Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “PEG”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 217 records · Page 12Linked to original sources
PubMed1999

Emulsion type new vehicle for soft gelatin capsule available for preclinical and clinical trials: effects of PEG 6000 and PVP K30 on physicochemical stability of new vehicle.

To prevent temperature-dependent gel-sol transformation of an o/w emulsion type new vehicle system for a soft gelatin capsule, which may be available for both preclinical and clinical trials, the basic new vehicle formulation (PEG 400:purified water:medium chain triglyceride:polyoxyethylene (20) cetylether = 77:10:10:3) was modified by partially (1, 2 or 3%) replacing PEG 400 with PEG 6000 or PVP K30. When 2 or 3% of PEG 400 was replaced with PEG 6000, temperature-dependent gel-sol transformation was prevented at temperatures below 40 degrees C, and the vehicle appeared to be stable during 8 weeks of storage at 4 to 40 degrees C; the particle size distribution remained unchanged. When 1% of PEG 400 was replaced with PEG 6000, gel-sol transformation was not prevented, though phase separation was not observed at sol state, and the particle size distribution was shifted to be in a larger particle size range after 2 weeks of storage. When PEG 400 was partially (1, 2 or 3%) replaced with PVP K30, temperature-dependent gel-sol transformation was not prevented and, after 2 weeks of storage at 40 degrees C, the particle size distributions of the vehicles were shifted to be in a larger particle size range and the vehicles were separated into two layers. These results suggested that a small amount of PEG 6000 plays an important role in preventing temperature-dependent gel-sol transformation of our developed vehicle system.

Capsules↗
PubMed2000

99mTc-PEG liposomes for the scintigraphic detection of infection and inflammation: clinical evaluation.

UNLABELLED: Polyethyleneglycol (PEG) liposomes have been shown to be excellent vehicles for scintigraphic imaging of infection and inflammation in various experimental models. In this article we report on a series of patients with possible infectious and inflammatory disease in whom the performance of 99mTc-PEG liposomes was evaluated. The results of 99mTc-PEG liposome scintigraphy were directly compared with those of 111In-immunoglobulin G (IgG) scintigraphy. METHODS: Thirty-five patients (22 men, 13 women; mean age, 51 y; range, 20-76 y), suspected of having infectious or inflammatory disease, received 740 MBq 99mTc-PEG liposomes intravenously. Imaging was performed at 4 and 24 h after injection. Patients received 75 MBq 111In-IgG 24 h after administration of the liposomes. The scintigraphic results were compared and verified by culture, biopsy, surgery, and follow-up of at least 6 mo. RESULTS: Of the 16 proven infections and inflammations, 15 were detected by 99mTc-PEG liposome scintigraphy: soft-tissue infection (n = 3), septic arthritis (n = 3), autoimmune polyarthritis (n = 2), infected hip prosthesis (n = 1), infected osteosynthesis (n = 1), spondylodiscitis (n = 1), infected aortic prosthesis (n = 1), colitis (n = 1), abdominal abscess (n = 1), and pneumonia (n = 1). 99mTc-PEG liposome and 111In-IgG scintigraphy both missed 1 case of endocarditis. In addition, an 111In-IgG scan of a patient with mild soft-tissue infection was false-negative. Concordantly false-positive scans were recorded from 2 patients, both with uninfected pseudarthrosis and focal signs of sterile inflammation. During liposomal administration, 1 patient experienced flushing and chest tightness, which rapidly disappeared after lowering the infusion rate. No other adverse events were observed. CONCLUSION: This clinical evaluation of 99mTc-PEG liposomes shows that focal infection and inflammation can be adequately imaged with this new agent. The performance of 99mTc-PEG liposomes is at least as effective as that of 111In-IgG. With the simple and safe preparation and the physical and logistic advantages of a 99mTc label, 99mTc-PEG liposomes could be an attractive agent for infection or inflammation imaging.

Female↗
PubMedDate not supplied

Synergistic antiviral effect of PEG-asparaginase (ONCASPAR), with protease inhibitor alone and in combination with RT inhibitors against HIV-1 infected T-cells: a model of HIV-1-induced T-cell lymphoma.

We evaluated the anti-HIV-1 activity of the T-cell-specific protein inhibitor PEG-asparaginase (PEG-ASNase) in human HIV-1-infected T-cells. We further examined the drug synergism between PEG-ASNase and the protease inhibitor Saquinavir (SAQ), both alone and in combination with nucleoside analog reverse transcriptase inhibitors (NRTI). Our drug synergism studies served as a model for an HIV-induced T-cell lymphoma. Phytohemagglutinin [PHA(+)] stimulated T-cells were infected with HIV-1 and then treated with one or more drugs 90 minutes from the viral exposure. To measure inhibition of viral replication, we examined HIV-1 RT and HIV-1 RNA in the supernatant and intracellularly on day 7 post-infection and drug treatment. Last, we examined the effect of administering drugs immediately after HIV-1 infection of T-cells to simulate treatment after an accidental exposure to the virus. PEG-ASNase, even when used alone, has anti-HIV-1 activity in PHA(+)-stimulated T-cells due to inhibition of protein synthesis. When the drug was used with SAQ, the combination was synergistic in inhibiting HIV-1 RT and RNA in the supernatant and intracellularly by 2.5 log10 in comparison with controls. PEG-ASNase and SAQ were even more effective in inhibiting HIV-1 replication when combined with the NRTI inhibitors azidothymidine (AZT) and (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC, lamivudine). The addition of ribonucleotide reductase inhibitor, 2-methyl-1H-isoindole-1,3-dione (MISID), further potentiated the antiviral effect of the regimen. HIV-1 RT and RNA analyses showed that the administration of the PEG-ASNase + SAQ drug combination immediately following exposure to HIV-1 completely inhibited the infection of T-cells in our in vitro T-cell model. From these results we conclude that PEG-ASNase is a valuable T-cell-specific protein inhibitor against HIV-1 infection, when used singly or in combination with a protease inhibitor, an RT inhibitor and an RR inhibitor. Since PEG-ASNase is a drug of choice for the treatment of T-cell lymphomas, a combination regimen containing PEG-ASNase could be very effective in the treatment of HIV-1-induced T-cell lymphoma and possibly AIDS. Future studies are needed in HIV-infected and/or HIV-induced T-cell lymphoma patients to investigate these findings.

Antineoplastic Agents↗
PubMed1995

Analysis of the routine use of polyethylene glycol (PEG) as an enhancement medium.

This study compared the performance of polyethylene glycol (PEG) and low-ionic saline solutions (LISS) as enhancement media for routine use in a large transfusion service. A PEG additive solution (PEG plus LISS) was compared to a LISS additive (LISS plus polymers) and to an albumin-indirect antiglobulin test (A-IAT). Fifty serum samples containing clinically significant alloantibodies and fifty samples without alloantibodies were tested. Following an acute hemolytic transfusion reaction (HTR) involving an anti-K that was not detected with LISS but was retrospectively found to be reactive with PEG, an additional 151 samples received for antibody screening were prospectively evaluated in parallel using PEG and LISS. PEG detected all clinically significant antibodies in the 50 previously tested samples, with mean reactivity scores greater than LISS or A-IAT. In the prospective study, PEG detected 35 clinically significant antibodies and 10 clinically insignificant antibodies, while LISS detected only 15 clinically significant antibodies and 33 clinically insignificant antibodies. PEG appears to increase detection of significant antibodies while decreasing detection of insignificant antibodies. PEG was therefore substituted for LISS as an enhancement medium and has been in routine use for 12 months, with no reported acute or anamnestic HTRs in 6,353 transfusions.

Journal Article↗
PubMed1997

Pharmacodynamic and safety results of PEG-Hirudin in healthy volunteers.

PEG-Hirudin, a chemically defined conjugate of recombinant hirudin and two molecules of polyethylene glycol (PEG)-5000 is a highly selective direct thrombin inhibitor with a significantly longer duration of action than non-conjugated recombinant hirudin permitting once daily subcutaneous administration. A series of placebo-controlled, randomized, Phase I clinical trials were conducted in 75 healthy volunteers to investigate the anticoagulant effects, safety and pharmacodynamics of PEG-Hirudin when administered intravenously as a bolus injection, infusion, and subcutaneously. After single i.v. injections of various doses of PEG-Hirudin (0.03-0.3 mg/kg) dose-dependent increases in anti-IIa activity and APTT were observed. Four hours after injection of 0.3 mg/kg, mean plasma concentration expressed in terms of anti-IIa activity was still 0.89 micrograms/ml, corresponding to a 1.8-fold prolongation of APTT. Continuous intravenous infusions of 0.01 and 0.02 mg/kg/h PEG-Hirudin resulted in maximum anti-IIa activities of 0.42 micrograms/ml and 0.77 micrograms/ml, respectively, at the end of a six-hour infusion period without having reached steady state at this time. After termination of the infusion, anticoagulant activity displayed an immediate exponential decrease. The anticoagulant activities of single subcutaneous doses of 0.05 to 0.6 mg/kg were studied in a further series of investigations and slow increases and prolonged durations of anti-IIa activity and APTT prolongation were found. Repeated, once daily subcutaneous administrations of 0.2 to 0.4 mg/kg for five days resulted in dose-dependent prolongations of APTT and increases in anti-IIa activity without completely reaching steady state conditions. In a further study, 0.3 mg/kg of PEG-Hirudin was given as an i.v. bolus injection followed by three repeated single daily s.c. injections. In this trial, the APTT was shorter than expected from previous studies; therefore, a direct comparison of various APTT reagents was made in the intravenous infusion trial. Of the APTT reagents tested, BioMérieux Silimat and IL-ellagic acid proved to be the most sensitive to PEG-Hirudin. The hirudin derivative PEG-Hirudin was tolerated very well without immuno-allergic side effects. In view of the significantly prolonged anticoagulant efficacy in comparison to non-conjugated r-hirudin, PEG-Hirudin is a promising compound especially for repeated once daily subcutaneous administration.

Adult↗
PubMed1997

Characterization of polyethyleneglycol-stabilized, manganese-substituted hydroxylapatite (MnHA-PEG). A potential MR blood pool agent.

PURPOSE: To optimize the performance (or efficacy) of a potential particulate blood pool agent for MR angiography by varying the particle size. The colloidal system under investigation was polyethylene glycol-stabilized manganese-substituted hydroxylapatite (MnHA-PEG). MATERIAL AND METHODS: Several MnHA-PEG formulations were prepared using various length PEGs (MW = 140-2000). Products were characterized in vitro by dynamic light scattering (DLLS), field flow fractionation (FFF), and relaxometry; and in vivo by blood clearance kinetics in rabbits, and by analytical electron microscopy (EM). RESULTS: The particle size distribution (PSD) consisted only of small particles (approximately 10-nm diameter) when approximately 40 mo1% PEG was used. At approximately 20 mo1% PEG, larger particles (approximately 100 nm), which are aggregates of the small ones, were also present. The water proton relaxation profiles of the particles in plasma were different from that of the free Mn2+. In plasma, the large aggregates were broken down into the smaller particles which were stable. Although the small particles were efficient relaxation enhancing agents, they were cleared from the blood approximately 3 times faster than the approximately 100-nm diameter aggregates, probably as a consequence of leakage into the extravascular space. Variation of PEG size had no effect on particle characteristics or on blood clearance. Analytical EM of rabbit liver specimens indicated some retention of Mn in mitochondria at the time point when Mn content of other subcellular structures returned to baseline. CONCLUSION: DLLS and FFF are complementary techniques for sizing particulate MR contrast media. Small MnHA particles are more efficient T1-shortening agents than large ones but they are prone to leakage from the vascular space. Within the MW range explored, the length of PEG molecule had no effect on blood clearance of the MnHA particles. Larger aggregates of MnHA-PEG break down into stable small particles in plasma. Mn clears from the subcellular structures within hepatocytes within 60 min after i.v. MnHA-PEG administration except from the mitochondria in which it appears to accumulate.

Animals↗
PubMedDate not supplied

PEG-hemoglobin: effects on tumor oxygenation and response to chemotherapy.

BACKGROUND: The study was undertaken to determine whether administration of PEG-hemoglobin could improve the oxygenation of a solid tumor prior to and after chemotherapy and to determine whether administration of PEG-hemoglobin could enhance the efficacy of chemotherapy in a solid tumor. MATERIALS AND METHODS: Rats bearing the 13762 mammary carcinoma were untreated or treated with cyclophosphamide, melphalan, taxol or cisplatin. Tumor oxygenation was determined 24 hrs. after chemotherapy with or without administration of PEG-hemoglobin while the animals breathed air, 28% oxygen or carbogen. Mice bearing the EMT-6 murine mammary carcinoma were treated with single doses of chemotherapy with or without co-administration of PEG-hemoglobin and tumor cell and bone marrow CFU-GM survivals were determined. Other EMT-6 tumor-bearing mice were treated with multiple doses of chemotherapy with or without PEG-hemoglobin and tumor growth delay was determined. RESULTS: Administration of PEG-hemoglobin was effective in decreasing hypoxia in the 13762 mammary carcinoma both prior to and after chemotherapy administration. Increasing the level of inspired oxygen further decreased the tumor hypoxia most effectively when the level of tumor cell killing by the chemotherapy was high. Administration of PEG-hemoglobin along with air breathing to mice bearing the EMT-6 tumor increased tumor cell killing by cyclophosphamide, BCNU, adriamycin and taxol without increasing toxicity to the bone marrow CFU-GM. PEG-Hemoglobin given prior to each dose of chemotherapy increased the tumor growth delay produced by cyclophosphamide, adriamycin, 5-fluorouracil, BCNU and taxol in a manner with increased level of inspired oxygen and with a concomitant decreased in lung metastases. CONCLUSIONS: Further investigation of PEG-hemoglobin as an oxygen delivery agent in oncology is warranted.

Animals↗
PubMed2005

Complement inhibition reduces material-induced leukocyte activation with PEG modified polystyrene beads (Tentagel) but not polystyrene beads.

With isolated leukocytes, inhibiting complement reduced material-induced leukocyte activation (CD11b) with polyethylene glycol modified polystyrene beads (PS-PEG), but not with polystyrene beads (PS). The PS-PEG beads (TentaGel) were complement activating as measured by SC5b-9 levels consistent with the sensitivity of these beads to leukocyte inhibition with complement inhibitors. Following contact with PS and PS-PEG beads, isolated leukocytes in plasma and in the absence in platelets were found to significantly upregulate CD11b, while TF expression and exposure of phosphatidylserine remained at background levels. Complement inhibition by means of sCR1 partially reduced CD11b upregulation on PS-PEG beads, but had no effect with PS beads. Pyridoxal-5-phosphate (P5P) was able to significantly reduce both CD11b upregulation and exposure of phosphatidylserine with PS-PEG beads, although it did not appear to inhibit SC5b-9 production. Pentamidine and NAAGA inhibited complement and were effective in reducing CD11b upregulation with both PS and PS-PEG. However, they also had an inhibitory effect on leukocyte signaling mechanisms, precluding their utility for further study in this context. Leukocyte adhesion occurred to similar extents on both PS and PS-PEG beads. While sCR1 and P5P blocked adhesion and activation (for adherent leukocytes) on PS-PEG beads, they had no effect on leukocytes adherent to PS beads. The role of complement in leukocyte activation and adhesion was found to be material-dependent. Thus, leukocyte-material compatibility may be resolved by complement inhibition in some but not all cases. For these other materials (example here was PS), other mechanisms, such as fibrinogen adsorption and direct leukocyte release, may need exploitation to minimize leukocyte activation and adhesion.

Biocompatible Materials↗
PubMed2006

Folic acid-PEG conjugated superparamagnetic nanoparticles for targeted cellular uptake and detection by MRI.

We report the development and in vitro study of a nanoconjugate serving as a targeted magnetic resonance imaging (MRI) contrast enhancement agent for detection of cancer cells overexpressing the folate receptor. The nanoconjugate was synthesized by coating superparamagnetic iron oxide nanoparticles with covalently bound bifunctional poly(ethylene glycol) (PEG), followed by conjugation with folic acid (FA). The specificity of the nanoconjugate targeting cancerous cells was demonstrated by comparative intracellular uptake of the nanoconjugate and PEG-/dextran-coated nanoparticles by human adenocarcinoma HeLa cells. Preferential targeting to cancerous cells was studied by comparing the uptake of the nanoconjugate by HeLa cells and by non-FR expressing osteosarcoma MG-63 cells. Uptake of the nanoconjugate by HeLa cells after 4 h incubation was found to be a 12-fold higher than that of PEG- or dextran-coated nanoparticles as quantified by inductively coupled plasma spectroscopy. A significant negative contrast enhancement was observed with magnetic resonance (MR) phantom imaging for HeLa cells over MG-63 cells, when both were cultured with the nanoconjugate. Specificity of the nanoconjugate for folate receptors was also verified with a competitive inhibition assay, in which HeLa cells were incubated with both NP-PEG-FA and free FA. The bifunctional PEG used has amide linkages within the PEG chains that can form interchain hydrogen bonding, leading to improved stability of the PEG coating. Self-assembled PEG can be controlled at the molecular level and are suitable for nanoscale coatings.

Drug Delivery Systems↗
PubMed2005

Progression elevated gene-3 (PEG-3) induces pleiotropic effects on tumor progression: modulation of genomic stability and invasion.

Progression elevated gene-3 (PEG-3) is a novel rodent gene, identified and cloned by subtraction hybridization, that associates with transformation progression in virus- and oncogene-transformed rat embryo (RE) cells. Previous reports document that ectopic expression of PEG-3 in rodent or human tumor cells produces an aggressive transformed/tumorigenic phenotype. Moreover, PEG-3 expression in rodent tumor cells correlates directly with genomic instability, as indicated by chromosomal alterations and gene amplification, and it promotes angiogenesis. The present studies were designed to further elucidate the functional significance and role of PEG-3 in cancer progression with a specific focus on genomic instability and cancer invasion. Genomic instability was assessed by micronucleus assays and staining of centrosomes to define centrosomal amplification. Immunocytochemical observations revealed that overexpression of PEG-3 in transformed rodent cells induced a loss of chromosomes as established by the appearance of micronuclei and staining of the centrosomes with gamma-tubulin antibody, thereby confirming centrosome amplification. Overexpression of PEG-3 modulated the expression of several genes involved in centrosomal duplication, such as p21CIP1/WAF1/MDA-6, nucleophosmin (NPM), and aurora-A kinase. In vitro invasion of transformed rodent cells was augmented by PEG-3, which correlated with an increase in the transcription and activity of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9), which play important roles in local invasion during cancer progression. These findings demonstrate that PEG-3 plays a central role in augmenting tumor progression by modulating several critical parameters of the carcinogenic process, such as genomic stability and local tumor cell invasion.

Animals↗
PubMed2004

Improvement of retroviral vectors by coating with poly(ethylene glycol)-poly(L-lysine) block copolymer (PEG-PLL).

BACKGROUND: Although some cationic reagents, such as polybrene, improve gene transduction in vitro, their use in vivo is prohibited due to their toxicity to the exposed cells. This paper demonstrates that a new cationic reagent, poly(ethylene glycol)-poly(L-lysine) block copolymer (PEG-PLL), improves gene transduction with retroviral vectors without increasing cell toxicity. METHODS: A retroviral vector derived from the Moloney leukemia virus, containing the lacZ gene, was modified with PEG-PLL prior to transduction into NIH3T3, Lewis lung carcinoma, and primary cultured mouse brain cells. LacZ transduction efficacy was evaluated by counting the number of X-Gal-positive cells. RESULTS: We have demonstrated that PEG-PLL is able to stably modify the viral particle surface due to the affinity of the PEG moiety to the biomembrane, and neutralizes negative charges by the cationic nature of the poly-lysine residue. Thus, PEG-PLL increased the gene transduction efficiency and minimized cell toxicity because free PEG-PLL was removable by centrifugation. We have shown that PEG-PLL increased the viral gene transduction efficiency 3- to 7-fold with NIH3T3 or Lewis lung carcinoma cell lines without increasing cytotoxicity. It improved retroviral gene transduction efficacy even against labile cells, such as primary cultured brain cells. CONCLUSIONS: PEG-PLL is a novel reagent that improves retroviral gene transduction efficacy without increasing cytotoxicity.

3T3 Cells↗
PubMed1999

Combination benefit of PEGylated soluble tumor necrosis factor receptor type I (PEG sTNF-RI) and dexamethasone or indomethacin in adjuvant arthritic rats.

OBJECTIVE: To determine the potential combination benefit receptor of treatment with PEGylated soluble tumor necrosis factor type I (PEG sTNF-RI) and dexamethasone (dex) or indomethacin (indo) in adjuvant arthritic rats. SUBJECTS: 160 male Lewis Rats. TREATMENT: PEG sTNF-RI, dex, indo. METHODS: Rats with adjuvant arthritis were given daily oral dex (0.025 or 0.006 mg/kg) or indo (0.5 or 0.25 mg/kg) day 9-14, alone or in combination with PEG sTNF-RI (sc on days 9, 11, and 13 of arthritis). Efficacy was monitored by volume measurement of ankle joints, final paw weights and histologic evaluation with particular emphasis on bone lesions. RESULTS: Treatment with 1 mg/kg PEG sTNF-RI alone resulted in 27% inhibition of final paw weights, dex alone (0.025 mg/kg) gave 25% inhibition and the combination resulted in 58% inhibition. Histologic evaluation of ankle joints demonstrated 48% inhibition of bone resorption with PEG sTNF-RI alone, 55% inhibition with dex alone and the combination treatment inhibited bone resorption by 100%. Inactive doses of PEG sTNF-RI (0.3 mg/kg) and dex (0.006 mg/kg) when combined resulted in 39% inhibition of paw swelling (AUC) and 39% inhibition of bone resorption. Combination treatment with indomethacin resulted in slight additive effects on inflammation parameters but no additive effects on bone resorption. CONCLUSION: Combination therapy with PEG sTNF-RI and dexamethasone results in additive or synergistic effects depending on the dose. Combination therapy with indomethacin resulted in slight additive effects on paw swelling parameters, but no additive benefit on bone resorption. Data from these studies support the clinical investigation of the use of combination therapy of PEG sTNF-RI and dex or other corticosteroids in rheumatoid arthritis patients.

Animals↗
PubMed1995

Effects of polyethylene glycol 400 (PEG 400) following 13 weeks of gavage treatment in Fischer-344 rats.

Fischer-344 rats (10/group/sex) were administered polyethylene glycol 400 (PEG 400) by gavage at 1.0, 2.5 or 5.0 ml/kg (1.1, 2.8 and 5.6 g/kg, respectively) body weight/day 5 days/wk for 13 wk. Animals in the control group received water by gavage (5.0 ml/kg body weight/treatment day). An additional 10 rats/sex/group were assigned to the control and high-dose groups for a 6-wk recovery period. Evaluation of potential renal toxicity was identified as a primary objective. There was no mortality or changes in haematology or clinical chemistry measurements attributed to PEG 400 toxicity. Loose faeces in the mid- and/or high-dose group of both sexes were attributed to bulk cathartic effects of PEG 400. Slight decreases in food consumption and body weights in the mid- and/or high-dose group of male rats and female rats were attributed to the physical presence of PEG 400 in the intestinal tract. However, a direct effect of PEG 400 on the intestinal tract was not ruled out. Increased water consumption was attributed to a possible increase in serum osmolality due to the absorption of the PEG 400 or a reflection of the water dosing received by the control animals. Increased urinary concentration and decreased urinary pH were at least partially attributed to absorption, possible metabolism, and urinary excretion of PEG 400. Small increases in absolute and/or relative kidney weights observed in many dose groups, were attributed to the osmotic effect of the test substance and/or metabolites in the urine. The significance of a slight increase in relative kidney weights in female rats following the recovery period was unknown. Although no microscopic changes were observed in the kidneys or urinary bladder, a slight, reversible renal toxicity may have resulted in male rats treated by gavage with 2.5 ml/kg/day and rats of both sexes treated by gavage with 5.0 ml PEG 400 kg/day. This was based on the increased concentration of protein and bilirubin, urinary vascular cell findings and N-acetyl-beta-D-glucosaminidase activity.

Acetylglucosaminidase↗
PubMed2004

PEG-Ara-C conjugates for controlled release.

The antitumour agent 1-beta-D arabinofuranosilcytosyne (Ara-C) was covalently linked to poly(ethylene glycol) (PEG) in order to improve the in vivo stability and blood residence time. Eight PEG conjugates were synthesised, with linear or branched PEG of 5000, 10000 and 20000 Da molecular weight through an amino acid spacer. Starting from mPEG-OH or HO-PEG-OH, conjugation was carried out to the one or two available hydroxyl groups at the polymer's extreme. Furthermore, to increase the drug loading of the polymer, the hydroxyl functions of PEG were functionalised with a bicarboxylic amino acid yielding a tetrafunctional derivative and, by recursive conjugation with the same bicarboxylic amino acid, products with four or eight Ara-C molecules for each PEG chain were prepared. A computer graphic investigation demonstrated that aminoadipic acid was a suitable bicarboxylic amino acid to overcome the steric hindrance between the vicinal Ara-C molecules in the dendrimeric structure. In this paper we report the optimised conditions for synthesis and purification of PEG-Ara-C products with a low amount of remaining free drug, studies toward the hydrolysis of PEG-Ara-C and the Ara-C deamination by cytidine deaminase, pharmacokinetics in mice and cytotoxicity towards HeLa human cells were also investigated. Increased stability towards degradation of the conjugated Ara-C products, in particular for the highly loaded ones, improved blood residence time in mice and a reduced cytotoxicity with respect to the free Ara-C form was demonstrated.

Animals↗
PubMed2005

Synthesis of a novel PEG-block-poly(aspartic acid-stat-phenylalanine) copolymer shows potential for formation of a micellar drug carrier.

A novel functionalised copolymer with three polymeric components, poly(ethylene glycol)-block-poly(aspartic acid-stat-phenylalanine), PEG-P(asp-phe), was synthesised and investigated for its potential to form micelles via ionic interactions with a model water-soluble drug, diminazene aceturate. Drug-free solutions of structurally related PEG-P(asp-phe) 5:6:4 and PEG-P(asp-phe) 5:4:6 copolymers indicated polymeric aggregation into micellar-type constructs. The size of PEG-P(asp-phe) 5:6:4 micelles was found to be pH and drug content-dependent. The drug-loaded systems existed as discreet units and were fairly uniform in size and shape. More drug could be included in the PEG-P(asp-phe) 5:6:4 micelles as compared to if only interaction with carboxyl groups from aspartic acid units was responsible for micelle formation, indicating the augmentative role of phenylalanine moieties in drug-incorporation. The slower in vitro drug release from PEG-P(asp-phe) 5:6:4 micelles as compared to PEG-Pasp (AB) micelles indicated the role of the phenylalanine moiety in controlling drug release. This study, therefore, confirmed the potential of a novel tri-component copolymer structure, PEG-P(asp-phe), for the formation of polyionic micelles for drug delivery.

Chemical Phenomena↗
PubMed2005

Stability of bovine serum albumin complexed with PEG-poly(L-histidine) diblock copolymer in PLGA microspheres.

The aim of this study was to examine the stability of bovine serum albumin (BSA) in poly(DL-lactic acid-co-glycolic acid) (PLGA) microspheres upon addition of a new excipient, poly(ethylene glycol)-poly(L-histidine) diblock copolymer (PEG-PH). Poly(L-histidine) component can form an ionic complex with BSA under acidic conditions within a narrow pH range. To optimize the ionic complexation conditions for BSA with PEG-PH, the resulting complex sizes were monitored using the Zetasizer. PLGA microspheres containing BSA as a model protein were prepared by w/o/w double emulsion method. BSA stability in aqueous solutions and after release from PLGA microspheres was determined using circular dichroism (CD) spectroscopy for secondary structure analyses and fluorescence measurements for tertiary structure analyses. The release profile of BSA from the microspheres was monitored using UV spectrophotometry. The rate of PLGA degradation was monitored by gel permeation chromatography. The pH profile within microspheres was further evaluated by confocal microscopy using a pH-sensitive dye. Approximately 19 PEG-PH molecules and one BSA molecule coalesced to form an ionic complex around a pH range of 5.0-6.0. Plain BSA/PLGA and BSA/PEG-PH/PLGA microspheres had a mean size of 27-35 microm. PLGA microspheres with a BSA loading efficiency >80% were prepared using the double emulsion method. PEG-PH significantly improved the stability of BSA both in aqueous solutions and in PLGA microspheres. The release profiles of BSA from different formulations of PLGA microspheres were significantly different. PEG-PH effectively buffered the local acidity inside the microspheres and improved BSA release kinetics by reducing initial burst release and extending continuous release over a period of time, when encapsulated as an ionic complex. PLGA degradation rate was found to be delayed by PEG-PH. There was clear evidence that PEG-PH played multiple roles when complexed with BSA and incorporated into PLGA microspheres. PEG-PH is an effective excipient for preserving the structural stability of BSA in aqueous solution and BSA/PLGA microspheres formulation.

Drug Stability↗
PubMed2006

Anti-angiogenic inhibition of tumor growth by systemic delivery of PEI-g-PEG-RGD/pCMV-sFlt-1 complexes in tumor-bearing mice.

Vascular endothelial growth factor (VEGF) is an endogenous mediator of tumor angiogenesis. Blocking associations of the VEGF with its corresponding receptors (Flt-1, KDR/flk-1) have become critical for anti-tumor angiogenesis therapy. Previously, we synthesized PEI-g-PEG-RGD conjugate and evaluated as an angiogenic endothelial polymeric gene carrier. In this study, PEI-g-PEG-RGD/pCMV-sFlt-1 complexes are evaluated in terms of tumor growth inhibition in vivo. Complexes were repeatedly injected systemically via tail vein into subcutaneous tumor-bearing mice. As a result, tumor growth was inhibited in the PEI-g-PEG-RGD/pCMV-sFlt-1 injected group. However, this effect was not identified in PEI-g-PEG/pCMV-sFlt-1 or PEI-g-PEG-RGD/pCMV-GFP control groups. Moreover, the survival rate increased in the PEI-g-PEG-RGD/pCMV-sFlt-1 group compared with the controls group. These results suggest that delivery of pCMV-sFlt-1 using PEG-g-PEG-RGD may be effective for anti-angiogenic gene therapy.

Angiogenesis Inhibitors↗
PubMed2005

Laccase-catalyzed removal of bisphenol-A from water: protective effect of PEG on enzyme activity.

The feasibility of using the enzyme laccase to treat synthetic wastewater containing bisphenol-A (BPA) was examined. Optimization of pH, laccase concentration, polyethylene glycol (PEG) as an additive for >95% conversion and precipitation of BPA over 3 h of reaction period was determined through colorimetric assay and HPLC. PEG reduced enzyme inactivation, allowing a 5.2-fold reduction in the amount of laccase required for >95% removal of BPA in the range of 0.1-1 mM over 3 h. The fate of PEG after the reaction was also monitored. Linear relationships were found between the concentration of BPA (0.1-1 mM) and the optimum concentrations of laccase and PEG. Little PEG remained in the solution when up to 75 mg/L of PEG was used to treat 0.5 mM BPA. Beyond this level, PEG concentration increased linearly in the supernatant. It is inferred that an interaction between PEG and the polymeric products resulted in the protection of laccase.

Benzhydryl Compounds↗