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PubMed2000

In situ gelation of PEG-PLGA-PEG triblock copolymer aqueous solutions and degradation thereof.

Aqueous solutions of poly(ethylene glycol-b-[DL-lactic acid-co-glycolic acid]-b-ethylene glycol) (PEG-PLGA-PEG) triblock copolymers form a free-flowing sol at room temperature and become a gel at body temperature. In this study, in situ gel formation was investigated in rats. Upon subcutaneous injection of 33 wt % aqueous solutions of PEG-PLGA-PEG triblock copolymer into rats, transparent gels were observed. The gel showed good mechanical strength and the integrity of gels persisted longer than 1 month. The gel underwent degradation by hydrolysis and turned opaque. Degradation study showed preferential mass loss of PEG-rich segment from the in situ formed gel. Number average molecular weight determined by gel permeation chromatography decreased from 3300 to 1900 and 30% mass loss was observed over 1 month.

Animals↗
PubMed2006

Stealth PEG-PHDCA niosomes: effects of chain length of PEG and particle size on niosomes surface properties, in vitro drug release, phagocytic uptake, in vivo pharmacokinetics and antitumor activity.

A series of novel niosomes with the amphiphilic copolymer of poly (methoxy-polyethyleneglycol cyanoacrylate-co-n-hexadecyl cyanoacrylate) (PEG-PHDCA) acted as surface modification materials were prepared and Hydroxycamptothecin (HCPT) was used as a model drug. This work concentrated on the effects of PEG chain length and particle sizes on the niosomes surface properties, in vitro drug release, phagocytic uptake, in vivo pharmacokinetics and antitumor activity. Within the range of PEG Mw from 2000 to 10000, the increasing zeta potential (from -16.08 to -5.25 mv) and thicker fixed aqueous layer (3.82 to 5.78 nm) would facilitate the niosomes' stealth effects, while the reduced PEG chain density (from 0.53 to 0.17 PEG/nm2) and the quickened speed of drug release would diminish the effects. As a result, the PEG5000-PHDCA niosomes had the least phagocytic uptake, the longest half-life of 11.46 h and the best tumor inhibition rate of 97.1%. In the groups different in particle size (PEG5000-PHDCA niosomes from 92.5 to 204.6 nm), the bigger particles could be uptaken by macrophages more quickly, regardless of the changes of other physicochemical parameters. Correspondingly, PEG5000-PHDCA niosomes with particle sizes of 92.5, 144.2, 204.6 nm could extend the half-life of HCPT to 11.46, 6.33, 4.46 h, respectively. At last, the tumor inhibition rate of PEG5000-PHDCA niosomes (92.5 nm) at a dose of 2 mg/kg was five times that of HCPT injection at 4 mg/kg. The stealth effects of the PEG-PHDCA niosomes and the enhanced stability of lactone form of HCPT were accountable for the powerful antitumor effects of niosomes.

Algorithms↗
PubMed1984

Effect of polyethyleneglycols (PEG 600 and PEG 6000) and bovine serum albumin on myeloperoxidase-mediated release of [3H]-serotonin from rat peritoneal mast cells in vitro.

Rat peritoneal mast cells in vitro released [3H]-serotonin in the presence of halide (I-), myeloperoxidase (MPO), and a H2O2-generating system. The degranulation was partly inhibited with low concentrations of bovine serum albumin (BSA; 0.1-1% w/v), or polyethyleneglycols (PEG 600 or PEG 6000, 0.1% w/v). Furthermore, PEG 600 and PEG 6000 enhanced the stabilization achieved with 0.1% BSA. The results may provide a new aspect on antigenicity of PEG-modified allergens, and on mast-cell response at an inflammatory site.

Animals↗
PubMed2006

The effect of methoxy-PEG chain length and molecular architecture on lymph node targeting of immuno-PEG liposomes.

The rate of drainage and lymphatic distribution of subcutaneously injected liposomes is controlled by inclusion of methoxypoly(ethyleneglycol), mPEG-phospholipid into the liposomal bilayer. The effect is most dramatic with liposomes containing 15 mol% mPEG-lipid, with an average PEG molecular mass of 350 Da. These vesicles are drained rapidly from the injection site into the initial lymphatics when compared to unmodified liposomes, and are retained more favourably by the scavengers of the regional lymph node. Liposomes decorated with longer surface mPEG chains (6.7 mol% of mPEG2000-lipid) exhibit faster drainage rates than vesicles having 15 mol% mPEG350-lipid in their lipid bilayer, but their lymph node retention is very poor. The lymph node retention of rapidly drained PEG-bearing vesicles was increased dramatically following conjugation of a non-specific IgG to the distal end of PEG, using a functionalized PEG2000 lipid. Adjusting the molecular architecture of surface mPEG and IgG-PEG chains to a "nearly overlapped mushroom" regime further enhanced target recognition of immuno-PEG2000 liposomes without compromising their drainage rate from the interstitium. The lymph node retention of these vesicles was further optimized by enriching their lipid bilayer with 20 mol% phosphatidylserine. These approaches have established important compositional and structural variables that control lymphatic targeting of immuno-PEG liposomes and their application in experimental medicine and biology is discussed.

Animals↗
PubMed2004

Self-porating polymersomes of PEG-PLA and PEG-PCL: hydrolysis-triggered controlled release vesicles.

Controlled release polymer vesicles are prepared using hydrolysable diblock copolymers of polyethyleneglycol-poly-l-lactic acid (PEG-PLA) or polyethyleneglycol-polycaprolactone (PEG-PCL). Encapsulation studies with a common anti-cancer agent, doxorubicin, show loading comparable to liposomes. Rates of encapsulant release from the hydrolysable vesicles are accelerated with an increased proportion of PEG but are delayed with a more hydrophobic chain chemistry (i.e. PCL). Rates of release also rise linearly with the molar ratio of degradable copolymer blended into membranes of a non-degradable, PEG-based block copolymer (PEG-polybutadiene (PBD)). With all compositions, in both 100 nm and giant vesicles, the average release time (from hours to days) reflects a highly quantized process in which any given vesicle is either intact and retains its encapsulant, or is porated and slowly disintegrates. Poration occurs as the hydrophobic PLA or PCL block is hydrolytically scissioned, progressively generating an increasing number of pore-preferring copolymers in the membrane. Kinetics of this evolving detergent mechanism overlay the phase behavior of amphiphiles with transitions from membranes to micelles allowing controlled release.

Delayed-Action Preparations↗
PubMed2005

A randomized single-blind trial of split-dose PEG-electrolyte solution without dietary restriction compared with whole dose PEG-electrolyte solution with dietary restriction for colonoscopy preparation.

BACKGROUND: Colonoscopy preparation regimens are poorly tolerated, requiring the use of a large volume of an unpalatable solution and diet restriction for adequate cleansing. The aim of this study was to compare the efficacy of two regimens of bowel preparation before colonoscopy: a whole dose of polyethylene glycol electrolyte solution (PEG-E), with diet restriction vs. a split dose with no diet restriction. METHODS: A total of 141 patients (ages 20-84 years, 81 men) were randomly assigned to receive either 4 L PEG-E, along with a liquid diet the day before colonoscopy (Group A) or 2 L PEG-E with a regular diet the day before colonoscopy followed by another 2 L PEG-E on the day of the procedure (Group B). The quality of the preparation was graded by the endoscopist (poor to excellent), who was blinded to the type of preparation. Tolerability of the assigned preparation and adverse effects were recorded by an independent investigator by using a questionnaire administered before colonoscopy. Intra- and interobserver variability was studied by using randomly chosen videotapes of colonoscopies performed as part of the study. RESULTS: There were 73 patients in Group A and 68 patients in Group B. The quality of the preparation was significantly better in Group B ( p = 0.011). The tolerability of the preparation regimen was not different overall between study groups in terms of side effects (except for bloating, which was more frequent in Group B, p = 0.039) or willingness to repeat the preparation. There was a nonsignificant trend toward improved adherence to the assigned preparation in favor of Group B ( p = 0.062). Inter- and intraobserver variability analysis showed good to excellent correlation among endoscopists. CONCLUSIONS: Colonic preparation with split-dose PEG-E and no dietary restriction provides better quality colon cleansing than whole-dose preparation, with no significant impact on patient tolerability and side effects.

Adult↗
PubMed2004

Characterization of aldehyde-PEG tethered surfaces: influence of PEG chain length on the specific biorecognition.

A functionalized poly(ethylene glycol) (PEG) layer possessing a reactive aldehyde group at the free end of the tethered PEG chain was constructed by simple coating on the substrate, using the acetal-PEG/poly(DL-lactide) block copolymer, followed by the hydrolysis of the acetal end group by an acid treatment. The reactivity of the aldehyde group at the distal end of the PEG tethered chain was evaluated via a reductive amination using 4-amino-2,2,6,6-tetramethylpiperidinyloxy as the model compound. Further conjugation of the aldehyde group with sugar moieties has demonstrated an increased recognition ability with lectins with an increasing PEG chain length, which was attributable to the mobility of the chain end. These results provide a novel idea for highly sensitive biorecognition, suggesting a method to create highly selective biosensing surfaces that are able to prevent the undesired nonspecific adsorption of biocomponents.

Aldehydes↗
PubMed1984

Intestinal permeability in healthy and allergic children before and after sodium-cromoglycate treatment assessed with different-sized polyethyleneglycols (PEG 400 and PEG 1000).

Gastrointestinal permeability was investigated in twenty-two children on two occasions, before and after treatment with sodium cromoglycate. The children were between 8 and 10 years old; half of them were classified as allergic according to history and laboratory tests, and half of them as healthy. The 6-hr urinary recovery of different-sized polyethyleneglycols (PEG 400 and PEG 1000) in combination with a mathematical model was used to assess the intestinal permeability barrier. No significant differences were seen in the first PEG test between healthy and allergic children, although those with gastrointestinal allergy showed a slightly lower, and those with other allergies a slightly higher recovery of the smaller PEGs than seen in the healthy individuals. After treatment with sodium cromoglycate, however, there was a significant decrease in uptake by allergic children, which could indicate that the permeability properties had returned to normal. The PEG method offers a simple, harmless and reproducible method to measure intestinal permeability properties. The change in permeability observed after sodium cromoglycate corresponds well with the clinical experience of usefulness of the drug in some children with food allergy.

Cell Membrane Permeability↗
PubMed1986

Intestinal permeability in small children during and after rotavirus diarrhoea assessed with different-size polyethyleneglycols (PEG 400 and PEG 1000).

The permeability properties of the small intestinal mucosa was investigated in nine previously healthy children with acute diarrhoea due to rotavirus. The investigation was performed after intake of a mixture in water of polyethyleneglycol molecules (PEG 400 and 1000) ranging from 282 to 1250 dalton in molecular weight. The 6-h urinary recovery of the PEGs was determined with high performance liquid chromatography and used to assess the permeability characteristics of the intestine. The patients served as their own controls and were investigated in the same manner after recovery 3-5 weeks later. A significantly lower urinary recovery of PEG was noted for all molecular sizes (326-1206 dalton) during acute diarrhoea in comparison with the results obtained after recovery (p less than 0.001-0.1). There was also a relatively lesser change in the urinary recovery of larger PEG molecules during infection, as reflected by a higher recovery ratio between 1074 and 370 dalton PEGs. The results indicate profound changes in the permeability characteristics of the intestine during acute rotavirus diarrhoea.

Diarrhea, Infantile↗
PubMed1985

Modelling of intestinal permeability in man to polyethylene glycols (PEG 400 and PEG 1000).

The intestinal permeability barrier was evaluated in four healthy individuals by the 6 h urinary recovery of a mixture of different-sized polyethylene glycols (PEG 400 and PEG 1000) after a liquid meal of probe molecules. The mixture of PEGs contained around 25 different PEG polymers, ranging from about 194 to 1294 dalton in size. Three models were employed to get a condensed formulation of the intestinal barrier, namely a filter function, describing exclusion of molecules due to the molecular weight, and two expressions for ultrafiltration through a pore due to the Stoke-Einstein radius. A factor reflecting unrestricted passage of probe molecules in the size-range used was also included in the mathematical expressions. It was found that a filter function showing half-maximum exclusion at 589-956 daltons (Da) PEG and a pore function yielding a pore-size of 8.0-8.5 A equally well described the intestinal barrier in the four subjects. The results are discussed in relation to structures of the intestinal epithelium that may restrict the passage of molecules.

Capillary Permeability↗
PubMedDate not supplied

To PEG or not to PEG.

Patients with adequate intestinal function who are unable to eat may benefit from enteral tube feeding. Percutaneous endoscopic gastrostomy (PEG) is preferred when prolonged treatment is envisaged. PEG feeding will reduce morbidity and mortality in many such patients by reversing malnutrition. The increasing numbers of elderly patients with chronic diseases have resulted in an increased demand for PEG placement that has stretched resources. Many patients who are referred for PEGs are frail and the procedure is associated with complications. Careful management and support for the carers in the community are essential. Not all patients benefit from PEG feeding. The aim must be an improvement in the quality of life, not a prolongation of terminal disease.

Age Factors↗
PubMed2005

Repeated injections of PEG-PE liposomes generate anti-PEG antibodies.

Liposomes containing the polyethylene glycol (PEG) derivative of phosphatidyl ethanolamine (PE) have recently been found to be promising drug carriers, as they facilitate controlled and target-oriented release of therapeutics. They also reduce the side effects of many drugs. Here, we present the results of a study on antiliposomal properties of rabbit sera obtained after weekly injections of small liposomes containing 20% PEG-PE. The effect was analysed as the level of induced carboxyfluorescein release from these liposomes in vitro. The incubation of liposomes with rabbit serum taken after the injections induced the release of carboxyfluorescein at a higher level than was seen for incubation with untreated animal's serum. The strongest effect was observed for serum obtained after the second injection, i.e. during the second week of the study. The effect was much smaller after the serum samples were preheated at 56 degrees C. The binding of serum proteins by PEGylated liposomes was analysed via gel filtration and via the immunoblot technique using goat anti-rabbit IgG; this revealed that the serum protein which bound to the liposomes in vitro had a molecular weight of 55 kD and reacted with the anti-IgG antibody. Competition with PEG or lipids indicate that this IgG has an anti-PEG activity. We therefore assume that these antibodies are responsible for the activation of complement and leakage induction of PEG-liposomes. Such antibodies could be responsible for increased phagocytosis by RES macrophages (in particular liver macrophages) and decreased circulation time.

Animals↗
PubMed2005

Open, randomized, multicentre italian trial on PEG-IFN plus ribavirin versus PEG-IFN monotherapy for chronic hepatitis C in HIV-coinfected patients on HAART.

BACKGROUND: Chronic hepatitis C is common and aggressive in HIV-positive patients, so the development of a well-tolerated HCV therapy is a priority. We evaluated the efficacy and safety of pegylated interferon alpha2b (PEG-IFN) plus ribavirin (RBV) versus PEG-IFN monotherapy in HIV/HCV-coinfected patients undergoing highly active antiretroviral therapy (HAART), and analysed the predictive factors of response. METHODS: An Italian, multicentre, open-label trial including 135 coinfected patients, randomized to PEG-IFN 1.5 microg/kg/week plus RBV 400 mg twice daily (n=69, arm A) or PEG-IFN 1.5 microg/kg/week (n=66, arm B) for 48 weeks. We assessed the predictive values of early virological response (EVR) at week 8 (HCV-RNA drop >2 log10 compared with baseline or undetectable levels) on sustained virological response (SVR). RESULTS: Fifty-five patients (28 from arm A and 27 from arm B) completed 48 weeks of therapy. At the end of treatment, 20/28 patients in arm A and 11/27 in arm B had HCV-RNA <50 IU/ml. In a per-protocol analysis, SVR was reached by 54% of patients in arm A (genotype 2-3, 11/16; genotype 1-4, 4/12) and 22% in arm B (genotype 2-3, 3/15; genotype 1-4, 3/12). In an intention-to-treat analysis, the SVR was 22% in arm A (genotype 2-3, 11/32; genotype 1-4, 4/37) versus 9% in arm B (genotype 2-3, 3/32; genotype 1-4, 3/34). The best predictors of SVR were the use of combination therapy, infection with HCV genotype 3 versus genotype 1, and EVR at week 8. Thirty patients (15 from arm A and 15 from arm B) dropped out of the trial prematurely due to side effects. The positive predictive value of EVR at week 8 was 65%, the negative predictive value was 86%. CONCLUSIONS: PEG-IFN plus RBV can be considered a solid option for the treatment of HIV/HCV-coinfected patients. The key to successfully improving efficacy is strong compliance through strict overall patient monitoring, in order to best manage drug toxicity. EVR assessment at week 8 may become a useful stategy in the management of therapy.

Administration, Oral↗
PubMed1981

Suppression of reaginic antibodies with modified allergens. IV. Induction of suppressor T cells by conjugates of polyethylene glycol (PEG) and monomethoxy PEG with ovalbumin.

Administration of multiple injections of conjugates of ovalbumin (OA) and polyethylene glycol (PEG) or its monomethoxy derivative (mPEG) into mice which had been sensitized with 2,4-dinitrophenylated OA (DNP3-OA) abrogated both the anti-OA and anti-DNP IgE responses, in spite of additional injections of the sensitizing dose of DNP3-OA in the presence of A1(OH)3. Treatment of mice with OA-PEG in A1(OH)3 stimulated preferentially helper T cells, whereas injection of mice with OA-PEG in the absence of adjuvant elicited predominantly suppressor T cells. The unresponsive state of mice which had been treated 21 days earlier with OA-PEG could not be broken by the transfer of normal spleen cells and an additional sensitizing dose of DNP3-OA. Transfer of spleen cells from tolerized animals to normal mice dampened the capacity of the latter to mount both anti-DNP and anti-OA IgE responses; however, the suppressive effect of these cells was eliminated by treatment of the normal recipients with cyclophosphamide, which is a procedure known to inactive suppressor T cells, and hence it may be concluded that this effect was not due to the carryover of the tolerogen with the transferred cells. All these results provide strong support for the conclusion that the suppressor cells induced by the treatment of mice with OA-PEG and OA-mPEG conjugates belonged to a T cell subpopulation, and that the B cells of these mice were devoid of suppressive activity.

Allergens↗
PubMed1998

Effect of PEG-recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) on growth and differentiation of the HEL cell line.

BACKGROUND AND OBJECTIVE: Thrombopoietin has been established as the major regulator of megakaryocyte and platelet production. In this study we evaluated the effects of PEG-recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), a pegylated and truncated form of thrombopoietin, on the growth and differentiation of the HEL cell line. As a model system we chose the pluripotent HEL line that acquires multiple markers of the megakaryocyte/platelet phenotype following treatment with phorbol esters, and, more importantly, expresses the receptor for thrombopoietin (Mpl receptor) at its cellular surface. DESIGN AND METHODS: The effect of PEG-rHuMGDF on HEL proliferation/differentiation was evaluated in a liquid culture assay. RESULTS: Peg-rHuMGDF do not increase the proliferative capacity of HEL cell but, in parallel experiments, HEL cells showed a more mature and differentiated pattern after exposure to the cytokine. Our results show that PEG-rHuMGDF, at the optimal doses of 100-150 ng/mL, is able to induce: 1) morphological changes with the formation of cytoplasmic protrusions; 2) increased ploidy as demonstrated by cytofluorimetric analysis; 3) increased expression of megakaryocyte markers, including glycoprotein IIb-IIIa and the platelet-specific alloantigen (PIA1). INTERPRETATION AND CONCLUSIONS: These findings show that HEL cells represent a useful model to investigate the differentiative properties of thrombopoietin in the megakaryocyte compartment.

Cell Differentiation↗
PubMed2005

Whole blood coagulation on protein adsorption-resistant PEG and peptide functionalised PEG-coated titanium surfaces.

The aim of this study was to investigate whole blood coagulation on low blood plasma protein adsorbing surfaces. For this purpose, the polycationic graft copolymer poly(L-lysine)-g-poly(ethylene glycol) (PLL-g-PEG), PLL-g-PEG grafted with a cell adhesive peptide containing the amino acid sequence -Arg-Gly-Asp- (RGD), and PLL-g-PEG with a control peptide -Arg-Asp-Gly- (RDG) were adsorbed onto titanium (oxide), forming stable monomolecular adlayers through electrostatic attraction. Free oscillation rheometry and complementary techniques were used to measure the coagulation time (CT) and other interactions of the surfaces with native whole blood, recalcified platelet-rich plasma (PRP), and recalcified citrated platelet-free plasma (PFP). The results show that the uncoated titanium surfaces (reference) activated platelets and quickly triggered the coagulation cascade via the intrinsic pathway, whereas the PLL-g-PEG surfaces displayed a prolonged CT, approximately 2-3 times longer compared to uncoated titanium. We hypothesise that blood coagulates outside the vascular system independent of low protein adsorption to or activation by surfaces, due to the absence of an active down-regulation of procoagulative processes by the vascular endothelium.

Blood Coagulation↗
PubMed2000

Drug release from biodegradable injectable thermosensitive hydrogel of PEG-PLGA-PEG triblock copolymers.

An aqueous solution of newly developed low-molecular-weight PEG-PLGA-PEG triblock copolymers with a specific composition is a free flowing sol at room temperature but becomes a gel at body temperature. Two model drugs, ketoprofen and spironolatone, which have different hydrophobicities, were released from the PEG-PLGA-PEG triblock copolymer hydrogel formed in situ by injecting the solutions into a 37 degrees C aqueous environment. Ketoprofen (a model hydrophilic drug) was released over 2 weeks with a first-order release profile, while spironolactone (a model hydrophobic drug) was released over 2 months with an S-shaped release profile. The release profiles were simulated by models considering degradation and diffusion, and were better described by a model assuming a core-shell structure of the gel.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMedDate not supplied

Caprolactonic poloxamer analog: PEG-PCL-PEG.

The aqueous solution of poly(ethylene glycol)-poly(caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG) triblock copolymers (> 15. wt. %) undergoing "clear sol-gel-turbid sol" transition as the temperature increases from 20 to 60 degrees C has been developed. Light scattering and 13C NMR study suggested that the transition mechanisms are the micellar aggregation for the clear sol to gel transition (lower transition), whereas the increase in PCL molecular motion for gel to turbid sol transition (upper transition). In contrast to the previous thermogelling biodegradable polymers with a sticky paste morphology, the powder form of the PEG-PCL-PEG triblock copolymers makes it easy to handle and allows fast dissolution in water. Therefore, the lyophilization into a powder form followed by facile reconstitution was possible. This system is believed to be promising for drug delivery, cell therapy, and tissue engineering.

Biocompatible Materials↗