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The anthelmintic properties of tanniferous plants and of their secondary metabolites represent one possible alternative to chemotherapy that is currently being explored as a means of achieving sustainable control of gastrointestinal nematodes in ruminants. Previous in vivo and in vitro results suggest that tanniferous plants can have direct anti-parasitic effect against different stages of nematodes. However, the mode of action of the bioactive plant compounds remains obscure. The objectives of the current study were (1) to examine the hypothesis that extracts of tanniferous plants might interfere with the exsheathment of third-stage infective larvae (L3); (2) to assess the role of tannins in the process by examining the consequence of adding an inhibitor of tannins (polyethylene glycol: PEG) to extracts. The effects of 4 tanniferous plant extracts on exsheathment have been examined on L3 of Haemonchus contortus and Trichostrongylus colubriformis. Artificial exsheathment was induced in vitro by adding hypochloride solution to larval suspension. The evolution of exsheathment with time was measured by repeated observations at 10-min interval for 60 min. The selected plants were: genista (Sarothamnus scoparius), heather (Erica erigena), pine tree (Pinus sylvestris), and chestnut tree (Castanea sativa), with tannin contents ranging from 1.5 to 24.7% of DM. Extracts of a non-tanniferous plant (rye grass, tannin content: 0.3% of DM) were included in the assay as negative controls. The extracts were tested at the concentration of 600 microg/ml and the effects were compared to the rate of exsheathment of control larvae in PBS. No statistical differences in the pattern of exsheathment was observed after addition of rye grass or genista extracts for both nematode species and with heather extracts for T. colubriformis. In contrast, pine tree extracts on larvae of both species and heather extracts with H. contortus induced a significant delay in exsheathment. Last, contact with chest nut extracts led to a total inhibition of the process for both nematodes. These results suggest that extracts of tanniferous plants might affect a key process in the very early stages of larval invasion of the host. In most cases, the addition of PEG led to a total or partial restoration towards control values. This suggests that tannins are largely involved in the inhibitory process. However, other secondary metabolites may also interfere with the process that would help to explain some of the differences in response observed between the two nematode species.
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PMID:Effects of four tanniferous plant extracts on the in vitro exsheathment of third-stage larvae of parasitic nematodes. 1638 90

A pH- and thermo-sensitive block copolymer was synthesized by adding pH-sensitive sulfamethazine oligomers (SMOs) to either end of a thermo-sensitive poly(epsilon-caprolactone-co-lactide)-poly(ethylene glycol)-poly(epsilon-caprolactone-co-lactide) (PCLA-PEG-PCLA) block copolymer. The resulting pH- and thermo-sensitive SMO-PCLA-PEG-PCLA-SMO block copolymer solution did not form a gel at high pH (pH 8.0) or at increased temperatures (ca. 70 degrees C), but did form a stable gel under physiological conditions (pH 7.4 and 37 degrees C). The degradation rate of the pH- and thermo-sensitive block copolymer decreased substantially compared with the control block copolymer of PCLA-PEG-PCLA, due to the buffering effect of the SMO-PCLA-PEG-PCLA-SMO sulfonamide groups on the acidic monomer-induced rapid degradation of PCLA-PEG-PCLA. This suitable sol-gel transition and sustained biodegradability of the pH- and thermo-sensitive SMO-PCLA-PEG-PCLA-SMO block copolymer resolves two of the major drawbacks associated with thermo-sensitive block copolymers, namely premature gelation and rapid degradation. Interestingly, SMO-PCLA-PEG-PCLA-SMO showed no evidence of cytotoxicity in vitro. However, subcutaneous injection of the pH- and thermo-sensitive block copolymer solution (20wt% in PBS at pH 8.0) into Sprague-Dawley (SD) rats resulted in rapid, stable gel formation, with the injected hydrogel being completely degraded in vivo in just 6 weeks. The injected hydrogel in vivo presented a typical acute inflammation within 2 weeks, although chronic inflammation was not observed during the first 6-week period. As such, the pH- and thermo-sensitive hydrogel of the SMO-PCLA-PEG-PCLA-SMO block copolymer is a suitable candidate for use in drug delivery systems and cell therapy.
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PMID:Biodegradability and biocompatibility of a pH- and thermo-sensitive hydrogel formed from a sulfonamide-modified poly(epsilon-caprolactone-co-lactide)-poly(ethylene glycol)-poly(epsilon-caprolactone-co-lactide) block copolymer. 1679 93

We report the encapsulation of MIN6 cells, a pancreatic beta-cell line, using thermally induced gelable materials. This strategy uses aqueous solvent and mild temperatures during encapsulation, thereby minimizing adverse effects on cell function and viability. Using a 2:1 mixture of PNIPAAm-PEG-PNIPAAm tri-block copolymer and PNIPAAm homopolymer that exhibit reversible sol-to-gel transition at approximately 30 degrees C, gels were formed that exhibit mechanical integrity, and are stable in H(2)O, PBS and complete DMEM with negligible mass loss at 37 degrees C for 60 days. MTT assays showed undetectable cytotoxicity of the polymers towards MIN6 cells. A simple microencapsulation process was developed using vertical co-extrusion and a 37 degrees C capsule collection bath containing a paraffin layer above DMEM. Spherical capsules with diameters ranging from 500 to 900 microm were formed. SEM images of freeze-dried capsules with PBS as the core solution showed homogenous gel capsule membranes. Confocal microscopy revealed that the encapsulated cells tended to form small aggregates over 5 days, and staining for live and dead cells showed high viability post-encapsulation. A static glucose challenge with day-5 cultured microencapsulated cells exhibited glucose-dependent insulin secretion comparable to controls of free MIN6 cells grown in monolayers. These results demonstrate the potential use of these thermo-responsive polymers as cell encapsulation membranes.
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PMID:Thermally induced gelable polymer networks for living cell encapsulation. 1689 33

Eight-arm poly(ethylene glycol)-poly(L-lactide), PEG-(PLLA)(8), and poly(ethylene glycol)-poly(D-lactide), PEG-(PDLA)(8), star block copolymers were synthesized by ring-opening polymerization of either L-lactide or D-lactide at room temperature in the presence of a single-site ethylzinc complex and 8-arm PEG (M(n) = 21.8 x 10(3) or 43.5 x 10(3)) as a catalyst and initiator, respectively. High lactide conversions (>95%) and well-defined copolymers with PLLA or PDLA blocks of the desired molecular weights were obtained. Star block copolymers were water-soluble when the number of lactyl units per poly(lactide) (PLA) block did not exceed 14 and 17 for PEG21800-(PLA)(8) and PEG43500-(PLA)(8), respectively. PEG-(PLA)(8) stereocomplexed hydrogels were prepared by mixing aqueous solutions with equimolar amounts of PEG-(PLLA)(8) and PEG-(PDLA)(8) in a polymer concentration range of 5-25 w/v % for PEG21800-(PLA)(8) star block copolymers and of 6-8 w/v % for PEG43500-(PLA)(8) star block copolymers. The gelation is driven by stereocomplexation of the PLLA and PDLA blocks, as confirmed by wide-angle X-ray scattering experiments. The stereocomplexed hydrogels were stable in a range from 10 to 70 degrees C, depending on their aqueous concentration and the PLA block length. Stereocomplexed hydrogels at 10 w/v % polymer concentration showed larger hydrophilic and hydrophobic domains as compared to 10 w/v % single enantiomer solutions, as determined by cryo-TEM. Correspondingly, dynamic light scattering showed that 1 w/v % solutions containing both PEG-(PLLA)(8) and PEG-(PDLA)(8) have larger "micelles" as compared to 1 w/v % single enantiomer solutions. With increasing polymer concentration and PLLA and PDLA block length, the storage modulus of the stereocomplexed hydrogels increases and the gelation time decreases. Stereocomplexed hydrogels with high storage moduli (up to 14 kPa) could be obtained at 37 degrees C in PBS. These stereocomplexed hydrogels are promising for use in biomedical applications, including drug delivery and tissue engineering, because they are biodegradable and the in-situ formation allows for easy immobilization of drugs and cells.
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PMID:In-situ formation of biodegradable hydrogels by stereocomplexation of PEG-(PLLA)8 and PEG-(PDLA)8 star block copolymers. 1702 54

The aim of this work was to develop a stable injectable formulation of the antimalarial drug halofantrine (Hf) based on nanocapsules (NC) prepared from biodegradable polymers with Miglyol 810N as the oily core. Poly(D,L-lactide) PLA and its copolymers with poly(ethyleneglycol) (PLA-PEG) were used together with the surfactants poloxamer 188 and lecithin to yield NC with different surface properties. Highly efficient loading of the free base form of Hf was obtained; zeta potential measurements indicated that a part of the associated Hf was at the NC surface, interacting with the lecithin. NC were 150-250 nm in diameter and more stable on storage than nanoemulsions formed from oil and lecithin without polymer. The most stable NC, showing minimal size changes and flocculation, were those with a high density of 20-kDa PEG chains covalently grafted at the surface. Hf release from NC occurred mainly by partition with the external medium. In PBS, even when Tween 80 was added, release was limited to 20% of the total content, whatever the formulation. Addition of serum to the medium allowed complete and rapid release from PLA NC stabilized with adsorbed poloxamer 188, because of the high affinity of Hf for lipoproteins. However, the presence of covalently grafted PEG chains at the surface limited release by providing a hydrophilic steric barrier at the particle surface. A dense coverage with long PEG chains provided the best reduction of release. Such systems could constitute a long-circulating intravenous formulation of Hf for treating severe malaria.
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PMID:Surface-modified and conventional nanocapsules as novel formulations for parenteral delivery of halofantrine. 1704 36

The aim of this work was to design a new multifunctional nano device (MND) for gene delivery. This MND was equipped with folic acid as ligand, which was conjugated to terminal amido of poly(aminopoly(ethylene glycol)cyanoacrylate-co-hexadecyl cyanoacrylate) (poly(H(2)NPEGCA-co-HDCA)) to synthesize poly(Folate-HNPEGCA-co-HDCA), protamine sulfate (PS) as DNA condenser and for nuclear transfer, PEG chain from poly(Folate-HNPEGCA-co-HDCA) for decreasing macrophages recognition and extending half-life, dioleoyl phosphatidylethanolamine (DOPE) for endosomal escape, and we supposed that the latent DOPE fusogenicity could be gently restored along with fast degradation of poly(Folate-HNPEGCA-co-HDCA) in MND membrane within endosome. Our experimental results showed that optimum complexation ( approximately 97%) of DNA was achieved at DNA:PS=1:3 (w/w). The MND showed different loading ratio by lipid film hydration technique with the highest loading ratio about 12%, the particle size range 200-400 nm, surface charge range 8 mV-15 mV. MND1 (poly(Folate-HNPEGCA-co-HDCA)/DOPE, 5:95, molar ratio) exhibited a high burst release effect with 60% of pDNA/PS released within 1 day at PBS (pH 4.5), but with 21.4% and 8.1% pDNA/PS release at PBS with pH 5.8 and 7.4 within 24 h, respectively. However, lesser pDNA/PS release occurred in MND2 (poly(Folate-HNPEGCA-co-HDCA)/DOPE, 10:90, molar ratio) with 46%, 16.9% and 7.8% of pDNA/PS released at PBS with pH 4.5, 5.8 and 7.4 within 24 h, respectively. After 1 day, pDNA/PS displayed a sustained release pattern. The amount of cumulated pDNA/PS release over 3 days was 75% and 51.2% at PBS with pH 4.5 for MND1 and MND2, respectively. The MND loading pDNA/PS showed that luciferase activity was over 0.5 ng luciferase/mg protein in KB cells, in particular, the MND1 showed the highest transfection efficiency (0.66 ng luciferase/mg protein) in KB cells, which was much higher compared with in A549 cells or other formulations such as LipofectAMINE, free pDNA/PS and control multifunctional nano device (CMND), whose lipid film was consisted of poly(H(2)NPEGCA-co-HDCA) and DOPE. In addition, MND also showed good protection during encapsulation and low cytotoxicity. As a result, MND could be a more potential non-viral vector for delivery of DNA.
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PMID:A multifunctional nano device as non-viral vector for gene delivery: in vitro characteristics and transfection. 1732 25

Poly(ethylene glycol) (PEG)-modified thiolated gelatin (PEG-SHGel) anoparticles were developed as a long-circulating passively targeted delivery system that responds to intracellular glutathione concentrations to enhance DNA delivery and transfection. Reporter plasmid expressing enhanced green fluorescent protein (EGFP-N1) was encapsulated in the nanoparticles. DNA-containing gelatin (Gel) and thiolated gelatin (SHGel) nanoparticles were found to have a size range of 220 to 250 nm, whereas surface modification with PEG resulted in particles with a slightly larger size range of 310 to 350 nm. PEG modification was confirmed by electron spectroscopy for chemical analysis (ESCA), where an increase in the ether peak intensities of the C1s spectra corresponds to the surface presence of ethylene oxide residues. In addition, the PEG-SHGel nanoparticles released encapsulate plasmid DNA in response to varying concentrations of glutathione (up to 5.0 mM GSH in phosphate-buffered saline, or PBS). The stability of the encapsulated DNA was confirmed by agarose gel electrophoresis. Finally, from the qualitative and quantitative results of in vitro transfection studies in murine fibroblast cells (NIH3T3), PEG-Gel and PEG-SHGel nanoparticles afforded the highest transfection efficiency of the reporter plasmid. The results of these studies show that PEG-modified thiolated gelatin nanoparticles could serve as a very efficient nanoparticulate vector for systemic DNA delivery to solid tumors where the cells are known to have significantly higher intracellular GSH concentrations.
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PMID:Poly(ethylene glycol)-modified thiolated gelatin nanoparticles for glutathione-responsive intracellular DNA delivery. 1737 67

An integrated microsampling approach based on solid-phase microextraction (SPME) was developed to provide a complete solution to highly efficient and accurate pharmacokinetic studies. The microsampling system included SPME probes that are made of poly(ethylene glycol) (PEG) and C18-bonded silica, a fast and efficient sampling strategy with accurate kinetic calibration, and a high-throughput desorption device based on a modified 96-well plate. The sampling system greatly improved the quantitative capability of SPME in two ways. First, the use of the C18-bonded silica/PEG fibers minimized the competition effect from analogues of the target analytes in a complicated sample matrix such as blood or plasma samples, which is a common problem associated with solid coating SPME fibers for quantitative analysis. Moreover, the C18-bonded silica/PEG fibers provide high sensitivity and a large dynamic range that covers the possible sample concentration range during diazepam administration and elimination. Second, the kinetic calibration method offers more accurate quantitation than the calibration curve method for in vivo SPME, because it compensates for convection and matrix effects during sampling. Therefore, it is especially suitable as a fast sampling technique for pre-equilibrium SPME. Furthermore, with the high-throughput desorption device, the integrated system offers compactness and high efficiency. Its feasibility for in vivo sampling was demonstrated by monitoring diazepam pharmacokinetics and validated by conventional chemical assays and equilibrium SPME. In addition, we propose a simple method to determine the apparent distribution constant between an SPME fiber and a blood matix (Kfs) and the distribution constant between an SPME fiber and a pure PBS buffer sample matrix (Kfb). As a result, both total and free concentrations of the drug and its metabolites can be detected simultaneously. Accordingly, the binding constants to the blood matrix can be obtained, which are of special significance for clinical diagnosis and drug discovery.
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PMID:Quantitative in vivo microsampling for pharmacokinetic studies based on an integrated solid-phase microextraction system. 1750 18

Biodegradable hydrogels (FPBe-G) were synthesized by the photopolymerization of two precursors: FPBe, a fumurate-based unsaturated poly(ester amide) (UPEA), and poly(ethylene glycol) diacrylate (PEG-DA). Depending on the feed ratio of these two precursors, the resultant FPBe-G hydrogels showed different crosslinking levels of network structure, mesh sizes (xi) and matrix morphology. When a lipophilic drug, paclitaxel, was preloaded into FPBe-G hydrogels, the two-month drug-release kinetics from FPBe-G hydrogels in both pure PBS buffer and alpha-chymotrypsin media were measured. The paclitaxel-preloaded FPBe-G hydrogels in a alpha-chymotrypsin solution had significantly faster drug release rate than the corresponding hydrogels in a pure PBS buffer due to an enzyme catalyzed biodegradation of FPBe-G hydrogels. Sustained paclitaxel releases over a two-month period without initial burst release were also achieved by using hydrogels having certain feed ratios of hydrogel precursors. These paclitaxel release data correlated well with the molecular mesh size (xi), molecular weight between cross-links (M(c)) and matrix morphological structure of FPBe-G hydrogels.
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PMID:Controlled release of paclitaxel from biodegradable unsaturated poly(ester amide)s/poly(ethylene glycol) diacrylate hydrogels. 1755 Jun 54

Dendrimers have been attracting growing attention because of their unique well-defined globular nanoscale architecture and numerous functional groups on the surface. Attachment of PEG to the dendrimer generates stealth dendrimers, which have promising structural advantages for drug delivery. In this study, synthetic methods were explored to deliver antiarrhythmic quinidine by stealth dendrimers. In particular, quinidine was covalently attached to anionic G2.5 and cationic G3.0 polyamidoamine (PAMAM) dendrimers via a glycine spacer, respectively. The resulting quinidine-PAMAM-PEG conjugates were characterized and confirmed by FT-IR and (1)H-NMR. In vitro hydrolysis was carried out in pH 7.4 PBS buffer at 37 degrees C to confirm the bioavailability of the conjugated quinidine.
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PMID:Stealth dendrimers for antiarrhythmic quinidine delivery. 1755 76


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