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Systemic delivery of siRNA to target tissues is difficult to achieve owing to its limited cellular uptake and poor serum stability. Herein, polymeric nanoparticles were developed for systemic administration of siRNA to inflamed tissues. The polymeric nanoparticles were composed of PK3 as a pH-sensitive polymer, folate-polyethyleneglycol-poly(lactide-co-glycolide) as a targeting ligand, and a DOTAP/siRNA core. The polymeric nanoparticles had a mean particle size of 142.6 ± 0.61 nm and a zeta potential of 3.6 ± 0.43 mV. In vitro studies indicated pH-dependent siRNA release from polymeric nanoparticles, with accelerated release at pH 5.0. Cellular uptake was efficient and gene silencing was confirmed by Western blot. In vivo , polymeric nanoparticles were shown to have inflammation-targeting activity and potent therapeutic effects in an adjuvant-induced arthritis rat model. These results suggest that pH-sensitive and folate receptor-targeted nanoparticles are a promising drug carrier for siRNA delivery for rheumatoid arthritis. Folate receptor-targeted pH-sensitive polymeric nanoparticles (FA-siRNA-PPNPs) were developed for Mcl-1 siRNA delivery for rheumatoid arthritis. These nanoparticles have prolonged blood circulation and accelerated siRNA release in acidic intercellular environment. The siRNA is released into cytoplasm and form RNA-induced silencing complex (RISC) with the mRNA, which induces targeted gene silencing. Unlabelled Image [ABSTRACT FROM AUTHOR]

The oral absorption of exenatide, a type 2 diabetes medication, can be increased by employing lipid nanocapsules (LNC). To increase mucus permeability and exenatide intestinal absorption, reverse micelle lipid nanocapsules (RM-LNC) were prepared and their surface was modified with DSPE-PEG-FA. The RM-LNC with surface modification of DSPE-PEG-FA (FA-RM-LNC) were able to target enterocytes and reduce mucus aggregation in the intestine. Furthermore, in vitro absorption at different intestinal sites and flip-flop intestinal loop experiments revealed that LNCs with surface modification significantly increased their absorption efficiency in the small intestine. FA-RM-LNC delivers more drugs into Caco-2 cells via caveolin-, macrophagocytosis-, and lipid raft-mediated endocytosis. Additionally, the enhanced transport capacity of FA-RM-LNC was observed in a study of monolayer transport in Caco-2 cells. The oral administration of exenatide FA-RM-LNC resulted in a prolonged duration of hypoglycemia in diabetic mice and a relative bioavailability (BR) of up to 7.5% in rats. In conclusion, FA-RM-LNC can target enterocytes and has promising potential as a nanocarrier for the oral delivery of peptides. [ABSTRACT FROM AUTHOR]

A novel phenylboronic acid and amino bifunctional modified silica gel (SiO2-NH2-FPBA) was prepared, which was 30–80 μm, had a pore size of 8.69 nm, a specific surface area of 206.89 m2/g, was stable at low temperature, and contained 0.4793 mmol/g of the phenylboronic acid group and 1.6377 mmol/g of the amino group. It was used to develop a rapid separation method for phenolic acids. The results showed that it could adsorb 93.64 mg/g caffeic acid, 89.35 mg/g protocatechuic acid and 79.66 mg/g gallic acid. The adsorption process was consistent with the pseudo-second-order model (R2 > 0.99), and fitted the Langmuir isotherm model well (R2 > 0.99). CH3COOH could effectively desorb phenolic acids (>90%) and did not destroy their structures. When SiO2-NH2-FPBA was added to crude extract of Clerodendranthus spicatus, 93.24% of the phenolic acids could be captured, and twenty-two kinds of phenolic acids were identified by Q Exactive HF LC-MS. Furthermore, the isolated phenolic acids from Clerodendranthus spicatus possessed great DPPH, ABTS, and hydroxyl radicals scavenging activities and ferric reducing power. They also demonstrated effective inhibition of α-amylase and α-glucosidase activities (IC50 = 110.63 ± 3.67 μg/mL and 64.76 ± 0.30 μg/mL, respectively). The findings indicate that SiO2-NH2-FPBA has significant potential in practical applications of separating active constituents from natural resources. [ABSTRACT FROM AUTHOR]

Fire accidents due to oil-immersed transformers seriously threaten the safe operation of power systems. In this paper, the similarity principle was used to design a high-pressure water mist fire-extinguishing test platform for a small-scale transformer fire, and the design method achieved a good fire extinguishing effect. The results indicate that a deflagration phenomenon, lasting about 2–4 s, could be observed after activating the high-pressure water mist system; the flame temperature rose rapidly at first, then dropped sharply, and finally cooled to the indoor temperature. The nozzle's flow rate in this system has a significant impact on the fire extinguishing time. Meanwhile, the adjustment of the upper nozzle height also influenced the fire suppression effectiveness of the system, where a height of 1800 mm achieved the best performance compared to the others. In addition, the ambient wind speed is a very unfavorable factor for transformer fire suppression, where the fire extinguishing efficiency decreases rapidly with the increase in wind speed. Therefore, under low wind speed conditions, the high-pressure water mist system has great advantages in the fire suppression of outdoor oil-immersed transformers, and the above research results can provide a reference for the optimization design of this system. [ABSTRACT FROM AUTHOR]

For the successful oral delivery of peptide drugs, considerable barriers created by the harsh environment of the gastrointestinal tract, mucus, and epithelial cells must be overcome. This study was to establish a core-shell structure with chitosan (CS) nanoparticles (NP) as the core and poly-N-(2-hydroxypropyl) methacrylamide (pHPMA) as the intelligent escape shell to overcome pH and mucus barriers and improve the delivery efficiency of peptide drugs. A core-shell system (COS) composed of pHPMA-AT-1002-cys-chitosan (LRA-PA-CNPs) was prepared and used for the treatment of type 2 diabetes mellitus with the large-molecule peptide drug liraglutide (LRA). The complete COS system was observed through electron microscopy; the particle size of the LRA-PA-CNPs was approximately 160 nm; the encapsulation efficiency was approximately 69% ± 5%; the zeta potential was close to neutral; the mucus and epithelial penetration of the COS system were increased; and animal experiments showed that the COS system enhanced the oral hypoglycaemic effect of LRA. Intelligent escape material of poly-N-(2-hydroxypropyl) methacrylamide as the shell. Core-shell nanoparticles penetrate the mucus layer and exposing the chitosan core. Overcome pH and mucus barriers to improve the delivery efficiency of peptide drugs. [ABSTRACT FROM AUTHOR]

A novel sulfopropyl ether γ-cyclodextrin polymer (SPE-γ-CDP) through polycondensating sulfated cyclodextrins (SCDs) was synthesized. This synthesis approach also has the potential of preparing other derived cyclodextrins (CDs) polymers. The polymerized SCDs took on both the properties of SCDs and certain characteristics of polymers, such as chiral selectivity and high viscosity. Synthesis parameters, including reactions sequence, sulfation, and polycondensation conditions were investigated systematically. The product was characterized by elemental analysis, infrared spectroscopy (IR), and indirect UV detections prior to use as background electrolytes additive. The separation conditions, including the concentration of SPE-γ-CDP, the concentration and pH of running buffer, separation voltage, as well as the additional organic solution were optimized during chiral separation of neutral, acidic, and basic enantiomers in capillary electrophoresis (CE). SPE-γ-CDP was proven to be an effective chiral resolving agent in CE with the advantages of simple synthesis process, low cost, similar ratio of charge-to-mass, low current, great reproducibility, and reusability. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Using ruthenium chloride as catalyst precursor, magnetic silicon spheres as support, 4-formylphenylboronic acid and ethylenediaminepentaacetic acid as functional ligands, a magnetic heterogeneous nano-ruthenium catalyst (Fe 3 O 4 @SiO 2 -FPBA-DTPA-Ru) was prepared for the first time. It was nano level with 20.17 emu/g saturation magnetic strength and thermal stability under 249.63 °C. Fe 3 O 4 @SiO 2 -FPBA-DTPA-Ru contained 0.38 mmol/g Ru and was successfully used to catalyze the oxidation reactions of 15 aromatic secondary alcohols. Results proved that Fe 3 O 4 @SiO 2 -FPBA-DTPA-Ru as catalyst had good catalytic activity for the oxidation of secondary aromatic alcohols with yields exceeding 90 % for 12 products and 95 % for 10 products. High TON and TOF values (6386 and 9158 h−1) in 1-phenylethanol oxidation were obtained. All the reactions of aromatic alcohols were carried out in a solvent-free system, so the prepared catalyst had the characteristics of green and pollution-free. It was'nt suitable for oxidation of aromatic primary alcohols. If there was steric hindrance around the hydroxyl group in substrate, the catalysis also may be limited. The Fe 3 O 4 @SiO 2 -FPBA-DTPA-Ru catalyst also exhibited the advantages of energy saving, satisfactory reusability and stability in 9 consecutive runs. It showed great potential for future large-scale industrial production. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • An economic, accessible and stable sulfopropyl ether β-CD polymer was prepared. • SPE-β-CDP was first time added into mobile phase to separate 13 chiral drugs. • SPE-β-CDP could be used in both of C8 and C18 columns. • It showed little effect on column pressure, good recyclability and reusability. • Resolutions of some chiral drugs in HPLC are better than that of CE. In this study, sulfopropyl ether β-cyclodextrin polymer (SPE-β-CDP) with simple synthesis steps using cheap reagents was large-scalely prepared. Characterization results showed the average sulfonic group substitution in each β-CD molecule was about 7.261, and there were 195.87 μmol/g β-CD units in polymer. It was low viscosity and produced a little effect on column pressure. It was used as chiral selectors first time to add into mobile phase to separate 13 chiral drugs in HPLC. After investigation, results showed buffer pH, chiral additive concentration, organic phase proportion in mobile phase and flow rate could affect chiral separation. High separation ability of SPE-β-CDP was proved through baseline separation of 12 drugs which attributed to the homogeneity of SPE-β-CDP in sulfonic acid group substitution degree and position. The resolutions of salbutamol, bisoprolol, chlorpheniramine, propranolol and metoprolol could be even up to 7.47–19.02, which were significantly better than that of some references. Separations of 4 chiral drugs were even better than that of CE. Compared with monomer, SPE-β-CDP showed better chiral separation ability. SPE-β-CDP could be used in both of C8 and C18 columns. It was stable in batches and showed good recyclability and reusability. These provided a new strategy for chiral separation. [ABSTRACT FROM AUTHOR]

A novel boronic acid and carboxyl‐modified glucose molecularly imprinted polymer were prepared through suspension polymerization, which is based on 1.0 mmol glucose as a template, 1.2 mmol methacrylamidophenylboronic acid, and 6.8 mmol methacrylic acids as monomers, 19 mmol ethyleneglycol dimethacrylate, and 1 mmol methylene‐bis‐acrylamide as crosslinkers. The prepared glucose‐molecularly imprinted polymer had a particle size of 25–70 μm, and was thermally stable below 215°C, with a specific surface area of 174.82 m2/g and average pore size of 9.48 nm. The best selectivity between glucose and fructose was 2.71 and the maximum adsorption capacity of glucose‐ molecularly imprinted polymer was up to 236.32 mg/g which was consistent with the Langmuir adsorption model. The similar adsorption abilities in six successive runs and the good desorption rate (99.4%) verified glucose‐molecularly imprinted polymer could be reused. It was successfully used for extracting glucose from cellulose hydrolysis. The adsorption amount of glucose was 2.61 mg/mL and selectivity between glucose and xylose reached 4.12. A newly established chromatography (glucose‐molecularly imprinted polymer) mediated hollow fiber membrane method in time separated pure glucose from cellulose hydrolysates on a large scale, and purified glucose solution with a concentration of 3.84 mg/mL was obtained, which offered a feasible way for the industrial production of glucose from cellulose hydrolysates. [ABSTRACT FROM AUTHOR]

• A magnetic hybrid organic-inorganic nanoparticles with Ru metal was prepared. • It is the first time to employ the support with boric acid groups to immobilize Ru. • It was spherical, stable, nano level, recycle, and contained 0.30 mmol/g Ru. • It was green, environment-friend and high efficiency in catalyzing oxidation of aromatic alcohols. A kind of magnetic hybrid organic-inorganic nanoparticles containing Ru metal (Fe 3 O 4 @SiO 2 -FPBA-Ru) was prepared. It was spherical with the characteristic lattice fringe of ruthenium atom. The size was in the range of 5–15 nm and it contained 0.30 mmol/g Ru. Its saturation magnetization value was 15.95 emu/g, which could be easily and efficiently recovered from solution through an external magnet. It was also stable below 240°C and hot filtration experiment proved Ru wasn't leaked from Fe 3 O 4 @SiO 2 -FPBA-Ru in 70°C oxidation reaction. It could be recovered and reused at least 7 cycles. The low amount of Fe 3 O 4 @SiO 2 -FPBA-Ru (75 mmol%) could convert the 99 % of 1-phenylethanol to acetophenone under solvent-free system, which verified its green and environment-friendly properties. The yield was exceed that of homogeneous (RuCl 3 , 85 %). Beside this, the TON (5181), TOF (7430 h−1) in oxidation of 1-phenylethanol and high conversion yields for a series of oxidation reactions of aromatic secondary alcohols proved the high catalytic ability of Fe 3 O 4 @SiO 2 -FPBA-Ru. These laid a foundation for its industrial applications. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • A magnetic heterogeneous Ru nanocatalyst was prepared. • It is the first time to employ multi-carboxyl groups to immobilize Ru. • It was spherical, thermostable and recyclable. • It was green, environment-friend and high efficiency in catalyzing oxidation of aromatic alcohols. A novel magnetic heterogeneous ruthenium catalyst (Fe 3 O 4 @SiO 2 -DTPA-Ru) was prepared by using magnetic silicon spheres as support, ethylenediaminepentaacetic acid (DTPA) as functional ligands, ruthenium chloride as catalyst precursor. The results obtained after a series of characterizations showed that the catalyst Fe 3 O 4 @SiO 2 -DTPA-Ru was 5–15 nm in size with a 0.205 nm lattice and contained 0.31 mmol Ru/g catalyst. It also had a good thermal stability under 232°C which was verified by thermal filtration method. Besides, the saturation magnetic intensity was as high as 20.54 emu/g. The catalyst Fe 3 O 4 @SiO 2 -DTPA-Ru was applied for the first time into thirteen oxidation reactions of aromatic alcohols and showed good catalytic activity even the yields of eleven aromatic alcohols were all over 90%. In catalyzing 1-phenylethanol to acetophenone, its TOF and TON were 9677 h−1 and 6991, respectively. The Fe 3 O 4 @SiO 2 -DTPA-Ru catalyst could still maintain good reusability and catalytic performance after 15 cycles of 1-phenylethanol oxidation, which was superior to many reported catalysts and had great potential in future industrial production. [ABSTRACT FROM AUTHOR]

Ketoprofen, a non-steroidal anti-inflammatory drug, can effectively relieve pain associated with arthritis, and microRNA-124 (miR-124) can inhibit the progression of the disease. In this study, poly (cyclohexane-1,4-diylacetone dimethylene ketal) (PCADK) nanoparticles (NPs) co-loaded with ketoprofen and miR-124 were successfully prepared using an emulsified solvent evaporation method. The co-loaded NPs exhibited a mean particle diameter of 160 nm. The acid sensitivity of the NPs was determined through in vitro release experiments. An adjuvant-induced arthritis rat model of arthritis was established for evaluating the pharmacodynamics of the NPs through clinical scoring and degree of swelling. The PCADK NPs exhibited more potent pharmacodynamic effects owing to the acid-sensitive properties of the carrier materials, compared with Poly (lactic- co -glycolic acid) (PLGA) NPs. Furthermore, PCADK co-loaded NPs exhibited superior anti-inflammatory effects compared to NPs loaded with either miR-124 or ketoprofen alone. In conclusion, co-delivery of ketoprofen and miR-124 through NPs is a promising strategy for the treatment of arthritis. [ABSTRACT FROM AUTHOR]

As a result of an error during figure assembly in Figure 3, the image for NPs at 1 h shows blue channel image for NPs-Fc at 1 h. Graph: Figure 3Confocal microscopy images of fluorescently labeled NPs and NPs-Fc incubation with Caco-2 cell for 0.5, 1, 2, and 4 h. [Extracted from the article]

Background: The use of drug nanocarriers to encapsulate drugs for oral administration may become an important strategy in addressing the challenging oral absorption of some drugs. In this study—with the premise of controlling single variables—we prepared model nanoparticles with different particle sizes, surface charges, and surface hydrophobicity/hydrophilicity. The two key stages of intestinal nanoparticles (NPs) absorption—the intestinal mucus layer penetration stage and the trans-intestinal epithelial cell stage—were decoupled and analyzed. The intestinal absorption of each group of model NPs was then investigated. Results: Differences in the behavioral trends of NPs in each stage of intestinal absorption were found to result from differences in particle properties. Small size, low-magnitude negative charge, and moderate hydrophilicity helped NPs pass through the small intestinal mucus layer more easily. Once through the mucus layer, an appropriate size, positive surface charge, and hydrophobic properties helped NPs complete the process of transintestinal epithelial cell transport. Conclusions: To achieve high drug bioavailability, the basic properties of the delivery system must be suitable for overcoming the physiological barrier of the gastrointestinal tract. [ABSTRACT FROM AUTHOR]

Oral chemotherapy offers a more convenient treatment option for cancer patients but the effectiveness is significantly hindered by the limited drug delivery efficiency. Herein, we designed legumain-activable melittin (LM) decorated polymeric nanovehicles loading IR-780 and sorafenib (LPN) to enhance their oral delivery to tumors, with efficient accumulation and penetration capacity, for combinational photothermal-chemotherapy of gastric cancer. The nanosized LPN displayed good stability in simulated gastrointestinal fluids. After oral administration, the oral bioavailability of sorafenib was remarkably improved (75.9-fold by LPN versus free drug suspension). Moreover, the orally administered LPN could preferentially accumulate at the tumor site and penetrate into the interior regions of the tumor mass. Upon combination with laser irradiation, LPN produced notable inhibition of tumor growth, which was more effective than the counterpart unmodified nanovehicles. Therefore, LPN represents an encouraging oral delivery nanoplatform with favorable tumor accumulation and penetration capability for oral combinational cancer therapy. Unlabelled Image • Legumain-activable melittin decorated polymeric nanovehicles (LPN) improve the oral delivery of water-insoluble sorafenib. • Orally administered LPN preferentially accumulates at the tumor site with deep penetrating capacity. • Upon combination with laser irradiation, LPN produced notable inhibition of tumor growth versus counterpart nanovehicles. • LPN represents an encouraging oral delivery nanoplatform for oral combinational cancer therapy. [ABSTRACT FROM AUTHOR]

To separate the fermentation products in real time and improve the fermentation yield, a novel poly-4-vinylpyridine-vinylbenzeneboronic acid polymer microspheres (p4VP-VPBA) with bifunctional groups was prepared by suspension polymerization. The spherical p4VP-VPBA was 5–20 μm and thermally stable below 355.4 °C. The elemental contents of N and O were 1.36% and 5.72%, respectively, and the content of boronic acid was 0.1357 mmol/g. Its adsorption performance to lactic acid was satisfactory. Under pH 4 and 20 °C, the maximum static adsorption of p4VP-VPBA was up to 185.31 mg/g in 3 h. Its selectivity on lactic acid to glucose was 70.05 at pH 2, 7.71 at pH 4, and only 0.81 at pH 10, which indicated a good selectivity to lactic acid at low pH fitting to fermentation process. Furthermore, a p4VP-VPBA-combined with hollow fiber membrane (HFM) separation system was proposed and the removal rate of 5 mg/mL lactic acid was maintained at about 90% after 5 consecutive cycles. These data showed a huge potential for future real-time capturing lactic acid from fermentation, which also was a reference for other fermentation inhibited by product concentration. [Display omitted] • A novel p4VP-VPBA microspheres with bifunctional groups is synthesized. • The p4VP-VPBA shows different selective adsorption to lactic acid from glucose. • A p4VP-VPBA combined with hollow fiber membrane separation system is established. • The tandem separation method is benefit to improve lactic acid fermentation yield. • It can effectively improve food safety and environmental issue. [ABSTRACT FROM AUTHOR]

A water-soluble negative sulfonic propyl ether β-CD polymer (SPE-β-CDP) to be used as chiral selector in capillary electrophoresis (CE) was polymerized. The sulfonic substitution degree of each β-CD in SPE-β-CDP was statistically homogenized. The only one negative peak in electrophoretogram with indirect ultraviolate method proved its uniformity of electrophoretic behavior. There were 7.12 sulfonic substitution in β-CD unit and 164 μmole β-CD units in each gram of SPE-β-CDP, which corresponded a molecular weight of 7000 or more. Compared with monomer, SPE-β-CDP was lower effect on electrical current of CE, indicating a high concentration of SPE-β-CDP could be added. Its separation ability was verified by 12 chiral drugs. SPE-β-CDP also showed advantages of good water solubility, easy preparation and recovery to reduce the overall cost. However, five of 12 chiral drugs were hardly to be fully separated which was normal for any kind of chiral selector. A newly adjustable gravity mediated capillary electrophoresis (AGM-CE) technology was proposed and combined with SPE-β-CDP to enhance the chiral separation efficiencies of propranolol, salbutamol, omeprazole, ofloxacin and phenoxybenzamine which were markedly improved to 3.02, 1.17, 7.63, 4.14, and 2.81, respectively. Furthermore, its gradient mode (AGMg-CE) was also used to improve resolution through utilizing the zero mobility point, at which the effective apparent mobility of one racemate was zero. Resolutions of five chiral drugs were significantly improved, especially resolution of carvedilol changed from 0.43 to 1.0. These indicated SPE-β-CDP as chiral selector, AGM-CE and AGMg-CE as new CE technologies had a great potential in chiral separation. [Display omitted] • A adjustable gravity mediated CE (AGM-CE) was proposed and verified. • Gravity effect could be precisely controlled by simply tilting angle of capillary. • A gradient CE was proposed and applied in chiral separation. • The sulfonic substitution degree of polymer was statistically homogenized. • The chiral selector has high chiral separation ability and was recycle. [ABSTRACT FROM AUTHOR]

To improve the oral efficiency of exenatide, we prepared polyethylene glycol-poly(lactic-co-glycolic acid) (PEG-PLGA) NPs modified with Fc (NPs-Fc) for exenatide oral delivery. Exenatide was encapsulated into the NPs by the w/o/w emulsion-solvent evaporation method. The particle size of the NPs-Fc was approximately 30 nm larger than that of the unmodified NPs with polydispersity indices in a narrow range (PDIs; PDI < 0.3) as detected by DLS, and the highest encapsulation efficiency of exenatide in the NPs was greater than 80%. Fc-conjugated NPs permeated Caco-2 cells faster and to a greater extent compared to unmodified NPs, as verified by CLSM and flow cytometry. Hypoglycemic effect studies demonstrated that oral administration of exenatide-loaded PEG-PLGA NPs modified by an Fc group extended the hypoglycemic effects compared with s.c. injection of the exenatide solution. Fluorescence-labeled NPs were used to investigate the effects of Fc targeting, and the results demonstrated that the NPs-Fc stayed in the gastrointestinal tract for a longer time in comparison with the unmodified NPs, as shown by the whole-body fluorescence images and fluorescence images of the dissected organs detected by in vivo imaging in live mice. Therefore, Fc-targeted nano-delivery systems show great promise for oral peptide/protein drug delivery. [ABSTRACT FROM AUTHOR]

Rotigotine behenate (RGTB), a long chain alkyl ester of the prodrug of rotigotine (RGT), has been synthesized for use in a sustained delivery system. The aim of the present report was to develop and validate a simple, sensitive and reliable LC–MS/MS method for the simultaneous determination of RGT and its prodrug RGTB in rat plasma samples. Detection was performed on a 1290 Infinity UPLC coupled Triple Quad 4500 mass spectrometer operated in positive MRM mode using an Eclipse XDB-CN chromatography column (2.1 mm × 100 mm, 3.5 μm) by isocratic elution using a 0.2% formic acid aqueous solution and acetonitrile, with stable isotope labeled RGT as an internal standard. The sample preparation method employed 50 μL of a plasma sample and liquid-liquid extraction with a mixture of diethyl ether–dichloromethane (3:2, v/v) as the extraction solvent. The proposed method was fully validated by assessing its specificity, linearity, precision and accuracy, recovery, matrix effects and stability. Good linearity was found within the range of 0.1–10.0 ng/mL for both analytes (r > 0.996). This method was successfully applied to a pharmacokinetic study of a slow release RGTB formulation in rats following a single intramuscular injection and biological conversion in vitro. [ABSTRACT FROM AUTHOR]

The novel antipsychotic isoperidone, a prodrug of paliperidone, was designed to improve liposolubility for the development of poly(D,L-lactide-co-glycolide) (PLGA)-based microspheres to achieve near zero-order release behaviour in vivo. Microspheres with a smooth surface were obtained using the oil-in-water emulsion solvent evaporation method and yielded a high encapsulation efficiency of 92%. Pharmacokinetic studies in beagle dogs showed a one-week plateau phase followed by a two-week quasi-zero-order release with no burst release. The in vitro release method with a good in vitro-in vivo correlation was also established. Pharmacodynamic evaluation was performed using the MK-801-induced schizophrenic behavioural mouse model, and the sustained suppressive effect lasted two weeks. The pharmacokinetic-pharmacodynamic (PK-PD) relationship of isoperidone microspheres was compared to that of oral administration of free drug. The results revealed a strong correlation between the plasma drug level and the antipsychotic effect. A stable drug plasma concentration was detected in mice both intraday and interday from 8 to 22 d after a single injection of isoperidone microspheres, and a sustained suppressive effect on the schizophrenic model was also observed. In comparison, the mouse group receiving oral daily administration exhibited more dose-dependent effects, and the pharmacological effect diminished rapidly in conjunction with a reduction of the plasma drug levels 8 h after the last administration of isoperidone on day 3. The above results confirm the superiority of long-acting release over oral administration and indicate a valuable alternative for the clinical treatment of schizophrenia. [ABSTRACT FROM AUTHOR]

development, single-factor experiments were employed to evaluate the effect of adding different matrix, enhancers, 5-HMT, ethanol and glycerol on drug skin development, single-factor experiments were employed to evaluate the effect of adding different matrix, enhancers, 5-HMT, ethanol and glycerol on drug skin permeation. Finally, Carbopol 940 was selected as the gel matrix with N-methyl pyrrolidone (NMP) chosen as the enhancer. The relationship between time and the steady accumulative percutaneous amount ( Q , μg cm − 2 ) of optimized 5-HMT hydrogels was Q 4–12 h = 1290.8 t 1/2 − 1227.7. The absolute bioavailability of 5-HMT hydrogels was 20.7% showed in pharmacokinetic study. No skin irritation was observed in 5-HMT hydrogels skin irritation study. In the pharmacodynamic study, the overactive bladder model was induced by 150 μg/kg of pilocarpine in rats. The significant effects of 5-HMT hydrogels on the inhibition of urine output on rat model were last to 12 h. The optimized 5-HMT hydrogels displayed prolonged pharmacological responses. 5-HMT hydrogels effectively avoided the metabolism difference of enzyme in bodies compared with tolterodine tablets, provided one single active compound in plasma to reduce the variability of having two active compounds. To further elucidate the transdermal mechanism, fourier transform infrared (FTIR) spectroscopy, differential scanning calorimeter (DSC) and activation energy measurements were used to study the transdermal routes and changes of stratum corneum during drug release. [ABSTRACT FROM AUTHOR]

The dual-ligand dendritic polyamidoamine-(polyethylene glycol) n -cyclic RGDyC peptide-(TAT peptide) (PP n R(T)) with various supplied molar ratios of polyethylene glycol (PEG) to polyamidoamine (PAMAM) (n = 5, 15, 30) were designed as drug-carriers for the treatment of neovascular diseases; their targeting and penetrating effects were subsequently evaluated. 1 H NMR demonstrated PP n R(T) was successfully synthesized. Compared with the unmodified PAMAM, in vitro cytotoxicity of PP n R(T) to αvβ3 negative cells (αvβ3-) was significantly reduced, whereas the lethality to pathologic neovascular endothelial cells (αvβ3+) was efficiently increased compared to PP n . Compared to PP 5 R(T) and PP 15 R(T), PP 30 R(T) exhibited the most selective and efficient cellular uptake by human umbilical vein endothelial cells (HUVECs, αvβ3+). Membrane interaction study indicated the cellular uptake process of PP 30 R(T) of HUVECs mainly involved specific RGD-αvβ3 recognition as well as electrostatic interactions. Intracellular localization results confirmed PP 30 R(T) was distributed in the cytoplasm in HUVECs. 3D tumor spheroids penetration studies demonstrated that PP 30 R(T) penetrated the A549 cells to reach the depths of the avascular tumor spheroids. In vivo imaging further demonstrated that PP 30 R(T) achieved profoundly improved distribution in tumor tissues where angiogenesis existed. Therefore, the bi-functional dendrimer PP 30 R(T) displayed great potential as a nano-carrier for targeted drug delivery both in vitro and in vivo , and had broad prospects as nanocarriers for the targeted treatment of neovascular diseases. [ABSTRACT FROM AUTHOR]

We have developed a novel nanoparticle delivery system fabricated from polyethylenimine (PEI) and poly( d , l -lactide-co-glycolide) (PLGA), which were able to deliver the chemotherapeutic agent Paclitaxel, while the biomacromolecule Herceptin acted as a targeting ligand that was conjugated onto the surfaces of the nanoparticles via electrostatic interactions. In this study, these electrostatically-conjugated Herceptin-bearing PEI/PLGA nanoparticles (eHER-PPNs) were optimized and employed as vectors to target HER2-positive breast cancer cells. The eHER-PPNs had an average diameter of ∼280 nm and a neutral surface charge (1.00 ± 0.73 mV), which remained stable under physiological conditions. The anticancer effects of eHER-PPNs were investigated in HER2-positive BT474 cells and HER2-negative MCF7 cells. The eHER-PPNs showed enhanced cytotoxicity that was dependent on the receptor expression levels and the incubation time. These conjugated nanoparticles deliver Paclitaxel more efficiently ( p < 0.001) than unmodified PPNs, Herceptin and the combined effects of these two monotherapies. Furthermore, the chemically-conjugated Herceptin-bearing PEI/PLGA nanoparticles (cHER-PPNs) were fabricated as a comparison. The eHER-PPNs exhibited lower cell viability (46.7%) than that of cHER-PPNs (65.1%). The targeting ability of eHER-PPNs was demonstrated through confocal microscopy images and flow cytometry, which showed that eHER-PPNs displayed higher cellular uptake efficiency ( p < 0.001) in comparison with cHER-PPNs. Therefore, eHER-PPNs could provide promising platforms for the delivery of therapeutic drugs against HER2-positive breast cancers. [ABSTRACT FROM AUTHOR]

The goal of this research is to prepare poly(cyclohexane-1,4 diyl acetone dimethylene ketal) (PCADK)/poly( d , l -lactide-co-glycolide) (PLGA) blend microspheres loaded with recombinant human growth hormone (rhGH). The effect of PCADK degradation products on the structural integrity, secondary and tertiary structure and pharmacodynamics of rhGH was evaluated by native-polyacrylamide gel electrophoresis (Native-PAGE), size-exclusion high performance liquid chromatography (SEC-HPLC), circular dichroism (CD), fluorescence spectroscopy and in hypophysectomized rat models. Compared with PLGA degradation products, rhGH was found to be more stable in the presence of PCADK degradation products. PCADK/PLGA blend microspheres were then prepared and the morphology, encapsulation efficiency, release behavior and rhGH stability were investigated. PCADK/PLGA microspheres had regular shapes and smooth surfaces when the proportion of PCADK was less than 50%. The late-releasable amount of rhGH in PCADK/PLGA microspheres was greater than that in PLGA microspheres. In addition, the PCADK/PLGA microspheres showed larger AUC and improved therapeutic effects on rats than PLGA microspheres. Furthermore, the pH inside the microspheres was detected by CLSM to explain the improved rhGH stability in the PCADK/PLGA microspheres. In conclusion, PCADK/PLGA blend microspheres showed potential to improve rhGH stability and the efficacy of sustained-release of rhGH compared with PLGA microspheres. [ABSTRACT FROM AUTHOR]

Oral vorinostat has the remarkable curative effect on aggravated and recurrent cutaneous T-cell lymphoma (CTCL), but is accompanied by serious adverse effects. Therefore, oral vorinostat is not applicable to the treatment of early stage CTCL. The aim of this study is to develop a novel vorinostat formulation which is effective for early stage CTCL and free of the serious adverse effects. A mixed-matrix hydrogel of vorinostat was prepared and characterized as a potential topical skin delivery system. Moisture retention, swelling behavior, viscosity, real-time morphology and differential scanning calorimeter analysis (DSC) of hydrogel were evaluated to select the solvent, matrix and humectant. The optimal HPMC/HPC ratio, pH, additive, dose and drug loading of vorinostat hydrogel were determined by evaluating the cumulative vorinostat amount of skin retention and transdermal amount of vorinostat through the skin in vitro . The optimal hydrogel presented a low transdermal amount of vorinostat through the skin, suggesting that the hydrogel reduced the amount of vorinostat that was absorbed in the systemic circulation. More importantly, in vivo percutaneous permeation experiments were also performed to evaluate the permeation behavior of vorinostat into the skin. The topical application with a much lower dose showed higher AUC (the cumulative vorinostat amount of skin retention) than oral application and the hydrogel achieved a sustained permeation of vorinostat in the skin for 24 h in vivo . It indicated that a higher relative bioavailability for hydrogel was achieved compared with oral vorinostat. Moreover, there was no damage, inflammation or cell swelling of the skin after administration. Thus, the mixed-matrix vorinostat hydrogel prepared in this study could deliver vorinostat into local skin more efficiently than oral administration. [ABSTRACT FROM AUTHOR]

Capillary electrophoresis (CE) has been applied to determine the percentage of enantiomeric excess (ee%) of chiral compounds. In such assays, the quality of chiral selectors (CSs) plays vital roles in resolving the enantiomers for accurate determination of the ee%. Selecting an efficient CS is usually by trial and error, and is, if ever possible, time-consuming and costly. Here we propose a new approach by using the velocity gap mode of CE (VGCE) method, to simplify the method development process for ee% determination. With VGCE, it is still possible to measure ee% even when the CS has a weak resolving power. This is especially important at the extreme cases where one of the enantiomers is significantly higher than the other one. The key point of VGCE in this case is to fractionate the small part of the mixture containing both enantiomers from the major component of the enantiomer, which is already enantiopure. Baseline separations can be achieved between the two enantiomers for the small mixture due to less longitudinal dispersion, making it possible to determine the ee%. The feasibility of this VGCE approach was confirmed by the ee% measurements of amlodipine and ofloxacin, respectively. And the practical application of VGCE was tested by analyzing levamlodipine besylate tablet. [ABSTRACT FROM AUTHOR]

Purpose: Exenatide, a potent insulinotropic agent, can be used for the treatment of non-insulin-dependent diabetes mellitus. However, the need for frequent injections seriously limits its therapeutic utility. The aim of present report was to develop an orally available exenatide formulation using goblet cell-targeting nanoparticles (NPs). Method: The exenatide-loaded nanoparticles were prepared with modified chitosan which was conjugated with a goblet cell-target peptide, CSKSSDYQC (CSK) peptide. Results: The CSK-chitosan nanoparticles shown reduced chitosan toxicity and enhanced the permeation of drugs across the Caco-2/HT-29 co-cultured cell monolayer, which simulated the intestinal epithelium. Following the oral administration of near-infrared fluorescent probe Cy-7-loaded NPs to mice, the distribution of the drugs was investigated with a near-infrared in vivo image system (FX Pro, Bruker, USA). The results showed that Cy-7 fluorescence disseminated from the oesophagus, then to stomach and small intestine and then was absorbed into hepatic, finally into the bladder; over time, Cy-7 was metabolized and excreted. The bioavailability of the modified nanoparticles was found to be 1.7-fold higher compared with the unmodified ones, and the hypoglycemic effect was also better. Conclusion: CSK peptide-modified chitosan nanoparticles could be a potential therapeutics for Type II diabetes patients. [ABSTRACT FROM AUTHOR]

In this paper, an active, recyclable and stable magnetic palladium nanocatalyst (Fe 3 O 4 @SiO 2 -DTPA-Pd) was reported which could catalyze Suzuki coupling reaction. The Pd was stably hold by the three nitrogen atoms at the inside and four acetic acid groups at the outside of the chelating ligand ethylenediaminepentaacetic acid (DTPA) on the surface of core-shell magnetic Fe 3 O 4 @SiO 2 microspheres. The prepared Fe 3 O 4 @SiO 2 -DTPA-Pd was systematically characterized. Results showed its size was 10–20 nm with 0.535 mmol/g Pd2+/Pd0. It could monodisperse in liquid, was thermally stable and good magnetic response from the high saturation magnetization value at 35.9 emu/g. Its activity was evaluated through Suzuki coupling reactions between 14 types of aryl halides and phenylboronic acid under optimized reaction conditions. It exhibited excellent activities and good applicability to substituted iodobenzene and bromobenzene. The yield of 4-bromobenzonitrile was up to 97.93%. Furthermore, the Fe 3 O 4 @SiO 2 -DTPA-Pd catalyst was stable, reusable and conveniently recovered by applying an external magnetic field. After 20 consecutive reaction cycles, the yield was still above 85%, which showed a superior heterogeneous advantage over other catalysts reported in the literature and had the huge potential in actual application of industry. [Display omitted] • Chelating agents DTPA modified Fe 3 O 4 @SiO 2 anchored Pd nanocatalyst was developed and used for catalyzing Suzuki coupling reactions. • The activity of the immobilized nanocatalyst (0.17 mol% Pd) was better than homogeneous Pd(OAc) 2 (1.00 mol% Pd). • Facile recycle for 20 consecutive runs with yield still over 85% exhibited a good reusability of Fe 3 O 4 @SiO 2 -DTPA-Pd. [ABSTRACT FROM AUTHOR]

Abstract: A transparent film-forming hydrogel formulation for tolterodine was developed using ternary phase diagram and Box-Behnken design (BBD). Carbopol 980 (neutralized by triethanolamine), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC) and Tween 80 were used as matrices. Solvent was the mixture of water and ethyl alcohol. The measured 24h cumulative drug release rate (86.02%) was consistent with the predicted value (85.42%) in mice. Steady-state flux (J) of tolterodine in optimized formulation across rat full skin, epidermal, dermis and subcutaneous tissue were 15.83, 18.55, 37.15 and 81.82μgcm−2 h−1, respectively. Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) results suggested that the hydrogels could impact lipid status in SC, which was consistent with E a (8.638kcal/mol) of tolterodine from optimized formulation in rats. In the pharmacokinetic studies, sustained-release over 24h and absolute bioavailability of the hydrogels (24.53%) was higher than tolterodine tablets (15.16%) in rats. The hydrogels were suitable for systemic administration of tolterodine for the treatment of overactive bladder. [Copyright &y& Elsevier]

Abstract: Novel biodegradable in situ forming organogel, obtained via the self-assembly of long chain fatty acid in pharmaceutical oil, was prepared and characterized. Different from traditional organogels, the use of organic solvent was avoided in this gel system, in consideration of its tissue irritation. Four kinds of fatty acids were employed as organogelators, which could successfully gel with injectable soybean oil. The gelation procedure was thermo-reversible. Phase transition temperature and time were depended on carbon chain length and concentration of gelators. Optimized formulations containing drug were then injected subcutaneously in rats for pharmacokinetic study. Results showed the steady drug release for one week with the well-controlled burst, which fitted well with the drug release mechanism of both drug diffusion and frame erosion. In vivo imaging of the organogel with fluorescence in live animals suggested that the organogel matrix was gradually absorbed and completely up-taken in nine days. Histopathological analysis of the surrounding tissues was carried out and revealed an overall good biocompatibility property of the implants over drug release period. This research demonstrates that this thermo-sensitive in situ forming organogel system represents a potentially promising platform for sustained drug delivery. [Copyright &y& Elsevier]

Purpose: To prepare acylated exenatide analogues and investigate their biological properties for guiding the development of PLGA formulations of exenatide. Methods: The acylated exenatide analogues were prepared by reaction with glycolic acid (GA), one constitutional unit of PLGA, and characterized by HPLC-MS/MS and Circular Dichroism (CD). The pharmacokinetic properties and anti-diabetic activities were studied in SD rats and db/db mice, respectively. Results: Structural characterizations of the acylated products showed that one to four glycolic acids (GAs) were connected to the primary amine groups of exenatide, and there was a conversion of α-helix to β-sheet to some extent. Pharmacokinetic studies in SD rats revealed that acylated exenatides had a similar Tmax with that of the prototype drug, whereas the Cmax and the AUC values of the adducts were significantly decreased. Biological activity tests demonstrated that exenatide and acylated exenatide analogues had similar in vivo antidiabetic activities in terms of controlling blood glucose concentration, HbA1c level, body weight and food intake. Conclusions: These findings suggest that GA conjugated exenatide had no influence on the peptide efficacy, therefore it's not necessary to inhibit exenatide acylation in PLGA formulations during the peptide release process. [ABSTRACT FROM AUTHOR]

Triptorelin, a gonadotropin-releasing hormone agonist, has been used in the treatment of hormone-responsive prostate cancer by inducing testosterone suppression. Research on the relationship between the time courses of triptorelin and testosterone is very important, but accurate quantification of triptorelin and testosterone simultaneously in biological specimens is a challenging analytical problem. In the present study, a rapid, sensitive, and selective method for simultaneous determination of triptorelin and testosterone in rat plasma by solid-phase extraction and liquid chromatography-tandem mass spectrometry was developed using a ZORBAX RRHD Eclipse Plus C8 column (2.1 × 50 mm, 1.8 μm) with a 0.05 % propionic acid/methanol gradient. In view of the polarity difference between the two analytes, two internal standards, i.e., leuprolide and testosterone-C, were used for individual quantitation of triptorelin and testosterone. Endogenous testosterone was determined by reference to a calibration curve prepared using testosterone-D as a surrogate analyte. The method exhibits excellent linearity over three orders of magnitude for each analyte. The lower limit of quantification was 0.01 ng/mL for triptorelin and 0.05 ng/mL for testosterone, with consumption of 100 μL of plasma. The method was successfully applied to characterize the pharmacokinetics and pharmacodynamics of slow-release 28-day form triptorelin acetate biodegradable microspheres in rats after intramuscular injections of three consecutive doses of 0.6 mg/kg per 28 days. The results revealed that the pharmacokinetic profile of triptorelin produced an initial flare-up in testosterone levels, rapid castration within 5 days after injection, and long-term castration until the next dose. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Abstract: Objective: The aim of this study was to develop a film-forming gel formulation of rotigotine with hydroxypropyl cellulose (HPC) and Carbomer 934. To optimize this formulation, we applied the Response Surface Analysis technique and evaluated the gel's pharmacokinetic properties. Methods: The factors chosen for factorial design were the concentration of rotigotine, the proportion of HPC and Carbomer 934, and the concentration of ST-Elastomer 10. Each factor was varied over three levels: low, medium and high. The gel formulation was evaluated and optimized according to its accumulated permeation rate (Flux) through Franz-type diffusion. A pharmacokinetic study of rotigotine gel was performed with rabbits. Results: The Flux of the optimized formulation reached the maximum (199.17μg/cm2), which was 3% rotigotine and 7% ST-Elastomer 10 with optimal composition of HPC: Carbomer 934 (5:1). The bioavailability of the optimized formulation compared with intravenous administration was approximately 20%. Conclusion: A film-forming gel of rotigotine was successfully developed using the response surface analysis technique. The results of this study may be helpful in finding an optimum formulation for transdermal delivery of a drug. The product may improve patients’ compliance and provide better efficacy. [Copyright &y& Elsevier]

Abstract: A solution model can be used to elucidate drug stability issues in a complex system. The aim of this study was to investigate the interaction between poly(d,l-lactide-co-glycolide) (PLGA) and exenatide in organic solvent-acetate buffer saline (ABS) solutions. The effect of solvent composition on exenatide stability was investigated first. In the selected 90:10 dimethyl sulfoxide (DMSO):ABS solution, exenatide stability was examined as a function of PLGA comonomer ratios, molecular weight (Mw) and concentrations. The specific rotation analysis and second derivative UV absorbance spectroscopy were used to monitor the variation of exenatide higher order structure. The effect of ABS pH on the interaction was also investigated. Exenatide degradation products were characterized by HPLC–MS/MS. It was found that exenatide was relatively stable in glacial acetic acid (HAc)–ABS solutions, whereas DMSO content had a strong influence on the conformation state and stability of exenatide. PLGA 50:50 promoted exenatide degradation more than PLGA 75:25 and poly(d,l-lactide) (PLA). Lower Mw and higher concentration of PLGA were beneficial for exenatide degradation. Exenatide was more stable in 90:10 DMSO:ABS (pH 3.0) solution than in 90:10 DMSO:ABS (pH 4.5 and 3.0) solutions during the incubation. HPLC–MS/MS analysis of exenatide demonstrated that acylation was the main degradation route of the peptide. [Copyright &y& Elsevier]

γ-Aminobutyric acid (GABA), a non-protein amino acid, is a bioactive component in the food, feed and pharmaceutical fields. To establish an effective single-step production system for GABA, a recombinant Corynebacterium glutamicum strain co-expressing two glutamate decarboxylase (GAD) genes ( gadB1 and gadB2) derived from Lactobacillus brevis Lb85 was constructed. Compared with the GABA production of the gadB1 or gadB2 single-expressing strains, GABA production by the gadB1- gadB2 co-expressing strain increased more than twofold. By optimising urea supplementation, the total production of l-glutamate and GABA increased from 22.57 ± 1.24 to 30.18 ± 1.33 g L, and GABA production increased from 4.02 ± 0.95 to 18.66 ± 2.11 g L after 84-h cultivation. Under optimal urea supplementation, l-glutamate continued to be consumed, GABA continued to accumulate after 36 h of fermentation, and the pH level fluctuated. GABA production increased to a maximum level of 27.13 ± 0.54 g L after 120-h flask cultivation and 26.32 g L after 60-h fed-batch fermentation. The conversion ratio of l-glutamate to GABA reached 0.60-0.74 mol mol. By co-expressing gadB1 and gadB2 and optimising the urea addition method, C. glutamicum was genetically improved for de novo biosynthesis of GABA from its own accumulated l-glutamate. [ABSTRACT FROM AUTHOR]

A composite micelle of ionic complex encapsulated into poly(ethylene glycol)-poly( d, l-lactide) (PEG-PLA) di-block copolymeric micelles was used for protein drug delivery to improve its pharmacokinetic performance. In this study, recombinant human erythropoietin (rhEPO, as a model protein) was formulated with lysine into composite micelles at a diameter of 71.5 nm with narrow polydispersity indices (PDIs < 0.3). Only a trace amount of protein was in aggregate form. The zeta potential of the spherical micelles was ranging from −0.54 to 1.39 mv, and encapsulation efficiency is high (80 %). The stability of rhEPO was improved significantly in composite micelles in vitro. Pharmacokinetic studies in rats showed significant, enhanced plasma retention of the composite micelles in comparison with native rhEPO. Areas under curve (AUCs) of the rhEPO released from the composite micelles were 4.5- and 2.3-folds higher than those of the native rhEPO and rhEPO-loaded PEG-PLA micelle, respectively. In addition, the composite micelles exhibited good biocompatibility using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay with human embryonic kidney (HEK293T) cells. All these features are preferable for utilizing the composite micelles as a novel protein delivery system. [ABSTRACT FROM AUTHOR]

Abstract: Peptide or protein degradation often occurs when water flows into the dosage form. The aim of this study was to investigate the effect of water on exenatide acylation in poly(lactide-co-glycolide) (PLGA) microspheres. Exenatide-loaded PLGA microspheres were incubated at different relative humidities (RH) as well as in solutions of different pH for 20 days. The stability of exenatide was monitored using HPLC and HPLC–MS analysis. The alteration of exenatide conformation caused by water was investigated by FT-IR spectroscopy. Exenatide and glycolide were incubated in DMSO–water solutions to verify the effect of exenatide conformation state on the peptide acylation. Exenatide was relatively stable in microspheres at lower RH, and the absorbed water could act as a plasticizer and thus promote the peptide acylation by PLGA. However, when the microspheres were incubated at 100% RH, the excessively absorbed water could cause conformation recovery of exenatide and play an inhibitory effect on acylation. The formation of acylated exenatide incubated in acetate buffer saline of pH 6.0 was more than that of pH 4.5 and 3.0. Stability studies of exenatide in glycolide solutions showed that exenatide in nonnative monomer state was easier to be acylated by eletrophiles than that in aggregation state. [Copyright &y& Elsevier]

Abstract: In this study, transdermal gel formulations for tolterodine were developed to investigate the effects of gel matrix and chemical enhancers on drug skin permeation from tolterodine hydrogels. In vitro permeation studies of tolterodine through excised mouse skin were carried out using Franz-type diffusion cells. In the optimum gel formulation, Carbopol 940 was selected as the gel matrix. Compared to gels without enhancer, tolterodine hydrogels with N-methyl pyrrolidone (NMP) showed significant enhancing effect on transdermal permeation of tolterodine (p <0.05). The results of in vitro percutaneous delivery experiment showed that the relationship of the steady accumulative percutaneous amount (Q, μgcm−2) of tolterodine hydrogels and time was Q 4–12h =770.19t 1/2 −966.99. Tolterodine permeated at the steady-state speed of 770.19μgcm−2 h−1 and its release coincided with Higuchi Equation. The pharmacokinetic properties of the optimized tolterodine formulation were studied in rabbits. The absolute bioavailability of tolterodine was 11.47%. Since the absence of hepatic first-pass metabolism, only a single active compound-tolterodine was detected in the plasma. A skin irritation study was also carried out on rabbits, and the results showed tolterodine hydrogels had no skin irritation. In the pharmacodynamic study, the significant effects of tolterodine hydrogels on the inhibition of pilocarpine-induced rat urinary bladder contraction were last to 12h, indicating that tolterodine hydrogels could produce prolonged pharmacological responses. In conclusion, tolterodine hydrogels were formulated successfully using Carbopol 940 and NMP and these results helped in finding the optimum formulation for percutaneous drug release. It is quite evident that tolterodine hydrogels may offer a possibility to avoid the first-pass effect, resulting in a single active compound of tolterodine in plasma, which may profit on the patient under the dose control and the reduction of potential adverse effect from two active compounds in the body. [Copyright &y& Elsevier]

Purpose: To prepare rotigotine loaded microspheres (RoMS) to achieve continuous dopaminergic stimulation (CDS) for the treatment of Parkinson's disease (PD) and investigate both the therapeutic benefit and inducibility of AIMs of administration of RoMS combination with L-DOPA in 6-OHDA-leisioned rats. Methods: Rotigotine was encapsulated into poly(lactic-co-glycolic acid) (PLGA) microspheres by an oil-in-water emulsion solvent evaporation technique. In vitro characteristics and in vivo pharmacokinetics of RoMS either in rat blood or brain (by microdialysis) were investigated. Contraversive rotations and AIMs were observed to investigate the therapeutic benefit and the propensity to induce dyskinesia of RoMS or RoMS combination with L-DOPA in 6-OHDA-lesioned rats. Results: RoMS displayed continuous-release characteristics of rotigotine in animals and exhibited a steady efficacy lasted for 2 weeks in 6-OHDA-lesioned rats. No significant difference of the therapeutic benefit between the treatment of RoMS and pulsatile L-DOPA combination and mono L-DOPA was found. While the dyskinesia was significantly decreased with the treatment of RoMS and pulsatile L-DOPA combination compared to mono L-DOPA. Conclusions: RoMS could supply an alternative of CDS for the treatment of PD and the study indicates a potential advantage of RoMS for the treatment of mild and advanced PD patient in combination with L-DOPA. [ABSTRACT FROM AUTHOR]

[Display omitted] With ideal optical properties, semiconducting polymer quantum dots (SPs) have become a research focus in recent years; a considerable number of studies have been devoted to the application of SPs in non-invasive and biosafety phototherapy with near-infrared (NIR) lasers. Nevertheless, the relatively poor stability of SPs in vitro and in vivo remains problematic. PCPDTBT was chosen to synthesize photothermal therapy (PTT) and photodynamic therapy (PDT) dual-model SPs, considering its low band gap and desirable absorption in the NIR window. For the first time, cetrimonium bromide was used as a stabilizer to guarantee the in vitro stability of SPs, and as a template to prepare SP hybrid mesoporous silica nanoparticles (SMs) to achieve long-term stability in vivo. The mesoporous structure of SMs was used as a reservoir for the hypoxia-activated prodrug Tirapazamine (TPZ). SMs were decorated with polyethylene glycol-folic acid (SMPFs) to specifically target activated macrophages in rheumatoid arthritis (RA). Upon an 808 nm NIR irradiation, the SMPFs generate intracellular hyperthermia and excessive singlet oxygen. Local hypoxia caused by molecular oxygen consumption simultaneously activates the cytotoxicity of TPZ, which effectively kills activated macrophages and inhibits the progression of arthritis. This triple PTT-PDT-chemo synergistic treatment suggests that SMPFs realize the in vivo application of SPs and may be a potential nano-vehicle for RA therapy with negligible side-toxicity. [ABSTRACT FROM AUTHOR]

LY03004, a novel investigational risperidone long-acting injection (LAI) microsphere formulation, can release risperidone more quickly after injection than Risperdal Consta®. This study aimed to investigate the effects of genetic polymorphisms on the pharmacokinetics of LY03004 compared with those on Risperdal Consta®. A total of 100 Chinese patients with stable schizophrenia were randomly assigned to the LY03004 or Risperdal Consta® treatment group. Each patient received five biweekly intramuscular injections of 25 mg risperidone long-acting injection microspheres. A total of 34 blood samples before and after injections from Day 1 to Day 113 were collected from each patient, and polymorphic alleles of cytochrome P450 enzymes CYP2D6 (*4, *10, *14), CYP3A5 (*3), and ABCB1 (C1236 > T, G2677T/A , and C3435T) were analyzed using Sanger sequencing and polymerase chain reaction-restriction fragment length polymorphism. The risperidone C max,ss , C min,ss , AUC 0-tau,ss , and the ratio of risperidone to 9-hydroxyrisperidone (9-OH-R) in CYP2D6 intermediate metabolizers (IMs) were significantly different compared with those in normal metabolizers (NMs) in both the LY03004 and Risperdal Consta® groups (P < 0.05). However, 9-OH-R was not significantly different between IMs and NMs (P > 0.05). The AUC 0-tau,ss of the active moiety (risperidone plus 9-OH-R) was 6.51 ± 3.34 in NMs and 7.00 ± 1.81 in IMs (P = 0.071) in the LY03004 group and 6.07 ± 2.31 and 7.95 ± 3.42 (P = 0.053) in NMs and IMs, respectively, in the Risperdal Consta® group. In the LY03004 group, the C max,ss of risperidone in carriers of the ABCB1-C3435T TT variant was significantly lower than that in CC and CT carriers (TT 7.76 ± 4.23 ng/mL, CT 11.6 ± 8.27 ng/mL, CC 14.3 ± 7.66 ng/ml; P = 0.045), but no significant differences were found in the active moiety. In the Risperdal Consta® group, C3435T TT carriers had significantly lower C min,ss of the active moiety (TT 5.09 ± 4.38 ng/mL, CT 11.4 ± 8.42 ng/mL, CC 14.3 ± 6.43 ng/mL; P = 0.007). Furthermore, C min,ss of the active moiety was significantly different among all ABCB1-G2677T/A genotypes (P < 0.05). The pharmacokinetics of risperidone and the ratio of risperidone to 9-OH-R were highly dependent on CYP2D6 activity. However, there was no significant effect in 9-OH-R. A future study involving a larger sample is required to verify whether CYP2D6 IMs have lower risperidone active moiety clearance than CYP2D6 NMs for LAI formulations. In addition, the risperidone active moiety was eliminated faster in ABCB1-G2677T/A and C3435T TT carriers receiving Risperdal Consta®. • We analyzed the effects of CYP2D6, 3A5, and ABCB1 gene polymorphisms on the pharmacokinetics of risperidone LAIs in Chinese. • IMs had significantly higher exposure to risperidone than CYP2D6 NMs; however, no significant difference in 9-OHRIS. • IMs probably had higher active moiety exposure than NMs, but a study with a larger sample is required to verify the results. • G2677TA and C3435T TT carriers receiving Risperdal Consta® injection had significantly lower C min,ss of the active moiety. • Formulation may be an influence factor that affects the level of risperidone exposure differences among different genotypes. [ABSTRACT FROM AUTHOR]

Myeloid cell leukemia-1 (Mcl-1), a member of the Bcl-2 anti-apoptotic family, is overexpressed in the synovial macrophages of patients with rheumatoid arthritis (RA). Small interfering RNA (siRNA) Mcl-1 can induce macrophage apoptosis in the joints and is a potential therapeutic target of RA. Nevertheless, the application of siRNA is limited owing to its instability and susceptibility to degradation in vivo. To address these shortcomings, we developed composite microspheres (MPs) loaded with hyaluronic acid (HA)–chitosan (CS) nanoparticles (NPs). First, we synthesized HA–CS/siRNA NPs (HCNPs) using ionotropic gelation process. Then, HCNPs, as an internal aqueous phase, were loaded into poly (D, L-lactide-co-glycolide) (PLGA) and poly (cyclohexane-1,4-diyl acetone dimethylene ketal) (PCADK) MPs using the double emulsion method. The NPs-in-MPs (NiMPs) composite system provided sustained release of NPs, protected siRNA against nuclease degradation in the serum, and could readily cross the cellular membrane. In addition, we evaluated the advantages of NiMPs in an adjuvant-induced arthritis rat model. Our experimental results demonstrate that NiMPs have greater pharmacodynamic effects than common MPs. Meanwhile, compared with HCNPs, NiMPs reduced the frequency of drug administration. Therefore, NiMPs are a promising and novel siRNA delivery vehicle for RA therapy. [ABSTRACT FROM AUTHOR]

An effective palladium nanocatalyst (Fe 3 O 4 @SiO 2 -FPBA-DTPA-Pd) was proposed and prepared, which was immobilized on magnetic silica with ethylenediamine pentaacetic acid and formylphenylboronic acid as biligands. A series of characterizations showed that Fe 3 O 4 @SiO 2 -FPBA-DTPA-Pd was 5-15 nm and contained 1.44 mmol/g Pd 2+ /Pd 0 . It was stable below 232.7 °C, and its saturation magnetization value was 21.17 emu/g which was easily recycled by a magnet. Its catalytic ability was evaluated through 7 Suzuki reactions and 15 Heck reactions. Results showed that the yields of 14 reactions catalyzed by Fe 3 O 4 @SiO 2 -FPBA-DTPA-Pd were more than 90%, while were better than those of the other two immobilized Pd catalysts on a single diethyltriamine pentaacetic acid (DTPA) group or boronic acid group. Moreover, Fe 3 O 4 @SiO 2 -FPBA-DTPA-Pd showed good reusability in both Suzuki and Heck reactions. In two model Suzuki and Heck reactions, after seven cycles, its yields were still above 95% without significant loss, which exceeded those of many reported catalysts; therefore, it has great potential in future large-scale industrial production., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

The dimension of the void area in pavement is crucial to its structural safety. However, there is no effective method to measure its geometric parameters. To address this issue, a void size extraction algorithm based on the continuous wavelet transform (CWT) method was proposed using ground-penetrating radar (GPR) signal. Firstly, the finite-difference time-domain (FDTD) method was used to investigate the GPR response of void areas with different shapes, sizes, and depths. Next, the GPR signal was processed using the CWT method, and a 3D image based on the CWT result was used to visualize the void area. Based on the differences between the void and normal pavement in the time and frequency domains, the signal with maximum energy from the CWT time-frequency result was extracted and combined to reconstruct the new B-scan image, where void areas have energy concentration phenomenon. Based on this, width and depth of void detection algorithm was proposed to recognize the void area. Finally, the detection algorithm was verified both in numerical model and physical lab model. The results indicated that the CWT time-frequency energy spectrum can be used to enhance the void feature, and the 3D CWT image can clearly visualize the void area with a highlighted energy area. After fully testing and validating in numerical and lab models, our proposed method achieved high accuracy in void width and depth detection, providing a precise method for estimating void dimension in pavement. This method can guide DOT departments to carry out pre-maintenance, thereby ensuring pavement safety., (© 2023. The Author(s).)

Cr(vi) is a great threat to the ecological environment and human health, so it is urgent to remove Cr(vi) from the environment. In this study, a novel silica gel adsorbent SiO 2 -CHO-APBA containing phenylboronic acids and aldehyde groups was prepared, evaluated and applied for removing Cr(vi) from water and soil samples. The adsorption conditions including pH, adsorbent dosage, initial concentration of Cr(vi), temperature and time were optimized. Its ability in removing Cr(vi) was investigated and compared with three other common adsorbents, SiO 2 -NH 2 , SiO 2 -SH and SiO 2 -EDTA. Data showed SiO 2 -CHO-APBA had the highest adsorption capacity of 58.14 mg g -1 at pH 2 and could reach adsorption equilibrium in about 3 h. When 50 mg SiO 2 -CHO-APBA was added in 20 mL of 50 mg L -1 Cr(vi) solution, more than 97% of Cr(vi) was removed. A mechanism study revealed that a cooperative interaction of both the aldehyde and boronic acid groups is attributed to Cr(vi) removal. The reducing function was gradually weakened with the consumption of the aldehyde group, which was oxidized to a carboxyl group by Cr(vi). This SiO 2 -CHO-APBA adsorbent was successfully used for the removal of Cr(vi) from soil samples with satisfactory results which indicates a good potential in agriculture and other fields., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Bacterial infection and oxidative stress hinder clinical wound healing. Therefore, wound dressings with antibacterial and antioxidative properties are urgently needed. In this study, a type of quaternized lignin (QL) functionalized poly(hexamethylene biguanide) hydrochloride (PHMB) complex incorporated polyacrylamide (QL-PHMB-PAM) hydrogel was developed as a multifunctional dressing material for the promotion of infected wound repair. Owing to the abundant catechol groups of quaternized lignin, the QL-PHMB-PAM hydrogel exhibited robust repeatable adhesiveness to various substrates with antioxidative properties. Additionally, the antibacterial components of PHMB in the QL-PHMB-PAM composite hydrogel showed high efficiency and long-term antibacterial activity against Staphylococcus aureus (S.aureus) , Escherichia coli (E.coli) , and methicillin-resistant S. aureus ( MRSA ; up to 100%). Furthermore, in vivo experiments indicated that this multifunctional hydrogel accelerated the healing of S. aureus -infected wounds by promoting the reconstruction of blood vessels and hair follicles. These results demonstrate that this antioxidative, antibacterial, and bioadhesive hydrogel is a promising alternative wound dressing material for the prevention of bacterial infections and the acceleration of infected wound regeneration.

Purpose: Effective therapy for rheumatoid arthritis (RA) keeps a challenge due to the complex pathogenesis of RA. It is not enough to completely inhibit the process of RA with any single therapy method. The purpose of the research is to compensate for the insufficiency of monotherapy using multiple treatment regimens with different mechanisms., Material and Methods: In this study, we developed a new method to synthesize mesoporous silica nanoparticles hybridized with photosensitizer PCPDTBT (HNs). Branched polyethyleneimine-folic acid (PEI-FA) could be coated on the surface of HNs through electrostatic interactions. It simultaneously blocked the hypoxia-activated prodrug tirapazamine loaded into the mesopores and binded with Mcl-1 siRNA (siMcl-1) that interfered with the expression of the anti-apoptotic protein Mcl-1. Released from the co-delivery nanoparticles (PFHNs/TM) Tirapazamine and siMcl-1 upon exposure to acidic conditions of endosomes/lysosomes in activated macrophages. Under NIR irradiation, photothermal therapy and photodynamic therapy derived from PCPDTBT, hypoxia-activated chemotherapy derived from tirapazamine, and RNAi derived from siMcl-1 were used for the combined treatment for RA by killing activated macrophages. PEI-FA-coated PFHNs/TM exhibited activated macrophage-targeting characteristics, thereby enhancing the in vitro and in vivo NIR-induced combined treatment of RA., Results: The prepared PFHNs/TM have high blood compatibility (far below 5% of hemolysis) and ideal in vitro phototherapy effect while controlling the TPZ release and binding siMcl-1. We prove that PEI-FA-coated PFHNs/TM not only protect the bound siRNA but also are selectively uptaked by activated macrophages through FA receptor-ligand-mediated endocytosis, and effectively silence the target anti-apoptotic protein by siMcl-1 transfection. In vivo, PFHNs/TM have also been revealed to be selectively enriched at the inflammatory site of RA, exhibiting NIR-induced anti-RA efficacy., Conclusion: Overall, these FA-functionalized, pH-responsive PFHNs/TM represent a promising platform for the co-delivery of chemical drugs and nucleic acids for the treatment of RA cooperating with NIR-induced phototherapy., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Li et al.)