroprotective effect, which is observed from the significant increase in the plasma albumin levels. Histopathological evaluation revealed no marked morphological changes in tissues of the isolated organs of the ethyl acetate extract-treated group, revealing the safe nature of P. tetrastromatica.
The objective of this study was to fabricate a novel drug delivery system using Soluplus® (polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer) and glycyrrhizic acid to improve solubility, bioavailability, and anti-hyperuricemic activity of aloe emodin (AE). The AE-loaded mixed micelles (AE-M) were prepared by thin-film hydration method. The optimal AE-M contained small-sized (30.13 ± 1.34 nm) particles with high encapsulation efficiency (m/m, %) of 90.3 ± 1.08%. The release rate of AE increased in the micellar formulation than that of free AE in the four media (DDW, pH 7.0; phosphate buffer solution, pH 7.4; phosphate buffer solution, pH 6.8; and hydrochloric acid aqueous solution, pH 1.2). In comparison to free AE, the pharmacokinetic study of AE-M showed that its relative oral bioavailability increased by 3.09 times, indicating that mixed micelles may promote gastrointestinal absorption. More importantly, AE-M effectively reduced uric acid level by inhibiting xanthine oxidase (XOD) activity in model rats. The degree of ankle swelling, serum levels of interleukin (IL)-1, and IL-6-related inflammatory factors levels all decreased in the gouty arthritis model established via monosodium urate (MSU) crystals. Taken together, the AE-M demonstrated the potential to improve the bioavailability, anti-hyperuricemic activity, and anti-inflammation of AE.Graphical abstract
This study sought to prepare a self-microemulsion drug delivery system containing zingerone (Z-SMEDDS) to improve the low oral bioavailability of zingerone and anti-tumor effect. Z-SMEDDS was characterized by particle size, zeta potential and encapsulation efficiency, while its pharmacokinetics and anti-tumor effects were also evaluated. Z-SMEDDS had stable physicochemical properties, including average particle size of 17.29 ± 0.07 nm, the zeta potential of -22.81 ± 0.29 mV, and the encapsulation efficiency of 97.96% ± 0.02%. In vitro release studies have shown the release of zingerone released by Z-SMEDDS was significantly higher than free zingerone in different release media. The relative oral bioavailability of Z-SMEDDS was 7.63 times compared with free drug. Meanwhile, the half inhibitory concentration （IC50）of Z-SMEDDS and free zingerone was 8.45 μg/mL and 13.30 μg/mL, respectively on HepG2. This study may provide a preliminary basis for further clinical research and application of Z-SMEDDS.
Hyperlipidemia has become a common disease in modern society with its prevalence becoming relatively high in the world. A series of complications that accompany hyperlipidemia are seriously threatening individuals’ health. Dihydromyricetin (DMY) is a kind of polyphenol hydroxy (OH) dihydroflavonol extracted from the stems and leaves of Ampelopsis grossedentata. It has a variety of pharmacological activities. This study aimed to develop a self‐microemulsifying drug delivery system (SMEDDS) to improve the oral bioavailability of DMY, and to evaluate its hypolipidemic activity in mice. The self‐microemulsion drug delivery system composed of MCT (oil phase), Tween 80 (emulsifier) and PEG 200 (co‐emulsifier). The prepared DMY‐SMEDDS stable physical and chemical properties, small droplet size (15.49 ± 0.15 nm), good polydispersity index (PDI = 0.160 ± 0.010), negative zeta potential (‐17.37 ± 0.09 mV) and high encapsulation efficiency (98.04 ± 0.25%). The results of in vitro dissolution and in vivo pharmacokinetics showed that the prepared DMY‐SMEDDS could significantly improve the solubility of DMY in aqueous medium, while its oral bioavailability 2.34 times higher than that of free drug. In conclusion, the DMY‐SMEDDS prepared in this study might prospectively improve the solubility and oral bioavailability of DMY as well as enhance the therapeutic effect.
Practical applications: This study is relevant in the sense that SMEDDS may be used as a new strategy to improve the oral bioavailability of hydrophobic drugs. This novel nanocarrier could increase (by 2.34 times) the relative bioavailability of oral DMY‐SMEDDS in rats comparative to dihydromyricetin (DMY) suspension. Thus, DMY‐SMEDDS may prospectively be applied in food, nutraceutical and pharmaceutical industries in view of its biocompatible excipients and good stability.
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Background. Hypertension (HTN) can be present in up to two-thirds of patients living with diabetes mellitus (DM). It is a risk factor for the development of diabetes as well as complications like coronary artery disease (CAD), nephropathy, retinopathy, and neuropathy. Hypertension is treatable, and the degree to which it is controlled determines the risk of development of cardiovascular diseases and other complications in a given individual patient. Even though antihypertensive drugs are available and issued to hypertensive diabetic patients, the rate of control of HTN is often inadequate. The aim of this study was to assess the prevalence of suboptimal blood pressure (BP) control, its associated factors, and the choice of antihypertensive drugs among type 2 DM patients at Kilimanjaro Christian Medical Centre (KCMC). Methods. A hospital-based cross-sectional study was conducted at the KCMC diabetes clinic from October 2018 to March 2019 among type 2 DM patients with HTN based on the inclusion criteria. Data were collected using structured questionnaires, and written informed consent was obtained. Suboptimal BP was defined as BP levels≥140/90 mmHg according to the American Diabetes Association guideline published in 2018. Data analysis was done using the Statistical Package for the Social Sciences (SPSS) version 25. Chi-square analysis was done to identify the independent predictors of BP control, and a p value of
Diet is one of the pillars in the prevention and management of diabetes mellitus. Particularly, eating patterns characterized by a high consumption of foods such as fruits or vegetables and beverages such as coffee and tea could influence the development and progression of type 2 diabetes. Flavonoids, whose intake has been inversely associated with numerous negative health outcomes in the last few years, are a common constituent of these food items. Therefore, they could contribute to the observed positive effects of certain dietary habits in individuals with type 2 diabetes. Of all the different flavonoid subclasses, flavan-3-ols are consumed the most in the European region. However, a large proportion of the ingested flavan-3-ols is not absorbed. Therefore, the flavan-3-ols enter the large intestine where they become available to the colonic bacteria and are metabolized by the microbiota. For this reason, in addition to the parent compounds, the colonic metabolites of flavan-3-ols could take part in the prevention and management of diabetes. The aim of this review is to present the available literature on the effect of both the parent flavan-3-ol compounds found in different food sources as well as the specific microbial metabolites of diabetes in order to better understand their potential role in the prevention and treatment of the disease.
For weakly basic drugs, the sharp decrease of drug solubility and the following drug precipitation after drugs transferring from the gastric fluid to the intestinal fluid in the gastrointestinal (GI) tract is a main reason for the poor oral bioavailability of drugs. Here, an anticoagulant dabigatran etexilate (DE) was used as a model drug, and a composite nanocarrier system of DE was developed to improve the drug dissolution by decreasing the drug leakage in the stomach and inhibiting the drug precipitation in the intestinal tract. With the encapsulation of drugs in nanocarriers, the precipitation percentage of DE in composite nanocarriers was 22.25 ± 3.88% in simulated intestinal fluid, which was far below that of the commercial formulation. Moreover, the relative bioavailability of DE-loaded composite nanocarriers (456.58%) was greatly enhanced and the peak of its activated partial thromboplastin time was also significantly prolonged (p < .01) compared with the commercial formulation, indicating that the anticoagulant effect of DE was effectively improved. Therefore, the designed composite nanocarrier system of DE presents great potentials in improving the therapeutic efficiency and expanding the clinical applications of poorly water-soluble weakly basic drugs.
Aim:
The purpose of this study was to prepare targeted cancer therapy formulation against insulinoma INS-1 cells and to study its effect on cell death with related mechanisms in vitro.
Methods:
Polylactide-co-glycolide (PLGA) nano-micelles were used for preparation of esculetin nano-formulation (nano-esculetin). The cells were treated with nano-esculetin and free esculetin. Apoptotic and necrotic cell death percentages, cell proliferation, ATP and GTP reductions and insulin levels were investigated on insulinoma INS-1 cells for both free and nano-esculetin formulations.
Results:
About 50 mg of PLGA was able to carry 20 mg esculetin in 20 ml of formulation. The obtained optimized formulation was 150 nm, with 92% encapsulation efficiency and a slow-release behaviour was observed during release studies. Nano-esculetin bearing 25, 50 and 100 μg esculetin and free esculetin in equivalent doses successfully decreased cell viability. The prevailing cell death mechanism was necrosis. Along with cell proliferation, intracellular insulin and the ratio of ATP and GTP were decreased even with 12.5, 25 and 50 μg esculetin bearing nano-formulation and its equivalent free esculetin.
Conclusions:
The results revealed that esculetin is able to show its anti-tumor afficacy after loading to PLGA nano-micelles and nano-encapsulation intensifies its cytotoxic activity in vitro. Current study shows that esculetin and its nano formulations are promising agents in treatment of insulinoma.
This study was designed to investigate the bioavailability and targeting of myricetrin-loaded ternary micelles modified with and without TPGS. The particle diameters of myricetrin-loaded micelles and myricetrin-loaded-TPGS micelle were 30.58 ± 1.34 nm and 26.83 ± 0.89 nm, respectively, while their respective encapsulation efficiencies (m/m, %) were 83.3 ± 1.08 and 93.8 ± 1.18. The release rate of myricetrin in the micellar system clearly exceeded the free myricetrin in the three media (pH 6.8 phosphate buffer, pH 1.2 HCl solution and double distilled water). In vivo studies displayed that the bioavailability of myricetrin mixed micelles was remarkably improved than the free drug after oral administration. Moreover, the results of tissue distribution showed that myricetrin-loaded-TPGS micelles accumulated well in the liver tissue. Based on these results, it was speculated that myricetrin-loaded-TPGS micelles might act as a promising carrier for liver targeting with improved hepatic concentration of myricetrin compared with the myricetrin-loaded micelles.
The lipophilic prodrug of hydrophobic drugs with well-designed molecular structures can form stable pure prodrug nanoparticles (NPs), but rapid NPs aggregation in plasma greatly restricted their direct use for intravenous chemotherapy. To address this, DSPE-mPEG2000 and Cremophor EL are two of the most widely used lipophilic PEG derivatives to enhance their colloidal stability in plasma. However, their drug delivery performances have never been comparatively studied. Here, a redox-responsive lipophilic prodrug of SN38 was chosen as the model drug for such comparative investigations. We found that Cremophor EL/NPs having a small diameter (∼15 nm) and poor kinetic stability displayed an enhanced cell internalization, higher cytotoxicity and prolonged circulation time as compared with DSPE-mPEG2000/NPs. Most importantly, these superiorities further resulted in a much more potent antitumor activity in CT26 colorectal cancer xenograft, but the increased loss of body weight was also noted. These results suggested that Cremophor EL could be more advantageous than DSPE-mPEG2000 in terms of the improvement of antitumor activity, but the enhanced toxicity warranted further attention in the future study.
：6-shogaol is a promising anti-cancer and anti-inflammatory agent. However, the treatment effectiveness of 6-shogaol is limited by poor water solubility, poor oral absorption and rapid metabolism. Herein, 6-shogaol loaded in micelles (SMs) were designed to improve 6-shogaol’s solubility and bioavailability. The micelles of a PEG derivative of linoleic acid (mPEG2k-LA) were prepared by the nanoprecipitation method with a particle size of 76.8 nm, and entrapment of 81.6 %. Intriguingly, SMs showed a slower release in phosphate buffer saline (PBS) (pH = 7.4) compared to free 6-shogaol while its oral bioavailability increased by 3.2–fold in vivo. More importantly, the in vitro cytotoxic effect in HepG2 cells of SMs was significantly higher than free 6-shogaol. Furthermore, SMs could significantly improve the tissue distribution of 6-shogaol, especially liver and brain. Finally, SMs showed a better hepatoprotective effect against carbon tetrachloride (CCl4)-induced hepatic injury in vivo than free 6-shogaol. These results suggest that the novel micelles could potentiate the activities of 6-shogaol in cancer treatment and hepatoprotection.
Isoliquiritigenin (ISL) possesses a variety of pharmacological activities amid poor solubility in water which has restricted its clinical application. In this study, Isoliquiritigenin-loaded F127/P123 polymeric micelles (ISL-FPM) were successfully prepared and evaluated in vitro and in vivo. The particle size, polydispersity index and zeta potential of the selected formulation were 20.12 ± 0.72 nm, 0.183 ± 0.046 and -38.31 ± 0.33mV, respectively, coupled with high encapsulation efficiency of 93.76 ± 0.31%. Drug loading test showed the solubility of ISL after formulating into micelles was 232 times higher than its
intrinsic solubility. Moreover, critical micelle concentration (CMC) was tested with fluorescence probe method and turned out to be quite low, which implied high stability of ISL-FPM. Release profile in HCl (pH = 1.2), double distilled water and PBS (pH = 7.4) of ISL-FPM reached over 80%, while free ISL was around 40%. Pharmacokinetic research revealed that formulated ISL-FPM significantly increased bioavailability by nearly 2.23-fold compared to free ISL. According to the results of in vitro antioxidant activity, scavenging DPPH activity of ISL was significantly strengthened when it was loaded into polymeric
micelles. Altogether, ISL-FPM can act as a promising approach to improve solubility as well as enhance bioavailability and antioxidant activity of ISL.
Despite intensive investigation of molecular mechanisms underlying the pathogenesis of sepsis, many aspects of sepsis remain unresolved; this hampers the development of appropriate therapeutics. In the present study, we developed a biologic nanomedicine containing a cationic antimicrobial decapeptide KSLW (KKVVFWVKFK), self-associated with biocompatible and biodegradable PEGylated phospholipid micelles (PLM), and analyzed its efficacy for treating sepsis. KSLW was modified with polyethylene glycol (PEG)–aldehyde or was conjugated with distearoylphosphatidylethanolamine (DSPE) –PEG–aldehyde. We compared the antibacterial and antiseptic effects of PEG–KSLW and PLM–KSLW with those of unmodified KSLW both in vitro and in vivo. We found that the PLM–KSLW improved the survival rate of sepsis mouse models without undesired immune responses, and inhibited lipopolysaccharide (LPS)-induced severe vascular inflammatory responses in human umbilical vein endothelial cells compared with unmodified KSLW or PEG–KSLW. Furthermore, PLM–KSLW dramatically reduced the bacterial count and inhibited bacterial growth. We also found a new role of PLM–KSLW in tightening vascular barrier integrity by binding to the glycine/tyrosine-rich domain of occludin (OCLN). Our results showed that PLM–KSLW had a more effective antiseptic effect than KSLW or PEG–KSLW, possibly because of its high affinity toward OCLN. Moreover, PLM–KSLW could be potentially used to treat severe vascular inflammatory diseases, including sepsis and septic shock.
The present work was designed to investigate the antihyperglycaemic and protective effects of two Hericium erinaceus intracellular polysaccharide (HIPS) purified fractions (HIPS1 and HIPS2) from mycelia of H. erinaceus SG-02 on pancreas, liver and kidney in streptozotocin (STZ)-induced diabetic mice. The supplementation of HIPS1 and HIPS2 significantly decreased the blood glucose (GLU) levels; suppressed the abnormal elevations of alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea nitrogen (BUN) and creatinine (CRE) levels in serum; improved the antioxidant enzymatic (superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT)) activities; and attenuated the pathological damage to these organs. The HIPS1 showed superior effects in antihyperglycaemia and organic protection than HIPS2 possible owing to the abundant functional groups (-NH2, -COOH and S=O) in HIPS1, indicating that H. erinaceus SG-02 could be used as a functional food and natural drug for the prevention of diabetes and its complications.
Esculetin, synonymous with 6,7-dihydroxycoumarin, is the main active ingredient of the traditional Chinese medicine Cortex Fraxini. The twig skin or trunk bark of Cortex Fraxini are used by herb doctors as a mild, bitter liver and gallbladder meridians' nontoxic drug as well as dietary supplement. Recently, with a variety of novel esculetin derivatives being reported, the molecular mechanism research as well as clinical application of Cortex Fraxini and esculetin are becoming more attractive. This mini-review will consolidate what is known about the biological activities, the mechanism of esculetin and its synthetic derivatives over the past decade in addition to providing a brief synopsis of the properties of esculetin.
Zeaxanthin (ZA), an important compound found in Lycium barbarum, shows various pharmacodynamic effects. In our present study, a high-fat, high-sucrose diet and streptozotocin (STZ)-induced diabetic rat model was used to investigate the antidiabetic activities of ZA. After a 4-week administration of 200 and 400 mg/kg of ZA and 100 mg/kg of metformin hydrochloride, various blood biochemical indexes were detected. ZA strongly normalized the reduced bodyweight and enhanced fasting blood glucose in diabetic rats. The positive data obtained from the oral glucose tolerance test further confirmed its antidiabetic effects. ZA displayed significant hypolipidemic activities indicated by its modulation of serum levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and total cholesterol. The antidiabetic nephropathy of ZA was confirmed by its regulation of pathological kidney structures, urine levels of n-acetyl-β-d-glucosaminidase and albuminuria, and serum levels of urea nitrogen. ZA inhibited the serum levels of inflammatory factors including interleukin-2 (IL-2), IL-6, tumor necrosis factor-α, and nuclear factor kappa B, further confirming its renal protection. Moreover, the serum imbalances in superoxide dismutase, glutathione peroxidase, methane dicarboxylic aldehyde, and catalase were normalized by ZA, suggesting its antioxidant properties. Altogether, ZA produced hypoglycemic, hypolipidemic, and antidiabetic nephritic effects in a diet-STZ-induced diabetic rat model.
Tamoxifen (TAM) is frequently prescribed for the management breast cancer, but is associated with the challenges like compromised aqueous solubility and poor bioavailability to the target site. It was envisioned to develop phospholipid-based mixed micelles to explore the promises offered by the biocompatible carriers. Various compositions were prepared, employing soya lecithin, polysorbate 80, sodium chloride/dextrose, and water, by self-assembled technique. The formulations were characterized for micromeritics and evaluated for in vitro drug release, hemolysis study, dermatokinetic studies on rodents, and cytotoxicity on MCF-7 cell lines. Cellular uptake of the system was also studied using confocal laser scanning microscopy. The selected composition was of sub-micron range (28.81 ± 2.1 nm), with spherical morphology. During in-vitro studies, the mixed micelles offered controlled drug release than that of conventional gel. Cytotoxicity was significantly enhanced and IC50 value was reduced that of the naïve drug. The bioavailability in epidermis and dermis skin layers was enhanced approx. fivefold and threefold, respectively. The developed nanosystem not only enhanced the efficacy of the drug but also maintained the integrity of skin, as revealed by histological studies. The developed TAM-nanocarrier possesses potential promises for safe and better delivery of TAM.
Objective:
To use structure-activity analysis to study the anti-Alzheimer's disease (anti-AD) activity of natural coumarins isolated from Angelica decursiva and Artemisia capillaris, along with one purchased coumarin (daphnetin).
Methods:
Umbelliferone, umbelliferone 6-carboxylic acid, scopoletin, isoscopoletin, 7-methoxy coumarin, scoparone, scopolin, and esculetin have been previously isolated; however 2'-isopropyl psoralene was isolated from Angelica decursiva for the first time to evaluate their inhibitory effects against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) enzyme activity. We scrutinized the potentials of coumarins as cholinesterase and BACE1 inhibitors via enzyme kinetics and molecular docking simulation.
Results:
Among the test compounds, umbelliferone 6-carboxylic acid, esculetin and daphnetin exhibited potent inhibitory activity against AChE, BChE and BACE1. Both esculetin and daphnetin have a catechol group and exhibit significant anti-AD activity against AChE and BChE. In contrast, presence of a sugar moiety and methoxylation markedly reduced the anti-AD activity of the coumarins investigated in this study. With respect to BACE1 inhibition, umbelliferone 6-carboxylic acid, esculetin and daphnetin contained carboxyl or catechol groups, which significantly contributed to their anti-AD activities. To further investigate these results, we generated a 3D structure of BACE1 using Autodock 4.2 and simulated binding of umbelliferone 6-carboxylic acid, esculetin and daphnetin. Docking simulations showed that different residues of BACE1 interacted with hydroxyl and carboxylic groups, and the binding energies of umbelliferone 6-carboxylic acid, esculetin and daphnetin were negative (-4.58, -6.25 and -6.37 kcal/mol respectively).
Conclusions:
Taken together, our results suggest that umbelliferone 6-carboxylic acid, esculetin and daphnetin have anti-AD effects by inhibiting AChE, BChE and BACE1, which might be useful against AD.
Background:
Edible mushrooms, especially the genus of Pleurotus, have been well studied for their nutrition as well as non-toxic medicinal properties. Recently, much attention has been paid to the therapeutic values of mushrooms in genus of Pleurotus with diabetes mellitus (DM), which was a complex metabolic disorder that induced by increased oxidative stress and characterized by hyperglycemia. However, scare attention has been paid to polysaccharides from P. djamor. Meanwhile, zinc is an essential trace element in the human body and it participates in various pathways of metabolism. Therefore, the objective of present study was aimed to evaluate the protective effects of the three extractable mycelium zinc polysaccharides (MZPS), including acidic-MZPS (Ac-MZPS), alkalic-MZPS (Al-MZPS) and enzymatic-MZPS (En-MZPS), on the liver and kidneys in diabetic mice induced by streptozocin (STZ) aiming to better understand the possible hypoglycemic mechanisms and their health benefits.
Methods:
The Ac-, Al-, and En-MZPS were extracted with hydrochloric acid (1 M), sodium hydroxide (1 M) and snailase (4 %) from P. djamor zinc-enriched mycelium, respectively. The diabetic mice were induced by injection of STZ. Besides the histopathological analyses of liver and kidney, the following biochemical analysis were processed to investigate the antioxidative effects, including activities of superoxide dismutase (SOD), GSH peroxide (GSH-Px) and catalase (CAT), and contents of malondialdehyde (MDA) in liver and kidney homogenate; activities of alamine aminotransferase (ALT) and aspertate aminotransferase (AST), and levels of urea nitrogen (BUN), creatinine (CRE), total cholesterol (TC), albumin (ALB), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein choles-terol (LDL-C) and very low-density lipoprotein cholesterol (VLDL-C) in serum.
Results:
Results showed that the activities of SOD, GSH-Px and CAT were significantly increased, the MDA contents remarkably reduced, and the values of ALT, AST, BUN, CRE, TC, LDL-C and HDL-C observably mitigated in the liver, kidneys and serum of diabetic mice by these three polysaccharides treatment. Biochemical and histopathological analyses also showed that MZPS could alleviate liver and kidneys injury.
Conclusion:
These results demonstrated that Ac-, Al-, and En-MZPS possessed potent antioxidant activities, and could be used as a potentially functional food for the prevention of diabetes and its complications induced by STZ.
Developing a promising carrier for the delivery of poorly water-soluble drugs, such as silybin, to improve oral absorption has become a very worthy of consideration. The goal of this study was to prepare a novel porous calcium phosphate microparticle using povidone-mixed micelles as template while evaluating its in vitro and in vivo properties with silybin as a model drug. The particle characterization, in vitro drug release behavior, and pharmacokinetic parameters of the prepared silybin-loaded calcium phosphate microparticle were investigated. The mean particle size was found to be 3.54 ± 0.32 μm with a rough surface porous structure. Additionally, the silybin-loaded calcium phosphate microparticle compared with the free silybin showed a prolonged 72-h release in vitro and a higher C
max (418.5 ± 23.7 ng mL−1) with 167.5% oral relative bioavailability. A level A in vitro–in vivo correlation (IVIVC), established for the first time, demonstrated an excellent IVIVC of the formulated silybin in oral administration. In conclusion, this povidone-mixed micelle-based microparticle was successfully prepared to enhance the oral bioavailability of silybin. Therefore, application of this novel porous calcium phosphate microparticle holds a significant potential for the development of poorly water-soluble drugs.
Pluronic/bile salt/phospholipid mixed micelles (Pluronic/BS/PS-MM) drug carrier system for solubilization hydrophobic drugs was developed. A typical hydrophobic compound, pyrene, was selected as a representative hydrophobic compound to model the hydrophobic drugs. Five Pluronics, F68, F88, F98, F108, and F127 with different PPO chain length were studied. CMC data and solubilization capacities were obtained from a pyrene solubilization method. A closed association model was used to obtain the thermodynamic parameters: Gibbs free energy (ΔG°), enthalpy, (ΔH°) and entropy (ΔS°) of micellization. The results obtained from these experiments suggest that the mixed micelles was more stable and solubilize more pyrene than single one; and the solubilization of pyrene was strong effected by the PPO block size, thus accentuating synergistic interaction mechanism in Pluronic/BS/PS-MM. The study generated an important dataset so as to compare the effect of different Pluronics on solubility capacity of Pluronic/BS/PS-MM.
Bile salt/phospholipid mixed micelles (MMs) are potent carriers used for oral absorption of drugs that are poorly soluble in water; however, there are many limitations associated with liquid formulations. In the current study, the feasibility of preparing bile salt/phospholipid MM precursor (preMM) pellets with high oral bioavailability, using fluid-bed coating technology, was examined. In this study, fenofibrate (FB) and sodium deoxycholate (SDC) were used as the model drug and the bile salt, respectively. To prepare the MMs and to serve as the micellular carrier, a weight ratio of 4:6 was selected for the sodium deoxycholate/phospholipids based on the ternary phase diagram. Polyethylene glycol (PEG) 6000 was selected as the dispersion matrix for precipitation of the MMs onto pellets, since it can enhance the solubilizing ability of the MMs. Coating of the MMs onto the pellets using the fluid-bed coating technology was efficient and the pellets were spherical and intact. MMs could be easily reconstituted from preMM pellets in water. Although they existed in a crystalline state in the preMM pellets, FB could be encapsulated into the reconstituted MMs, and the MMs were redispersed better than solid dispersion pellets (FB:PEG = 1:3) and Lipanthyl®. The redispersibility of the preMM pellets increased with the increase of the FB/PEG/micellar carrier. PreMM pellets with a FB:PEG:micellar carrier ratio of 1:1.5:1.5 showed 284% and 145% bioavailability relative to Lipanthyl® and solid dispersion pellets (FB:PEG = 1:3), respectively. Fluid-bed coating technology has considerable potential for use in preparing sodium deoxycholate/phospholipid preMM pellets, with enhanced oral bioavailability for poorly water-soluble drugs.
The clinical applications of paclitaxel (PTX), a natural compound with broad-spectrum antitumor effects, have been markedly limited owing to its poor oral bioavailability and lack of targeting ability. Recently, several drug carriers, such as TPGS2k, gelatin (Gel), cyclodextrin (CD), and hyaluronic acid (HA), have been identified as promising enhancers of drug efficacy. Therefore, Gel-grafted CD (GEL-CD) and HA-grafted CD (HA-CD) were synthesized via grafting, and PTX-loaded TPGS2k/GEL-CD/HA-CD nanoparticles (TGHC-PTX-NPs) were successfully prepared using the ultrasonic crushing method. The mean particles size, polydispersity index, and Zeta potential of TGHC-PTX-NPs were 253.57 ± 2.64 nm, 0.13 ± 0.03, and 0.087 ± 0.005 mV, respectively. TGHC-PTX-NPs with an encapsulation efficiency of 61.77 ± 0.47% and a loading capacity of 6.86 ± 0.32% appeared round and uniformly dispersed based on transmission electron microscopy. In vitro release data revealed that TGHC-PTX-NPs had good sustained-release properties. Further, TGHC-PTX-NPs had increased the targeted uptake by HeLa cells as HA can specifically bind to the CD44 receptor at the cell surface, and its intestinal absorption is related to caveolin-mediated endocytosis. The pharmacokinetic results indicated that TGHC-PTX-NPs significantly enhanced the absorption of PTX in vivo compared to the PTX suspension, with a relative bioavailability of 227.21%. Such findings indicate the potential of TGHC-PTX-NPs for numerous clinical applications.
Esculetin is a natural dihydroxy coumarin; it is mainly extracted from twig skin and the trunk bark of the Chinese herbal medicine Fraxinus rhynchophylla Hance. Emerging evidence suggests that esculetin has a wide range of pharmacological activities. Based on its fundamental properties, including antioxidant, antiinflammatory, antiapoptotic, anticancer, antidiabetic, neuroprotective, and cardiovascular protective activities, as well as antibacterial activity, among others, esculetin is expected to be a therapeutic drug for specific disease indications, such as cancer, diabetes, atherosclerosis, Alzheimer's disease (AD), Parkinson's disease (PD), nonalcoholic fatty liver disease (NAFLD), and other diseases. The oral bioavailability of esculetin was shown by studies to be low. The extensive glucuronidation was described to be the main metabolic pathway of esculetin and C-7 phenolic hydroxyl to be its major metabolic site. With the development of scientific research technology, the pharmacological effects of esculetin are identified and its potential for the treatment of diseases is demonstrated. The underlining mechanisms of action and biological activities as well as the pharmacokinetic data of the analyzed compound reported so far are highlighted in this review with the aim of becoming a proven, and applicable insight and reference for further studies on the utilization of esculetin.
Syringic acid (SA), a natural polyphenol found in fruits and vegetables, is claimed to show notable hepatoprotection. Nevertheless, low solubility and bioavailability hamper the application of SA. This study aimed to investigate the potential of TPGS/F127/F68 mixed polymeric micelles as a sustained and liver-targeting nanocarrier for SA. Herein, the prepared SA-loaded TPGS/F127/F68 mixed polymeric micelles (SA-TPGS-Ms) were spherically-shaped and homogeneously-distributed nanoparticles with high entrapment efficiency (94.67 ± 2.05%) and sustained release. Besides, in-vitro cell culture studies revealed that SA-TPGS-Ms substantially promoted cellular uptake with excellent biocompatibility. After oral administration, SA-TPGS-Ms demonstrated an increased bioavailability (2.3-fold) and delayed in-vivo elimination compared with the free SA. Furthermore, the alleviation of oxidative stress and amelioration of hepatic injury in CCl4-induced hepatotoxicity mice further demonstrated the excellent hepatoprotection of SA-TPGS-Ms. Collectively, SA-TPGS-Ms could be a promising nanocarrier for the utilization of SA in functional foods, with enhanced bioavailability and hepatoprotection.
Esculetin, a natural coumarin derived from herbs, has shown different potential pharmacological activities. However, the poor aqueous solubility of esculetin may limit its therapeutic efficacy. Nanocrystal is a promising dosage form to overcome this drawback by enhancing drug saturation solubility. Hence, a laboratory-scale wet-bead milling approach was employed to develop an esculetin nanocrystal formulation. Povacoat™ was selected as a stabilizer after screening different surfactants and polymers. Design of experiments was applied to identify and understand the relationship between process parameters and formulation compositions at the stage of formulation optimization. Furthermore, the optimized formulation was solidified using two different approaches (spray-drying and freeze-drying) and characterized by dynamic light scattering, laser diffraction, transmission electron microscopy, scanning electron microscopy, thermal analysis, and X-ray powder diffraction. An esculetin-Povacoat™ nanocrystal formulation that maintained a 200 nm particle size for 180 days was successfully obtained with specific critical process parameters and formulation composition within the design space.
Myricitrin has many pharmacological effects, such as anti-inflammation, liver
protection and anti-oxidation. However, its clinical application is limited by poor
solubility and low oral bioavailability. The preparation of myricitrin-loaded
proliposomes (MPs) was achieved via the combination of thin-film dispersion
technique and freeze-drying method. The in vitro release of MPs compared with
free myricitrin was measured in different dissolution media while the
pharmacokinetic study was also conducted in rats. Moreover, the uric acidlowering activity of MPs was investigated in the hyperuricemic rat model. The
prepared myricitrin appeared to be spherical. Notably, compared with the free
myricitrin, the cumulative release in vitro and in vivo oral bioavailability of MPs
were markedly increased. Besides, the MPs could significantly lower the serum
uric acid level as well as ameliorate liver and kidney damage in hyperuricemic
rats compared with the model group. Therefore, the present work supports the
fact that MPs improved the oral bioavailability of myricitrin for the prospect of
clinical application.
Aims:
To provide global estimates of diabetes prevalence for 2019 and projections for 2030 and 2045.
Methods:
A total of 255 high-quality data sources, published between 1990 and 2018 and representing 138 countries were identified. For countries without high quality in-country data, estimates were extrapolated from similar countries matched by economy, ethnicity, geography and language. Logistic regression was used to generate smoothed age-specific diabetes prevalence estimates (including previously undiagnosed diabetes) in adults aged 20-79 years.
Results:
The global diabetes prevalence in 2019 is estimated to be 9.3% (463 million people), rising to 10.2% (578 million) by 2030 and 10.9% (700 million) by 2045. The prevalence is higher in urban (10.8%) than rural (7.2%) areas, and in high-income (10.4%) than low-income countries (4.0%). One in two (50.1%) people living with diabetes do not know that they have diabetes. The global prevalence of impaired glucose tolerance is estimated to be 7.5% (374 million) in 2019 and projected to reach 8.0% (454 million) by 2030 and 8.6% (548 million) by 2045.
Conclusions:
Just under half a billion people are living with diabetes worldwide and the number is projected to increase by 25% in 2030 and 51% in 2045.
In order to improve oral bioavailability and anti-diabetic efficacy of amentoflavone with multi-mechanisms, an oral micelle system was developed by using N-vinyl pyrrolidone-maleate-guerbet alcohol monoester polymer for the first time, which was designated as P(NVP-MGAM)/AF. After oral administration, P(NVP-MGAM)/AF enhanced the oral bioavailability of amentoflavone, which was approximately 3.2 times as much as that of amentoflavone solution. The animal study using the KKAy insulin resistant diabetes mouse model indicated that it regulates the expression and activity of downstream signaling factors and proteins by lowering blood lipids, reducing inflammatory responses, activating PPAR γ signaling pathway and PI3K/Akt signaling pathway. After being made into micelles, it is more effective because of its better absorbability and bioavailability. The results from this study provide a theoretical basis for the clinical application of diabetes treatment with amentoflavone. The oral micelles of P(NVP-MGAM)/AF may become one of the most potent drugs in treatment diabetes mellitus, which opens up a new way for the prevention and treatment of diabetes.
The insertion of specific derivatives into pre-formed colloidal systems has been shown to be a useful method for modifying their pharmacokinetic characteristics and biodistribution profiles.
In this experimental work the effect of the post-insertion of different PEG-derivatives into pre-formed 100-nm liposomes made up of various lipid mixtures (DMPC, DPPC, DOPC, DSPC and cholesterol at different molar ratios) was investigated. The vesicles were incubated with increasing amounts of DSPE-mPEG2000 as sterically stabilized micelles (5, 10 and 15% w/w with respect to the liposomal lipid mixture) in order to favour the insertion of the PEG-lipid into the liposomal bilayer. The colloidal formulations were characterized by photo-correlation spectroscopy; the DSPE-mPEG2000 integrated into the pre-formed liposomes was demonstrated by means of field flow fractionation while the amount of post-inserted compound was quantified using a suitable spectrophotometric assay (I2 assay). Similar investigations have been performed using PEG-derivatives characterized by a different molecular weight.
The physico-chemical properties of the various liposomal formulations were influenced by the post-insertion of PEG-derivatives. The lipid mixture made up of saturated phospholipids and cholesterol proved to be the best, post-insertion (P.I.E.).
The post-insertion technique may be a suitable approach to be used in personalized (nano)medicine.
We investigated if the self-assembled micelles of rebaudioside A (RA) could potentially be utilized as an ocular drug-delivery system in this investigation. RA self-assembled into micelles with ultra-small particle sizes (< 4 nm) in a homogeneous distribution state (polydispersity index < 0.3). RA had good cellular tolerance and no cytotoxicity was observed at concentrations ≤ 18.5 mg/ml at 72 h of incubation. RA also did not cause cell apoptosis at concentration ≤ 12 mg/ml. Coumarin-6 (Cou6)-loaded RA micelles had good cellular tolerance and in vivo non-irritants to the rabbit eyes. RA micelles dramatically improved the cellular uptake of Cou6 (compared to free-Cou6 P < 0.05); an energy-independent, active, intracellular endocytosis pathway was apparently involved, and cellular organelles such as lysosomes, endoplasmic reticuli, and mitochondria were observed with a high distribution of Cou6, while a much more sophisticated endocytosis pathway was apparently involved in the ex vivo corneal endocytosis mechanism tests. The use of RA micelles significantly improved in vivo corneal permeation of the encapsulated Cou6 when compared to free-Cou6 eye drops (P < 0.05). These findings indicate that RA micelle formulations have great potential as a novel ocular drug-delivery system to improve the bioavailability of hydrophobic drugs.
Introduction
Esculetin was identified to inhibit cell proliferation and induce apoptosis or cell cycle arrest in several cancer cell lines. However, the effect of esculetin on lung cancer remains elusive.
Methods
The anti-proliferative role of esculetin in murine Lewis lung carcinoma (LLC) cells was evaluated by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and colony formation assays. BALB/c mice were subcutaneously injected with LLC cells to investigate the inhibitory effect of esculetin on the growth of lung cancer xenograft. Invasive ability was detected in esculetin treated and untreated LLC cells by transwell assay. The association between esculetin and Wnt/β-catenin signaling, as well as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), was confirmed by testing the expression of c-myc, Cyclin D1 and NF-κB using Western blot.
Results
Esculetin treatment in LLC cells led to significant decrease of cell proliferation in a time- and dose-dependent manner. After injection of LLC cells into mice, reduced size and weight of tumors were observed in esculetin treated mice compared to untreated mice. However, no difference in cell invasion was observed between the treated and untreated LLC cells. Notably decreased expression of c-myc, Cyclin D1 and NF-κB were observed in LLC cells with esculetin treatment compared to untreated cells.
Conclusion
Esculetin plays an inhibitory role in the growth of lung cancer by down-regulating c-myc, Cyclin D1 and NF-κB.
Introduction:
Esculetin was identified to inhibit cell proliferation and induce apoptosis or cell cycle arrest in several cancer cell lines. However, the effect of esculetin on lung cancer remains elusive.
Methods:
The anti-proliferative role of esculetin in murine Lewis lung carcinoma (LLC) cells was evaluated by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and colony formation assays. BALB/c mice were subcutaneously injected with LLC cells to investigate the inhibitory effect of esculetin on the growth of lung cancer xenograft. Invasive ability was detected in esculetin treated and untreated LLC cells by transwell assay. The association between esculetin and Wnt/β-catenin signaling, as well as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), was confirmed by testing the expression of c-myc, Cyclin D1 and NF-κB using Western blot.
Results:
Esculetin treatment in LLC cells led to significant decrease of cell proliferation in a time- and dose-dependent manner. After injection of LLC cells into mice, reduced size and weight of tumors were observed in esculetin treated mice compared to untreated mice. However, no difference in cell invasion was observed between the treated and untreated LLC cells. Notably decreased expression of c-myc, Cyclin D1 and NF-κB were observed in LLC cells with esculetin treatment compared to untreated cells.
Conclusion:
Esculetin plays an inhibitory role in the growth of lung cancer by down-regulating c-myc, Cyclin D1 and NF-κB.
[6]-Gingerol, one of the components of the rhizome of Ginger, has a variety of biological activities such as anticoagulant, antioxidative, antitumor, anti-inflammatory, antihypertensive, and so forth. However, as one of the homologous phenolic ketones, [6]-gingerol is insoluble in water which limits its applications. Herein, we prepared [6]-gingerol proliposomes through modified thin-film dispersion method, which was spherical or oval, and physicochemically stable with narrow size distribution. Surprisingly, in vitro release of [6]-gingerol loaded proliposome compared with the free [6]-gingerol was significantly higher and its oral bioavailability increased 5-fold in vivo. Intriguingly, its antitumor effect was enhanced in the liposome formulation. Thus, our prepared [6]-gingerol proliposome proved to be a novel formulation for [6]-gingerol, which significantly improved its antitumor effect.
Introduction:
Coumarins belong to the benzopyrone family. They are naturally plant-derived or synthetically obtained substances, presenting a wide variety of biological activities, offering an extented therapeutic profile. Their structural characteristics correlated to physicochemical properties define their pleiotropic biological responses.
Areas covered in this review:
Recent patent publications (2015-2016), describing coumarins and their derivatives are analyzed. Synthesis, biological evaluations in vitro /in vivo e.g. antiviral, anticancer, cytotoxic, antioxidant, anti-inflammmatory protocols are included. Furthermore, several pharmaceutical applications and pharmaceutical compositions are also described. Expert opinion: Several synthetic coumarins, hybrids and derivatives (azoles, sulfonyl, furazan, pyrazole etc) have been found to possess promising anticancer, antitumor anti-proliferative activities. Their clinical evaluation will be critical to assess therapeutic utility. The compounds for which the mechanism of action is well defined can serve as lead compounds for the design of new more potent molecules.
This study investigated the effects and mechanism of esculetin (6,7-dihydroxycoumarin) on non-alcoholic fatty liver in diabetic mice fed high-fat diet (HFD). The diabetic mice model was induced by injection of streptozotocin, after which they were fed HFD diet with or without esculetin for 11 weeks. Non-diabetic mice were provided a normal diet. Diabetes induced hepatic hypertrophy, lipid accumulation and droplets; however, esculetin reversed these changes. Esculetin treatment in diabetic mice fed HFD significantly down-regulated expression of lipid synthesis genes (Fasn, Dgat2 and Pap) and inflammation genes (Tlr4, Myd88, Nfkb, Tnfα and Il6). Moreover, the activities of hepatic lipid synthesis enzymes (fatty acid synthase and phosphatidate phosphohydrolase) and gluconeogenesis enzyme (glucose-6-phosphatase) in the esculetin group were decreased compared with the diabetic group. In addition, esculetin significantly reduced blood HbA1c, serum cytokines (TNF-α and IL-6) and chemokine (MCP-1) levels compared with the diabetic group without changing the insulin content in serum and the pancreas. Hepatic SOD activity was lower and lipid peroxidation level was higher in the diabetic group than in the normal group; however, esculetin attenuates these differences. Overall, these results demonstrated that esculetin supplementation could protect against development of non-alcoholic fatty liver in diabetes via regulation of lipids, glucose and inflammation.
For quantitative and other related bioactive studies of hydnocarpin, there is a need to establish an efficient, specific and sensitive analytical method (in vitro and in vivo). In this paper, an efficient HPLC method has been established and validated to analyze hydnocarpin in nanomicelles formulation for the first time. The different chromatographic conditions for in vitro and in vivo determinations were investigated, with the application examined by pharmacokinetics and tissue distribution studies. The analysis was carried out using an HPLC system with Waters symmetry C18 column (4.6 × 150 mm, 5 µm) at 25 °C with a detecting wavelength of 342 nm. Eluted at a rate of 1.0 mL/min, 65 % methanol and 35 % acetic acid solution (0.1%) served as the mobile phase for the in vitro determinations while 62 % methanol and 38 % acetic acid solution (0.1%) was used for in vivo analysis with isoliquiritigenin as internal standard. The established in vitro linearity ranges for hydnocarpin was 0.2 - 20 µg/mL (R(2) = 0.9996), with the biological (in vivo) samples following the same trend. The accuracy of the method was > 99% (in vitro) and between 92.4 % - 105.3 % (in vivo). Also, the precisions met the acceptance criterion. These results indicate that the established method exhibited high specificity, accuracy, linearity and precision. Additionally, this efficient HPLC method was well applied on pharmacokinetics and tissue distribution studies. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Type 2 diabetes mellitus (T2DM) being a worldwide challenge to public health. The aim of this study was to examine the effect of esculetin, a major compound present in the herbal plant of Matricaria chamomilla L., on the key enzymes of carbohydrate metabolism in streptozotocin (STZ) induced diabetic rats. At first, the rats were induced intraperitonial injection of STZ (40 mg/kg bw) to attain diabetes and were then treated with different concentrations of esculetin (10, 20 and 40 mg/kg bw) for 45 days. The diabetic rats had elevated levels of plasma glucose and glycated haemoglobin (HbA1c) and decreased plasma insulin and haemoglobin (Hb) levels. Food intake, water intake and oral glucose tolerance test were also measured. Activities of carbohydrate metabolic enzymes such as glucose-6-phosphatase, fructose 1,6-bisphosphatase increased and glucokinase, glucose-6-phosphate dehydrogenase decreased significantly. Oral administration of esculetin significantly decreased the levels of plasma glucose, HbA1c and increased the levels of Hb and insulin. The activities of the key enzymes such as glucokinase and glucose-6-phosphate dehydrogenase had significantly increased whereas, glucose-6-phosphatase and fructose-1,6-bisphosphatase had significantly decreased. Further, protection against body weight loss of diabetic rats was observed. Among the three doses, 40 mg/kg bw of esculetin exerted a more pronounced antihyperglycemic effect against STZ-induced diabetic rats.
The purpose of this work was to explore the feasibility of using Soluplus® in preparing a fenofibrate (FBT) nanosuspension adopting wet media milling technology. HPMC and Soluplus® were used as stabilizers to prepare FBT/HPMC nanosuspension (F1) and FBT/Soluplus® nanosuspension (F2), respectively. The nanosuspensions were subjected to evaluations involving particle size, dissolution, preliminary stability and pharmacokinetic behavior. A marked reduction in particle size was achieved by nanosuspensions (from 17.55 μm to 642 nm (F1) and 344 nm (F2)). The nanosuspensions displayed almost complete dissolution while percentages of 30% and 13% were obtained by physical mixtures and coarse FBT separately. Soluplus® could stabilize the nanosuspension more effectively due to a weaker Ostwald ripening effect resulting from a slower diffusion of micelles formed by Soluplus® entrapping dissolved FBT than FBT exposed to pure water directly. In the in vivo evaluation, larger AUC0–72 h and Cmax, and shorter Tmax were obtained by the nanosuspensions. Significant differences were observed between the physical mixtures. The phenomenon of double peaks was present in this study. The major factor may be the multiple absorption sites of FBT. The current work indicated that Soluplus® is well suited for preparation of a nanosuspension with good stability and improved dissolution and bioavailability.
Although previous studies have demonstrated that the natural coumarin compound esculetin possesses various pharmacological properties, the molecular mechanism of esculetin-mediated anti-inflammatory potential is not fully understood. In this study, we determined the effects of esculetin on lipopolysaccharide (LPS)-induced inflammatory responses of murine RAW 264.7 macrophages. The results indicate that esculetin inhibits LPS-induced nitric oxide and prostaglandin E2 production in a concentration-dependent manner, and inhibits inducible nitric oxide synthase and cyclooxygenase-2 expression in RAW 264.7 cells. Esculetin also significantly suppresses the production of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, which was concomitant with a decrease in their expression levels. Furthermore, it was observed that esculetin attenuated the LPS-mediated nuclear factor-kappa B (NF-κB) translocation associated with the blocking of inhibitor of NF-κB (IκB)-α degradation as well as reactive oxygen species (ROS) production, without any significant cytotoxicity. These data suggest that, by blocking NF-κB activation, esculetin suppresses LPS-elicited inflammatory events, and this is mediated, at least in part, by inhibiting the generation of ROS. Collectively, these findings provide mechanistic insights into the anti-inflammatory action of esculetin in macrophages.
It is commonly observed that hydrophobic molecules alone cannot self-assemble into stable nanoparticles, requiring the employ of amphiphilic and/or ionic materials to support nanoparticle stability and function in vivo. We report herein newly self-assembled nanomedicines through entirely different mechanisms. We present proof-of-concept methodology and results in support of our hypothesis that disulfide-induced nanomedicines (DSINMs) are promoted and stabilized by the insertion of a single disulfide bond into hydrophobic molecules, in order to balance the competition between intermolecular forces involved in the self-assembly of nanomedicines. This hypothesis has been explored through diverse synthetic compounds, which include four first-line chemotherapy drugs (paclitaxel, doxorubicin, fluorouracil and gemcitabine), two small-molecule natural products with their derivatives, as well as a fluorescent probe. Such an unprecedented and highly reproducible system thus shows the potential to serve as a synthetic platform for a wide array of safe and effective therapeutic and diagnostic nanomedicine strategies.
E. coli O157:H7 is the most common cause of hemorrhagic colitis, and no effective therapy exists for E. coli O157:H7 infection. Biofilm formation is closely related to E. coli O157:H7 infection and constitutes a mechanism of antimicrobial resistance. Hence, the antibiofilm or antivirulence approach provides an alternative to antibiotic strategies. Coumarin and its derivatives have a broad range of biological effects, and in this study, the antibiofilm activities of nine coumarins were investigated against E. coli O157:H7. Coumarin or umbelliferone at 50μg/ml was found to inhibit biofilm E. coli O157:H7 formation by more than 80% without affecting bacterial growth. Transcriptional analysis showed that coumarins repressed curli genes and motility genes in E. coli O157:H7, and these findings were in-line with observed reductions in fimbriae production, swarming motility, and biofilm formation. In addition, esculetin repressed Shiga-like toxin gene stx2 in E. coli O157:H7 and attenuated its virulence in vivo in the nematode Caenorhabditis elegans. These findings show that coumarins have potential use in antivirulence strategies against persistent E. coli O157:H7 infection.
The objective of this study was to prepare apigenin-loaded polymeric micelles to improve the solubility of apigenin in water. The polymeric micelles composed of Pluronic P123 and Solutol HS 15 were prepared by a thin-film dispersion method and the formulation was optimized with a central composite design (CCD). The obtained micelles were spherical under transmission electron microscope (TEM) with an average diameter of 16.9 nm, the entrapment efficiency and drug loading was 96.36% and 1.32%, respectively. The in vitro drug release study showed nearly 84% of apigenin was released from micelles within 36 h, showing the sustained release property. Cell toxicity assay indicated that the cytotoxicity of apigenin-loaded polymeric micelles against HepG2 and MCF-7 cancer cell in vitro was remarkably higher than that of the free drug. All the results provided the evidence for the great potential of polymeric micelles as nanocarrier for apigenin as a poorly water soluble drug.
The purpose of this study was to develop a high-drug-loading nanoemulsion by self-assembly to improve the oral absorption of high dosing poorly water-soluble drugs. Probucol was selected as a model drug and the probucol-loaded self-assembled nanoemulsion (PSN) was prepared and characterized. Moreover, the intestinal absorption and in vivo pharmacokinetic behavior of PSN were evaluated in rats after oral administration. The experimental results indicated that PSN was nanometer-sized droplets with the mean diameter of 40.32 ± 0.31 nm and polydispersity index of 0.184 ± 0.005. The aqueous solubility of probucol was remarkably increased after its incorporation into PSN. Compared with free drug suspension, the intestinal absorption of PSN was not significantly increased in duodenum, but obviously enhanced 3.62- and 13.1-fold in jejunum and ileum, respectively. In particular, the in vivo pharmacokinetic results indicated that the oral bioavailability of probucol was greatly improved 8.97-fold by PSN.
Thereby, the high-drug-loading self-assembled nanoemulsion was very effective in enhancing the oral absorption of high-dosing poorly water-soluble drugs.
Introduction:
Additional oral antidiabetic agents to metformin, sulfonylureas (SU) and thiazolidinediones (TZD) are approved for the treatment of type 2 diabetes.
Areas covered:
The efficacy and safety of metformin, SUs, TZDs, dipeptidyl peptidase-IV (DPP-4) inhibitors, meglitinide analogs, α-glucosidase inhibitors (AGIs), bile-acid sequestrants (BAS) and bromocriptine will be reviewed.
Expert opinion:
Several new oral agents have been approved for type 2 diabetes management in recent years. It is important to understand the efficacy and safety of these medications in addition to the older agents to best maximize oral drug therapy for diabetes. Of the recently introduced oral hypoglycemic/antihyperglycemic agents, the DPP-4 inhibitors are moderately efficacious compared with mainstay treatment with metformin with a low side-effect profile and have good efficacy in combination with other oral agents and insulin. They are a recommended alternative when metformin use is limited by gastrointestinal (GI) side effects or when SU treatment results in significant hypoglycemia or weight gain. Meglitinide analogs are limited by their frequent dosing, expense and hypoglycemia (repaglinide > nateglinide), while AGIs are also limited by their dosing schedule and GI side-effect profile. BAS and bromocriptine have the lowest efficacy with regard to HbA(1c) reduction, also are plagued by GI adverse reactions, but have a low risk of hypoglycemia.
Diabetes mellitus is the most common serious metabolic disorder and it is considered to be one of the five leading causes of death in the world. Hyperglycemia-mediated oxidative stress plays a crucial role in diabetic complications. Hence, this study was undertaken to evaluate the protective effect of esculetin on the plasma glucose, insulin levels, tissue antioxidant defense system and lipid peroxidative status in streptozotocin-induced diabetic rats. Diabetic rats exhibited increased blood glucose with significant decrease in plasma insulin levels. Extent of oxidative stress was assessed by the elevation in the levels of lipid peroxidation markers such as thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (HP) and conjugated dienes (CD); reduction in the enzymic antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST); nonenzymic antioxidants Vitamin C, E and reduced glutathione (GSH) were observed in the liver and kidney tissues of diabetic control rats as compared to control rats. Oral supplementation of esculetin to diabetic rats for 45 days significantly brought back lipid peroxidation markers, enzymic and nonenzymic antioxidants to near normalcy. Moreover, the histological observations evidenced that esculetin effectively rescues the hepatocytes and kidney from hyperglycemia mediated oxidative damage without affecting its cellular function and structural integrity. These findings suggest that esculetin (40 mg/kg BW) treatment exerts a protective effect in diabetes by attenuating hyperglycemia-mediated oxidative stress and antioxidant competence in hepatic and renal tissues. Further, detailed studies are in progress to elucidate the molecular mechanism by which esculetin elicits its modulatory effects in insulin signaling pathway.
In this study, curcumin (Cur) loaded mixed micelles (Cur-PF), composed of Pluronic P123 (P123) and Pluronic F68 (F68), was prepared using the thin-film hydration method and evaluated in vitro. The preparation process was optimized with a central composite design (CCD). The average size of the mixed micelles was 68.2 nm, and the encapsulating efficiency for Cur was 86.93%, and 6.996% for drug-loading. Compared with the Cur propylene glycol solution, the in vitro release of Cur from Cur-PF presented the sustained-release property. The in vitro cytotoxicity assay showed that the IC(50) values on MCF-7 cells for Cur-PF and free Cur in DMSO solution were 5.04 μg/mL and 8.35 μg/mL, while 2.52 μg/mL and 8.27 μg/mL on MCF-7/ADR cells. It could be concluded from the results that P123/F68 mixed micelles might serve as a potential nanocarrier to improve the solubility and biological activity of Cur.
Understanding the in-vitro release profile of drugs from drug eluting devices such as cardiac stent is crucial in designing and optimizing the drug embedded matrices. Sirolimus (SRL), a widely used anti-inflammatory/antiproliferative/immunosuppressive hydrophobic drug undergoes irreversible changes such as hydrolysis leading to erroneous assessment of the release profile. The release profile mainly depends on the drug release medium. The present study aims to develop and optimize the aqueous medium for the solubilization of SRL and in-vitro release method from drug eluting stent (DES). In the first stage of study several release media containing different buffer compositions, pH, and a series of micelle forming PEO-PPO-PEO block copolymers (known as Pluronic(®)) were examined for solubility and stability of SRL by reversed phase high performance liquid chromatography (RP-HPLC). SRL showed good solubility and stability at pH 4.0 (both in acetate buffer as well in phosphate buffer) in the presence of block copolymers. Solubilization of SRL was remarkably higher in P103 and P123 micelles than more hydrophilic F68 and F127. To get further insight into the underlying drug dissolution mechanisms, critical micellization temperature (CMT), and hydrodynamic size of micelles with and without drug incorporation were determined by UV-visible spectroscopy and dynamic light scattering (DLS) respectively. The micelle-water partition coefficient (P) and location of solubilized drug were also evaluated from a thermodynamics viewpoint. Finally, the optimized media were examined for the release of SRL from drug eluting stent; the data suggest that a release medium consisting of 0.1% P123 in phosphate buffer pH 4.0 is most suitable for evaluation of in-vitro release of SRL from DES.