A novel lonidamine derivative targeting mitochondria to eliminate cancer stem cells by blocking glutamine metabolism.

Cancer stem cells (CSCs) have been blamed as the main culprit of tumor initiation, progression, metastasis, chemoresistance, and recurrence. However, few anti-CSCs agents have achieved clinical success so far. Here we report a novel derivative of lonidamine (LND), namely HYL001, which selectively and potently inhibits CSCs by targeting mitochondria, with 380-fold and 340-fold lower IC50 values against breast cancer stem cells (BCSCs) and hepatocellular carcinoma stem cells (HCSCs), respectively, compared to LND. Mechanistically, we reveal that HYL001 downregulates glutaminase (GLS) expression to block glutamine metabolism, blunt tricarboxylic acid cycle, and amplify mitochondrial oxidative stress, leading to apoptotic cell death. Therefore, HYL001 displays significant antitumor activity in vivo, both as a single agent and combined with paclitaxel. Furthermore, HYL001 represses CSCs of fresh tumor tissues derived from liver cancer patients. This study provides critical implications for CSCs biology and development of potent anti-CSCs drugs.

A Simple Glutathione-Responsive Turn-On Theranostic Nanoparticle for Dual-Modal Imaging and Chemo-Photothermal Combination Therapy.

Constructing a tumor microenvironment stimuli activatable theranostic nanoparticle with simple components and preparation procedures for multimodality imaging and therapy remains a major challenge for current theranostic systems. Here we report a novel and simple glutathione (GSH)-responsive turn-on theranostic nanoparticle for dual-modal imaging and combination therapy. The theranostic nanoparticle, DHP, consisting of a disulfide-bond-linked hydroxyethyl starch paclitaxel conjugate (HES-SS-PTX) and a near-infrared (NIR) cyanine fluorophore DiR, is prepared with a simple one-step dialysis method. As DiR is encapsulated within the hydrophobic core formed by HES-SS-PTX, the fluorescence of DiR is quenched by the aggregation-caused quenching (ACQ) effect. Nonetheless, once DHP is internalized by cancer cells, the disulfide bond of HES-SS-PTX can be cleaved by intracellular GSH, leading to the synchronized release of conjugated PTX and loaded DiR. The released PTX could exert its therapeutic effect, while DiR could adsorb onto nearby endosome/lysosome membranes and regain its fluorescence. Thus, DHP could monitor the release and therapeutic effect of PTX through the fluorescence recovery of DiR. Remarkably, DHP can also be used as an in vivo probe for both fluorescent and photoacoustic imaging and at the same time achieves potent antitumor efficacy through chemo-photothermal combination therapy. This study provides novel insights into designing clinically translatable turn-on theranostic systems.

Preparation of Coenzyme Q10 nanostructured lipid carriers for epidermal targeting with high-pressure microfluidics technique.

OBJECTIVE: The objective of this work was to prepare coenzyme Q10 loaded nanostructured lipid carriers (Q10-NLC) and evaluate its epidermal targeting effect. METHODS: Q10-NLC was prepared by high-pressure microfluidics technique. Formulations and preparation parameters were optimized with response surface design. Q10-NLC was characterized by PCS, TEM, DSC and PXRD. The penetration of Q10 from the Q10-NLC formulations through skins and into skins were evaluated in vitro using Franz diffusion cells fitted with SD rat skins. In vitro release, long-term stability and light stability were also evaluated. RESULTS: The results showed that the concentration of solid lipid and emulsifier in formulation had a significant influence on particle size. The optimized preparation parameters were magnetic stirring for 20 min, high stirring at 8000 rpm for 1 min and high-pressure microfluidics at 1200 bar for three cycles. The size of Q10-NLC prepared by optimized formulation and parameters was (151.7 ± 2.31) nm, polydispersity (PDI) 0.144, ζ potential was (-44.1 ± 1.68) mV, drug loading 2.51%, encapsulation efficiency 100%. In vitro release study, Q10-NLC showed fast release during the first 3 hours and prolonged release afterwards. In vitro skin permeation study, the accumulative uptake of Q10 in epidermal of Q10-NLC was 10.11 times over Q10 emulsion. After exposure to day light for 24 hours, the amount of Q10 in Q10-NLC decreased only 5.59%, while in Q10 emulsion decreased 24.61% and Q10-ethanol solution 49.74%. CONCLUSION: Q10-NLC exhibited a significant epidermal targeting effect, which was proved to be a promising carrier for topical delivery of Q10.

Preparation and optimization of triptolide-loaded solid lipid nanoparticles for oral delivery with reduced gastric irritation.

Triptolide (TP) often causes adverse reactions in the gastrointestinal tract when it is administered orally. This study aimed to prepare and optimize triptolide-loaded solid lipid nanoparticles (TP-SLN) with reduced gastric irritation. The microemulsion technique was used to formulate TP-SLN employing a five-level central composite design (CCD) that was developed for exploring the optimum levels of three independent variables on particle size, encapsulation efficiency (EE) and drug loading (DL). Quadratic polynomial models were generated to predict and evaluate the three independent variables with respect to the three responses. The optimized TP-SLN was predicted to comprise fraction of lipid of 49.73%, surfactant to co-surfactant ratio of 3.25, and lipid to drug ratio of 55.27, which showed particle size of 179.8 ± 5.7 nm, EE of 56.5 ± 0.18% and DL of 1.02 ± 0.003% that were in good agreement with predicted values. In addition, the optimized nanoparticles manifested a sustained-release pattern in vitro and were stable during 3 h of incubation in simulated gastric fluids without significant size change and the majority (91%) of the drug was protected. Furthermore, the nanoparticles did not show obvious gastric irritation caused by oral administration of TP in rats.

Mussel-inspired methacrylated gelatin-dopamine/quaternized chitosan/glycerin sponges with self-adhesion, antibacterial activity, and hemostatic ability for wound dressings.

It is one of the most emergent challenges to prepare wound dressings for quickly and effectively controlling profuse bleeding in clinical surgery and emergent accident. In this work, a novel strategy has been developed to prepare methacrylated gelatin-dopamine (GelMA-DA)/quaternized chitosan (QCS)/glycerol (Gly) composite sponges with good biocompatibility, tissue self-adhesion, antibacterial activity, and hemostatic ability. Results show that the GelMA-DA/QCS/Gly sponges display good biocompatibility and water absorption capacity. The lap shear strength of the GelMA-DA/QCS/Gly sponge with the GelMA-DA content of 5 W/V% is approximately 128.36 ± 8.45, 125.17 ± 7.18, 138.29 ± 7.94, and 113.83 ± 9.28 kPa for skin, liver, muscle, and fat, respectively. The GelMA-DA/QCS/Gly sponge displays better antibacterial activity against Gram positive and negative bacteria than the commercial Gelatin hemostatic sponge and CS hemostatic sponge. Animal experiments using rat tail and liver bleeding model show that the hemostasis time and blood loss in the GelMA-DA/QCS/Gly sponge group is approximately 33.3 ± 6.7 s and 0.19 ± 0.05 g, respectively, which is also better than that of the commercial Gelatin hemostatic sponge and CS hemostatic sponge. These results demonstrate promising potential of the GelMA-DA/QCS/Gly sponges for applications as hemostatic wound dressings in clinical surgery and emergent treatment.

Unimolecular Self-Assembled Hemicyanine-Oleic Acid Conjugate Acts as a Novel Succinate Dehydrogenase Inhibitor to Amplify Photodynamic Therapy and Eliminate Cancer Stem Cells.

Photodynamic therapy with reactive oxygen species production is a prospective treatment to combat cancer stem cells (CSCs). However, the innate drawbacks, including short lifetime and diffusion distance of reactive oxygen species and hypoxia within solid tumors, have become bottlenecks for clinical applications of photodynamic therapy. Here, we develop a mitochondria-targeting hemicyanine-oleic acid conjugate (CyOA), which can self-assemble into supramolecular nanoparticles (NPs) without any exogenous excipients. CyOA is also shown for targeting the mitochondrial complex II protein succinate dehydrogenase to inhibit oxidative phosphorylation and reverse tumor hypoxia, resulting in 50.4-fold higher phototoxicity against breast cancer stem cells (BCSCs) compared to SO3-CyOA NPs that cannot target to mitochondria. In 4T1 and BCSC tumor models, CyOA NPs achieve higher tumor inhibition and less lung metastasis nodules compared to the clinically used photosensitizer Hiporfin. This study develops a self-assembled small molecule that can serve as both oxidative phosphorylation inhibitor and photosensitizer for eradication of CSCs and treatment of solid tumors.

Nature-inspired preparation of self-adhesive, frost-resistant, and ion-conductive hydrogels for flexible strain sensors.

A nature-inspired strategy has been developed to prepare polyvinyl alcohol (PVA)/catechol-modified quaternized chitosan (QCS-C)/MXene hydrogels with good self-adhesion, frost-resistance, and high ion-conductivity. The PVA/QCS-C/MXene hydrogel shows an ionic conductivity of 8.82 S m-1 and a gauge factor of 33.53 at low strain (0-10%), and remains flexible and conductive at -47 °C. The PVA/QCS-C15/MXene hydrogel displays promising potential as an ionically conductive hydrogel sensor for applications in flexible electronic devices.

Fabrication of Fe3O4@PVA microspheres by one-step electrospray for magnetic resonance imaging during transcatheter arterial embolization.

Magnetic resonance imaging (MRI) has attracted increasing attention as a feasible alternative or adjunctive imaging modality for X-ray digital subtraction angiography because of the high tissue resolution and non-ionization radiation. In this study, a one-step electrospray method was developed to fabricate PVA microspheres encapsulated with in situ synthesized Fe3O4 nanoparticles. Fe3O4@PVA microspheres were mono-dispersed black spheres with a wide range of sizes (262-958 µm). The in situ-synthesized Fe3O4 nanoparticles were used as the contrast agent of MRI and the cross-linkers of PVA matrixes for the embolization purpose. In vivo evaluation of renal arteries of normal rabbits showed that Fe3O4@PVA microspheres had good embolic effect and enhanced capability of MRI. In vitro and in vivo biosafety assessment confirmed that Fe3O4@PVA microspheres had favorable biocompatibility. The DOX-loaded Fe3O4@PVA microspheres showed a typical drug-sustained release profile. These results suggest that the prepared DOX-loaded Fe3O4@PVA microspheres have the function of MRI, embolotherapy and chemotherapy. We expect our study could provide a simple and useful approach for the systematic design, fabrication, and application of a new type of magnetic microspheres as a triple-functional embolic agent for the development of MRI-guided TACE. STATEMENT OF SIGNIFICANCE: Due to the low tissue resolution and hazardous ionization radiation of X-ray digital subtraction angiography, it is beneficial to study MR imaging embolic microspheres for the development of MRI-guided TACE. In this study, a one-step electrospray method was firstly developed to fabricate PVA microspheres encapsulated with in situ synthesized Fe3O4 nanoparticles. Then, chemotherapeutic agent (DOX), contrast media of MRI (Fe3O4) and embolic agent (PVA matrix) were combined together in one body (DOX-loaded Fe3O4@PVA microspheres) to achieve the triple effects of chemotherapy, MR imaging and embolization. This triple-functional embolic agent offers potential for the future development of MRI-guided TACE.

Graphene oxide-reinforced poly (ether-ether-ketone)/silica composites with improved mechanical performance and surface bioactivity.

The control of interfacial interaction between polymers and fillers is essential for the fabrication of high-performance polymer composites. In this work, poly(ether-ether-ketone)/silica (PEEK/SiO2) and PEEK/SiO2/graphene oxide (GO) composite were prepared by ball milling-ultrasonic dispersion combined with melt extrusion injection molding. GO nanosheets were introduced as the interfacial enhancer to improve interfacial binding between SiO2 and PEEK. Mechanical tests showed that the incorporation of SiO2 and GO greatly optimized the modulus, strength, and fracture toughness of the composites. The tensile strength and Young's modulus of the PEEK/SiO2 composites increases with the increase of SiO2 content. The maximum tensile strength and Young's modulus of the PEEK/SiO2 composites are approximate 95.9 ± 0.6 MPa and 4.007 ± 0.005 GPa at 30 wt% of SiO2, an increase of 6.4% and 21.2% than that of pure PEEK. The maximum tensile strength and Young's modulus of the PEEK/SiO2/GO composite are further improved to approximate 101.5 ± 0.7 MPa and 4.62 ± 0.08 GPa at a GO content of 1.5% wt, which is 12.6% and 39.4% higher than that of pure PEEK. In addition, SEM images show that numerous HA formed on the surface of the PEEK/SiO2/GO composite after immersion in SBF for 7 days, and the HA layer becomes gradually thicker after 14 days, implying the good osteogenic activity of PEEK/SiO2/GO composites. Therefore, these results suggest that the use of GO as a novel filler surface modifier for the preparation of high-performance composites may become a novel interfacial design strategy for the development of high-performance composites.

Preparation of carbon nanofibrous mats encapsulating zero-valent Fe nanoparticles as Fe reservoir for removal of organic pollutants.

Zero-valent iron nanoparticles (ZVI NPs) display promising potential in the removal of organic pollutants and heavy metal ions for environmental remediation. However, it is crucial to prevent the oxidation of ZVI NP and control the release of Fe ions under storage and working conditions. In this study, ZVI NPs are encapsulated in single-axial and co-axial carbon nanofibers by electrospinning polyacrylonitrile (PAN)/Fe3+ nanofibrous mats with different structures and then annealing the PAN nanofibrous mats in reduction atmosphere. SEM images show that the diameter of the carbon nanofibers is affected by the structure of the nanofibers and the ZVI NPs content after the annealing treatment. The formation of ZVI NPs is confirmed through XPS spectra and HRTEM characterization. The catalytic degradation of organic pollutants by ZVI NPs encapsulated in the carbon nanofibrous mats is evaluated using methylene blue (MB). The results show that the degradation rate of MB is significantly improved when the ZVI NP content encapsulated in the nanofibers increased. MB is completely degraded by the nanofibrous mats with either the single-axial structure or the co-axial structure, but at a higher degradation rate by the single-axial structure than that by the co-axial structure. These results provide alternatives to utilize the carbon nanofibrous mats encapsulating ZVI NPs as Fe reservoir for the removal of organic pollutants in an emergent or long-term situation for environmental remediation.

The composition of oil phase modulates venous irritation of lipid emulsion-loaded diallyl trisulfide.

INTRODUCTION: In this study, a nanoemulsion system (LE) was investigated for intravenous delivery of diallyl trisulfide (DT), which was a lipophilic and venous irritant drug for systemic therapy of bacterial and fungal infection. METHODS: Egg phospholipid was chosen as the only emulsifier, soybean oil, medium chain triglyceride (MCT), and olive oil were used as the oil phases, forming stable DT LEs (o/w) with small particle sizes. The venous irritation of DT LEs was evaluated by in vitro human umbilical cord endothelial cells (HUV-EC CRL 1730) tolerance model with the intracellular ATP and GTP concentrations as the indices. RESULTS: The intracellular ATP and GTP reduction changed with the incorporation of a variety of oils, which were strongly related with the free DT concentration of DT LEs. DISCUSSION: It was deduced that the free DT concentrations of LEs made of various oils depended on the particle sizes of the DT LEs. In conclusion, the oil phases modulated the free DT concentrations by forming DT LEs with different particle sizes, and optimization of the oil phase was an effective method to alleviate the venous irritation of DT LEs.

Disulfide based prodrugs for cancer therapy.

Advances in the tumor microenvironment have facilitated the development of novel anticancer drugs and delivery vehicles for improved therapeutic efficacy and decreased side effects. Disulfide bonds with unique chemical and biophysical properties can be used as cleavable linkers for the delivery of chemotherapeutic drugs. Accordingly, small molecule-, peptide-, polymer- and protein-based multifunctional prodrugs bearing cleavable disulfide bonds are well accepted in clinical settings. Herein, we first briefly introduce a number of prodrugs and divide them into three categories, namely, disulfide-containing small molecule conjugates, disulfide-containing cytotoxic agent-targeted fluorescent agent conjugates, and disulfide-containing cytotoxic agent-macromolecule conjugates. Then, we discuss the complex redox environment and the underlying mechanism of free drug release from disulfide based prodrugs in in vivo settings. Based on these insights, we analyze the impact of electronics, steric hindrance and substituent position of the disulfide linker on the extracellular stability and intracellular cleavage rate of disulfide containing prodrugs. Current challenges and future opportunities for the disulfide linker are provided at the end.

Preparation of Poly(ether-ether-ketone)/Nanohydroxyapatite Composites with Improved Mechanical Performance and Biointerfacial Affinity.

Poly(ether-ether-ketone) (PEEK) displays promising potential in hard tissue repair and orthopedic surgery due to its adaptable mechanical performance, good chemical resistance, and bioinertness. However, the low biointerfacial affinity of pure PEEK implants and the decrease of mechanical strength after processing greatly limit their clinical applications. In this work, the influences on mechanical performance and biointerfacial affinity of the PEEK/nanohydroxyapatite (nHA) composites are systematically investigated. Results show that the mechanical performance of PEEK/nHA composites was improved by adjusting the nHA content. The maximum values of the tensile, compressive, bending, and impact strength of the composites were increased by approximately 16.2, 25, 54, and 21%, respectively, when compared with that of pure PEEK. Studies in vitro show that PEEK/nHA composites display good cytocompatibility and promote the biomimic formation of HA, adhesion, and proliferation of L929 cells on the surface. Studies in vivo demonstrate that, compared to the pure PEEK, PEEK/nHA composites exhibit higher biointerfacial affinity, including the adhesion and encapsulation of muscle tissues on the surface of the implants and the suppression of inflammatory reaction around the implants. Our findings could pave the way for extensive applications of PEEK/nHA composites in hard tissue repair, particularly orthopedic surgery.

Multifunctional hierarchical mesoporous silica and black phosphorus nanohybrids as chemo-photothermal synergistic agents for enhanced cancer therapy.

Synergistic therapy with high efficacy and low side effects is of great significance in cancer treatment, and therefore the elaborate design of advanced nanocarriers to benefit diverse loading requirements of size-varied therapy agents is of critical importance. Herein, we demonstrate a multifunctional drug carrier platform based on a hierarchical porous and -NH2-modified silica nanocarrier (FMSN) with a super high specific surface area and a large pore volume, which not only improves the loading capacity of both doxorubicin, a chemotherapeutic drug, and black phosphorus quantum dots (BPQDs), a kind of biocompatible photothermal agent, but also enhances the photothermal stability and biostability of the degradable BPQDs. The unique structure and surface design enable our multimodal platform with heat-stimulative, pH-responsive and sustained-release properties for chemo-photothermal synergistic cancer therapy. Both cytotoxicity experiments and in vivo study reveal that the combined therapy based on our multifunctional nanohybrids mediates the highest death rate of cancer cells compared to that of single chemotherapy or photothermal therapy. Our hierarchical mesoporous strategy provides an excellent drug delivery model for advanced chemo-photothermal synergistic targeted cancer therapy.

Coadministration with Tea Polyphenols Enhances the Neuroprotective Effect of Defatted Walnut Meal Hydrolysate against Scopolamine-Induced Learning and Memory Deficits in Mice.

The present study aimed to investigate the combined effects of defatted walnut meal hydrolysate (DWMH) and tea polyphenols (TP) on learning improvement and to explain mechanistically why the combined treatments were more effective than either subject alone. In the step-down avoidance test and the Morris water maze test, codelivery of DWMH and TP was more effective than either individual supplement in reversing memory impairment in scopolamine-treated mice. Mixing with TP significantly facilitated the protective effects of DWMH or DWMH-derived peptides (cationic peptide P1 and anionic peptide P2) on H2O2-injured SH-SY5Y cells. Although combination treatment with TP and DWMH did not significantly alter systemic exposure to P1 or P2 in rats, it significantly increased the accumulation of the two peptides in the mouse brain. In addition, TP significantly improved cellular uptake of P1 and P2 by brain capillary endothelial cells, indicating that TP enhanced the blood-brain barrier permeation of DWMH-derived peptides. The proposed explanation for the advantage of combined treatment with TP and DWMH in reversing memory impairment was that TP enhanced both the protective effects of DWMH on nerve cells and the accumulation of DWMH in the brain. Our study can aid efforts to develop products and investigate the effects of nutrient combinations on brain disorders.

A novel method for the separation and determination of non-encapsulated pyrene in plasma and its application in pharmacokinetic studies of pyrene-loaded MPEG-PLA based nanoparticles.

During the pharmacokinetic processes of nanoparticles, encapsulated drugs and non-encapsulated (free and protein-bound) drugs are the drug forms existing in plasma. It is necessary and important to measure the bioavailable drug concentration, namely, the non-encapsulated drug concentration, in pharmacokinetic studies of nanoparticles. A new method using liquid-liquid extraction was first developed and validated for the separate determination of non-encapsulated drugs in plasma. The method was based on the significant difference of extractability between non-encapsulated and encapsulated drugs, and used n-heptane as an extractant. Satisfactory results were obtained with a good linear relationship in the range of 1-80 ng ml(-1) (r = 0.9999) and good reproducibility with coefficients of variation (CVs) less than 10% of intra- and inter-day evaluation results, and the accuracy of intra- and inter-day evaluation results ranged from 92.4% to 109.2%. The extraction recovery was stable in the range 68.6%-75.6%. The developed method had been proven to be an ideal method with high specificity and sensitivity, and the method is simple and rapid. The method described herein has been successfully applied for pharmacokinetic studies in female Wistar rats after the administration of a 5 mg equivalent pyrene kg(-1) dose of pyrene-loaded nanoparticles. The results showed that the non-encapsulated drug had a different pharmacokinetic behavior compared with that of the total drug.

The decrease of PAMAM dendrimer-induced cytotoxicity by PEGylation via attenuation of oxidative stress.

Due to their unique structure, poly(amidoamine) (PAMAM) dendrimers have been widely used in medical applications. However, PAMAM dendrimers bearing amino terminals show certain cytotoxicity. In order to improve their biocompatibility, we modified Generation-5 PAMAM dendrimers by conjugating them with poly(ethylene glycol) (PEG) of two different molecular weights and different number of chains. The IC(50) values of PEGylated dendrimers were 12-105 fold higher than those of PAMAM dendrimers. To investigate the influence of PEGylation on PAMAM-induced cytotoxicity, the intracellular responses, reactive oxygen species (ROS) content, mitochondrial membrane potential (MMP), and apoptosis were examined. The results indicated that conjugation with PEG could effectively reduce the PAMAM-induced cell apoptosis by attenuating the ROS production and inhibiting PAMAM-induced MMP collapse. Meanwhile, dendrimers conjugated with less PEG of lower molecular weight did not significantly change the endocytic properties. Dendrimers conjugated with more PEG of higher molecular weight were much less cytotoxic. This study provided a novel insight into the effects of PEGylation on the decrease of cytotoxicity at the molecular level.

Emulsifiers' composition modulates venous irritation of the nanoemulsions as a lipophilic and venous irritant drug delivery system.

In this study, a nanoemulsion (NE) system was investigated for intravenous delivery of lipophilic and venous irritant drugs. NEs were prepared to deliver diallyl trisulfide (DT) for systemic therapy of bacterial and fungal infection, egg phospholipid was chosen as the main emulsifier, and two co-emulsifiers were also incorporated, including Poloxamer 188 (P188) and Solutol HS 15 (S15). Soybean oil was used as the dispersed phases, forming stable DT NEs with small particle sizes. The venous irritation of DT NEs was evaluated by in vitro human umbilical cord endothelial cells (CRL 1730) compatibility model with the intracellular adenosine triphosphate (ATP) and guanosine triphosphate (GTP) concentrations as the indices. The intracellular ATP and GTP reduction changed with the incorporation of a variety of co-emulsifiers, which varied in a free DT concentration-dependent manner. It was deduced that the free DT concentrations of NEs containing co-emulsifiers were determined by the partition coefficient of DT between oil and surfactant buffer solution. In conclusion, NE was an appropriate delivery system for lipophilic and venous irritant drug, and optimization of the composition of emulsifiers was an effective method to alleviate the venous irritation of DT NEs.

Antioxidative Effects and Mechanism Study of Bioactive Peptides from Defatted Walnut ( Juglans regia L.) Meal Hydrolysate.

The peptide components of defatted walnut ( Juglans regia L.) meal hydrolysate (DWMH) remain unclear, hindering the investigation of biological mechanisms and exploitation of bioactive peptides. The present study aims to identify the peptide composition of DWMH, followed by to evaluate in vitro antioxidant effects of selected peptides and investigate mechanisms of antioxidative effect. First, more than 1 000 peptides were identified by de novo sequencing in DWMH. Subsequently, a scoring method was established to select promising bioactive peptides by structure based screening. Eight brand new peptides were selected due to their highest scores in two different batches of DWMH. All of them showed potent in vitro antioxidant effects on H2O2-injured nerve cells. Four of them even possessed significantly stronger effects than DWMH, making the selected bioactive peptides useful for further research as new bioactive entities. Two mechanisms of hydroxyl radical scavenging and ROS reduction were involved in their antioxidative effects at different degrees. The results showed peptides possessing similar capacity of hydroxyl radical scavenging or ROS reduction may have significantly different in vitro antioxidative effects. Therefore, comprehensive consideration of different antioxidative mechanisms were suggested in selecting antioxidative peptides from DWMH.

A new solid self-microemulsifying formulation prepared by spray-drying to improve the oral bioavailability of poorly water soluble drugs.

The objectives of the present work were, first, to develop a new solid self-microemulsifying drug delivery system (SMEDDS) for oral poorly water-soluble drugs such as nimodipine; and second, to evaluate its oral bioavailability in healthy rabbits. The liquid SMEDDS consisted of ethyl oleate, Labrasol, Cremophor RH 40 and nimodipine. The solid SMEDDS was prepared by spray-drying the liquid SMEDDS in a laboratory spray dryer, using dextran as solid carrier. The imaging of TEM and photo correlation spectroscopy revealed no difference in the droplet size of reconstituted microemulsion between both SMEDDS. Solid state characterization of the solid SMEDDS was performed by SEM, DSC, and X-ray powder diffraction. The same dose of nimodipine in the solid SMEDDS and in the liquid SMEDDS resulted in similar AUC and C(max) values, but the maximum absorption was retarded by the solid SMEDDS. AUC and C(max) after oral administration of the solid SMEDDS were 2.6- and 6.6-fold higher, respectively, compared with those of the conventional tablet. These results demonstrate that the solid SMEDDS may preserve an improved bioavailability with releasing microemulsion lipid droplets from the formulation in vivo. Thus, this solid self-microemulsifying system may provide a useful solid dosage form for oral poorly water-soluble drugs.