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PubMed2005

Ultrasound enhances in vivo tumor expression of plasmid DNA by PEG-introduced cationized dextran.

This study is an investigation to experimentally confirm whether or not ultrasound (US) irradiation is effective in enhancing the in vivo gene expression of plasmid DNA in tumor. Dextran was cationized by introducing spermine to the hydroxyl groups to allow to polyionically complex with a plasmid DNA. The cationized dextran prepared was additionally modified with poly(ethylene glycol) (PEG) molecules which have an active ester and methoxy groups at each terminal, to obtain cationized dextran with different percentages of PEG introduced. Various cationized dextrans with or without PEG introduction were mixed with a plasmid DNA of LacZ to form cationized dextran-plasmid DNA complexes. Electrophoretical examination revealed that the plasmid DNA was complexed both with the cationized dextran and PEG-introduced cationized dextran, irrespective of the PEG introduction percentage, although the higher N/P ratio was needed for plasmid DNA complexation with the latter. By complexation with the cationized dextran, the zeta potential of plasmid DNA was changed to be positive. The charge of PEG-introduced cationized dextran-plasmid DNA complexes became close to 0 mV as their percentage of PEG introduced increased, although the molecular size was about 250 nm, irrespective of the PEG introduction. When cationized dextran-plasmid DNA complexes with or without PEG introduction were intravenously injected to mice carrying a subcutaneous Meth-AR-1 fibrosarcoma mass and the subsequent US irradiation to the tumor mass percutaneously, the PEG-introduced cationized dextran-plasmid DNA complex plus US irradiation enhanced the tumor level of gene expression to a significantly high extent compared with the cationized dextran-plasmid DNA complex and free plasmid DNA with or without US irradiation. The enhanced level depended on the time period and timing of US irradiation. Fluorescent microscopic studies revealed that the localization of plasmid DNA and the gene expression were observed in the tumor tissue injected with the PEG-introduced cationized dextran-plasmid DNA complex plus the subsequent US irradiation. We conclude that complexation with the PEG-introduced cationized dextran combined with US irradiation is a promising way to target the plasmid DNA to the tumor for gene expression.

Animals↗

PubMedDate not supplied

PEG-doxorubicin conjugates: influence of polymer structure on drug release, in vitro cytotoxicity, biodistribution, and antitumor activity.

Polymer-drug conjugates (polymer therapeutics) are finding increasing use as novel anticancer agents. Here a series of poly(ethylene glycol) PEG-doxorubicin (Dox) conjugates were synthesized using polymers of linear or branched architecture (molecular weight 5000-20000 g/mol) and with different peptidyl linkers (GFLG, GLFG, GLG, GGRR, and RGLG). The resultant conjugates had a drug loading of 2.7-8.0 wt % Dox and contained <2.0% free drug (% total drug). All conjugates containing a GFLG linker showed approximately 30% release of Dox at 5 h irrespective of PEG molecular weight or architecture. The GLFG linker was degraded more quickly (approximately 57% Dox release at 5 h), and the other linkers more slowly (<16% release at 5 h), by lysosomal enzymes in vitro. In vitro there was no clear relationship between cytotoxicity toward B16F10 cells and the observed Dox release rate. All PEG conjugates were more than 10-fold less toxic (IC50 values > 2 microg/mL) than free Dox (IC50 value = 0.24 microg/mL). Biodistribution in mice bearing sc B16F10 tumors was assessed after administration of PEGs (5000, 10000, or 20000 g/mol) radioiodinated using the Bolton and Hunter reagent or PEG-Dox conjugates by HPLC. The 125I-labeled PEGs showed a clear relationship between Mw and blood clearance and tumor accumulation. The highest Mw PEG had the longest plasma residence time and consequently the greatest tumor targeting. The PEG-Dox conjugates showed a markedly prolonged plasma clearance and greater tumor targeting compared to free Dox, but there was no clear molecular weight-dependence on biodistribution. This was consistent with the observation that the PEG-Dox conjugates formed micelles in aqueous solution comprising 2-20 PEG-Dox molecules depending on polymer Mw and architecture. Although PEG-Dox showed greater tumor targeting than free Dox, PEG conjugation led to significantly lower anthracycline levels in heart. Preliminary experiments to assess antitumor activity against sc B16F10 in vivo showed the PEG5000linear (L)-GFLG-Dox and PEG10000branched (B)-GLFG-Dox (both 5 mg/kg Dox-equiv) to be the most active with T/C values of 146 and 143%, respectively. Free Dox did not show significant activity in this model (T/C = 121%). Dose escalation of PEG5000(L)-GFLG-Dox to 10 mg/kg Dox-equiv prolonged further animal survival (T/C = 161%). Using the Dox-sensitive model ip L1210 (where Dox displayed a T/C = 150% after single ip dose), the PEG5000(L)-GFLG-Dox displayed a maximum T/C of 141% (10 mg/kg Dox-equiv) using a once a day (x3) schedule. Further studies are warranted with PEG5000(L)-GFLG-Dox to determine its spectrum of antitumor activity and also the optimum dosing schedule before clinical testing.

Animals↗

PubMedDate not supplied

Poly(ethylene glycol)-supported enzyme inactivators. Efficient identification of the site of covalent attachment to alpha-chymotrypsin by PEG-TPCK.

A new methodology utilizing an enzyme inactivator covalently attached to poly(ethylene glycol) (PEG) is described in which the PEG affords facile and mild quantification, isolation, and identification of the site of enzyme inactivation. As proof of concept, the known affinity labeling agent for alpha-chymotrypsin, N-tosyl-L-phenylalanine chloromethyl ketone (TPCK), was linked to PEG. The synthesis of the PEG-bound inactivator PEG-TPCK was carried out in good yields using standard solution-phase chemistry. Inactivation of alpha-chymotrypsin with PEG-TPCK was monitored via UV-vis spectroscopy in aqueous conditions, which resulted in less than 3% remaining activity, indicating that 97% of the alpha-chymotrypsin was covalently modified with PEG-TPCK. The MALDI-TOF mass spectrum showed only one new peak that was distinct in shape and corresponded to the mass of PEG-TPCK-alpha-chymotrypsin. Following proteolytic digestion, the PEG-TPCK-peptide was easily discernible from the rest of the digest in a HPLC trace because of its characteristic prolonged retention time and broad polymer shape. MALDI-TOF MS was used to determine the mass of the PEGylated peptide. Without prior removal of the PEG, the amino acid site to which PEG-TPCK covalently bound was determined via Edman sequencing. In comparison to other methods, the PEG-supported inactivator system is significantly cheaper and safer than the synthesis of radiolabeled compounds; furthermore, isolation of the PEGylated peptide is milder and more selective than standard affinity binding columns. Edman sequencing provides an exact determination of the site of inactivator covalent attachment without extensive, tedious LC-MS analysis of a complex peptide mixture. The method described here could be applied to a variety of enzymes as an alternative to current techniques.

Chromatography, High Pressure Liquid↗

PubMedDate not supplied

Tumor cell targeting of transferrin-PEG-TNF-alpha conjugate via a receptor-mediated delivery system: design, synthesis, and biological evaluation.

PEGylation is a procedure of growing interest for enhancing the therapeutic and biotechnological potential of peptides and proteins. Transferrin (Tf) has been proposed to be useful for targeting cancer cells. The aim of this study was to modify PEGylated recombinant human tumor necrosis factor alpha (PEG-TNF-alpha) with Tf to form Tf-PEG-TNF-alpha conjugates, which would maintain the advantages of PEGylation and also achieve the function of active targeting to tumor cells. In PEGylation reactions with 5-, 20-, 40-, and 60-fold molar excess of 3.4 kDa N-hydroxysuccinimide-PEG-maleimide (PT1, PT2, PT3, and PT4, respectively), PEG-TNF-alpha conjugates with different PEG chains were synthesized. A perfusion chromatography technique using a cation-exchange column was introduced to purify PEG-TNF-alpha conjugates. PT4 with about five PEG chains was selected as a lead candidate due to highest extent of PEGylation and maximum reaction yield. Thiolated Tf was conjugated to the maleimide group at the distal end of the PEG chains on the PEG-TNF-alpha conjugates, with the resulting Tf-PEG-TNF-alpha conjugates after purification containing approximately one Tf ligand on one TNF-alpha molecule. The conjugate of Tf and PT4 (TPT4) was selected to assess the specificity and affinity to transferrin receptor (TfR) on two kinds of tumor cells, K562 and KB. Both the receptor binding assays and the competition experiments were performed using radioligand binding analysis. The results demonstrated that TPT4 as well as Tf bound specifically to the TfR on the tumor cell surface and the affinity of the conjugate to TfR was similar to that of native Tf. In contrast, PEG-TNF-alpha demonstrated no specificity. The biodistribution and antitumor effects were investigated in S-180 tumor-bearing mice. It was found that TPT4 could markedly alter in vivo behavioral characteristics of TNF-alpha. Compared with TNF-alpha and PT4, extravasated TPT4 in tumor tissues exhibited a significantly delayed blood clearance and the highest intratumoral TNF-alpha levels. Furthermore, the inhibitory rate of tumor of TPT4 enhanced 5.3- and 1.8-fold over that of TNF-alpha and PT4, indicating that TPT4 exhibited the highest antitumor activity. These results suggested that Tf-PEG-TNF-alpha was a useful long circulating conjugate with the capabilities of specific receptor binding resulting in enhanced antitumor activity of TNF-alpha.

Animals↗

PubMed2005

Synthesis and micellar characteristics of dendron-PEG conjugates.

Urethane-amide dendrons of up to the third generation were synthesized via a convergent route. These dendrons were coupled with MeO-PEG (Mn = 2000), and the micellar characteristics of dendron-PEG conjugates in water were investigated. The conjugates with the second or third generation dendron (PEG-2GOc and PEG-30c) formed micellar aggregates in an aqueous phase. However, the conjugate with the first generation dendron (PEG-1GOc) did not exhibit micellar aggregates detectable by dynamic light scattering possibly due to the high ratio of the hydrophilic moiety to hydrophobic periphery. The critical aggregation concentrations of PEG-2GOc and PEG-3GOc determined by fluorescence techniques were 7.5 and 2.0 mg/L, respectively. The mean diameters of the micelles ofPEG-2GOc and PEG-3GOc, measured by dynamic light scattering, were 90 and 170 nm. The partition equilibrium constants (Kv) of pyrene in the micellar solution increased by increasing the size of the dendritic block, for example, 6.17 x 10(4) for PEG-2GOc and 1.58 x 10(5) for PEG-3GOc. The steady-state fluorescence anisotropy values (r) of 1,6-diphenyl-1,3,5-hexatriene (DPH) were 0.107 for PEG-2GOc and 0.178 for PEG-3GOc. When the third generation dendritic moiety is incorporated into the conjugates, the Kv and r values become comparable to those for typical block copolymer micelles.

Journal Article↗

PubMed2005

Potential molecular mechanism for rodent tumorigenesis: mutational generation of Progression Elevated Gene-3 (PEG-3).

Progression Elevated Gene-3 (PEG-3) was cloned using subtraction hybridization as an upregulated transcript associated with transformation and tumor progression of rat embryo fibroblast cells. PEG-3 is a unique gene facilitating tumor progression by modulating multiple pathways in transformed cells, including genomic stability, angiogenesis and invasion. PEG-3 originates from mutation in the growth arrest and DNA damage inducible gene GADD34. A one base deletion in rat GADD34 results in a frame-shift and premature appearance of a stop-codon resulting in a C-terminally truncated molecule that is PEG-3. We now document that mutation in the GADD34 gene is a frequent event during transformation and/or immortalization of rodent cells. Sequencing of the GADD34 gene in a number of independent rat tumor cell lines revealed that in a majority of these the GADD34 gene is mutated to either PEG-3 or a PEG-3-like gene with similar C-terminal truncations. An important function of GADD34 is to inhibit cell growth, predominantly by apoptosis, and we demonstrate that PEG-3 or C-terminal truncations of human GADD34 resembling PEG-3 prevent growth inhibition by both human and rat GADD34. Phosphorylation of p53 by GADD34 is one mechanism by which it inhibits growth and PEG-3 could prevent GADD34-induced p53 phosphorylation. In contrast, PEG-3 was unable to block other GADD34-induced changes, including eIF2 alpha dephosphorylation, indicating that its effects on GADD34 may be related more to its effect on cell growth rather than a global inhibitor of all GADD34 functions. We hypothesize that mutational generation of PEG-3 or a similar molecule is a critical event during rodent carcinogenesis. The inherent property of PEG-3 to function as a dominant negative of the growth inhibitory property of GADD34 might rescue cells from DNA damage-induced apoptosis leading to growth independence and tumorigenesis.

Animals↗

PubMed2003

Percutaneous endoscopic gastrostomy (PEG) in patients with ALS and bulbar dysfunction.

OBJECTIVE: To compare characteristics of ALS patients with and without percutaneous endoscopic gastrostomy (PEG). METHODS: Using the ALS Patient Care Database, data from patients with and without PEG with ALS Functional Rating Scale-bulbar subscale (ALSFRSb) scores < or = 5 were analyzed; follow-up data were also collected. RESULTS: PEG use was markedly increased with declining ALSFRSb scores. Demographics did not differ, but ALSFRS composite scores and bulbar and arm subscale scores were lower (P<0.0001). PEG patients used significantly more assistive devices, multidisciplinary care, home care nurses and aides, had more frequent physician and emergency department visits and hospital admissions (P<0.0001), and had lower health status based on the mini-SIP scale (P=0.0047). PEG use varied greatly between ALS centers. In the follow-up study, positive impact of PEG was noted in 79 % of PEG patients but in only 37.5% of patients who received PEG later, based on a small number of patients. PEG use showed no survival benefit. CONCLUSION: Patients did not receive PEG until bulbar function was severely reduced and overall ALS had markedly progressed. PEG may have been performed too late to demonstrate survival benefits. Aggressive proactive nutritional management appears essential in patients with ALS. To determine whether PEG provides benefits, it must be performed at earlier stages of the disease and prospectively studied.

Amyotrophic Lateral Sclerosis↗

PubMed2002

Improved blood compatibility and decreased VSMC proliferation of surface-modified metal grafted with sulfonated PEG or heparin.

Although the technique of coronary stenting has remarkably improved long-term results in recent years, (sub)acute thrombosis and late restenosis still remain problems to be solved. Metallic surfaces were regarded as thrombogenic, due to their positive surface charges, and stenosis resulted from the activation and proliferation of vascular smooth muscle cells (VSMCs). In this study, a unique surface modification method for metallic surfaces was studied using a self-assembled monolayer (SAM) technique. The method included the deposition of thin gold layers, the chemisorption of disulfides containing functional groups, and the subsequent coupling of PEG derivatives or heparin utilizing the functional groups of the disulfides. All the reactions were confirmed by ATR-FTIR and XPS. The surface modified with sulfonated PEG (Au-S-PEG-SO3) or heparinized PEG (Au-S-PEG-Hep) exhibited decreased static contact angles and therefore increased hydrophilicity to a great extent, which resulted from the coupling of PEG and the ionic groups attached. In vitro fibrinogen adsorption and platelet adhesion onto the Au-S-PEG-SO3 or Au-S-PEG-Hep surfaces decreased to a great extent, indicating enhanced blood compatibility. This decreased interaction of the modified surfaces should be attributed to the non-adhesive property of PEG and the synergistic effect of sulfonated PEG. The effect of the surface modification on the adhesion and proliferation of VSMCs was also investigated. The modified Au-S-PEG-SO3 or Au-S-PEG-Hep surfaces also exhibited decreased adhesion of VSMCs, while the deposited gold layer itself was effective. The enhanced blood compatibility and the decreased adhesion of VSMCs on the modified metallic surfaces may help to decrease thrombus formation and suppress restenosis. It would therefore be very useful to apply these modified surfaces to stents for improved functions. A long-term in vivo study using animal models is currently under way.

Animals↗

PubMed2006

Control of hyperuricemia in subjects with refractory gout, and induction of antibody against poly(ethylene glycol) (PEG), in a phase I trial of subcutaneous PEGylated urate oxidase.

PEG-modified recombinant mammalian urate oxidase (PEG-uricase) is being developed as a treatment for patients with chronic gout who are intolerant of, or refractory to, available therapy for controlling hyperuricemia. In an open-label phase I trial, single subcutaneous injections of PEG-uricase (4 to 24 mg) were administered to 13 such subjects (11 had tophaceous gout), whose plasma uric acid concentration (pUAc) was 11.3 +/- 2.1 mg/dl (mean +/- SD). By day seven after injection of PEG-uricase, pUAc had declined by an average of 7.9 mg/dl and had normalized in 11 subjects, whose mean pUAc decreased to 2.8 +/- 2.2 mg/dl. At doses of 8, 12, and 24 mg, the mean pUAc at 21 days after injection remained no more than 6 mg/dl. In eight subjects, plasma uricase activity was still measurable at 21 days after injection (half-life 10.5 to 19.9 days). In the other five subjects, plasma uricase activity could not be detected beyond ten days after injection; this was associated with the appearance of relatively low-titer IgM and IgG antibodies against PEG-uricase. Unexpectedly, these antibodies were directed against PEG itself rather than the uricase protein. Three PEG antibody-positive subjects had injection-site reactions at 8 to 9 days after injection. Gout flares in six subjects were the only other significant adverse reactions, and PEG-uricase was otherwise well tolerated. A prolonged circulating life and the ability to normalize plasma uric acid in markedly hyperuricemic subjects suggest that PEG-uricase could be effective in depleting expanded tissue stores of uric acid in subjects with chronic or tophaceous gout. The development of anti-PEG antibodies, which may limit efficacy in some patients, is contrary to the general assumption that PEG is non-immunogenic. PEG immunogenicity deserves further investigation, because it has potential implications for other PEGylated therapeutic agents in clinical use.

Adult↗

PubMed2006

The use of PEG-Hirudin in chronic hemodialysis monitored by the Ecarin Clotting Time: influence on clotting of the extracorporeal system and hemostatic parameters.

AIM: The aim of our study was to investigate the use of polyethylene glycol (PEG)-Hirudin (PEG-H) as an anticoagulant in hemodialysis including drug monitoring with the Ecarin Clotting Time (ECT) in whole blood and to compare this regimen with standard anticoagulant unfractionated heparin (UFH) for influence on hemostatic parameters and clot frequency of the extracorporeal system. PATIENTS AND METHODS: The application of PEG-H as an anticoagulant in patients on chronic HD was studied in 20 patients (12 males, 8 females) from a single center in an exploratory, open-label, controlled, single-blind, dose-finding study. The patients were divided in 2 groups with 10 patients each (Group I and II); both received 3 dialyses with UFH, thereafter Group I received 5 dialyses with PEG-H and Group II 10 dialyses with PEG-H. Starting dose of PEG-H in the first dialysis was a bolus of 0.08 mg/kg bwt, the mean dose of the following HD was 0.041 mg/kg bwt (range 0.026 0.065 mg/kg bwt). PEG-H was applied as an intravenous bolus-dose followed by a 0.9% saline as a placebo-infusion. HD was performed regularly 3 times a week. All dialysis treatments were performed exclusively with a hollow fiber dialyzer type. Fibrinogen, antithrombin III, prothrombin fragments, thrombin-antithrombin and soluble fibrin were measured with commercial tests. ECT was determined in a mechanical coagulometer. A semiquantitative score was given for the presence of clots in the extracorporeal system after each dialysis. RESULTS: PEG-H was effectively used as an anticoagulant in 150 chronic dialysis treatments using ECT as a simple monitoring method. The optimal whole blood concentration for PEG-H is 600-1000 ng/ml. Clotting in the whole extracorporeal system was decreased by 45% (p = 0.059) with PEG-H anticoagulated HD in comparison to UFH. Fibrinogen, prothrombin fragments (F1+2-fragments) and thrombin-antithrombin-complex showed no significant change in comparison with UFH, antithrombin III (AT III) increased to normal concentrations. Highly sensitive coagulation markers such as a soluble fibrin showed a significant decrease (p < 0.001) before and after HD with PEG-H compared with UFH. CONCLUSION: PEG-H can be used effectively as an alternative anticoagulant in patients on chronic HD using ECT as a simple drug monitoring method. The lower frequency of clots in the extracorporeal system, the stronger and more efficient inhibition of coagulation during HD as indicated by soluble fibrin, may have a positive influence on the disturbed blood coagulation of these patients.

Adult↗

PubMedDate not supplied

The synergism of 6-mercaptopurine plus cytosine arabinoside followed by PEG-asparaginase in human leukemia cell lines (CCRF/CEM/0 and (CCRF/CEM/ara-C/7A) is due to increased cellular apoptosis.

BACKGROUND: The only effective drug against ALL that inhibits protein synthesis is Asparaginase (ASNase). The drug depletes asparagine (Asn) in serum and cells and since the leukemic T-cells (thymic origin cells) lack asparagine synthetase, the amino acid starvation leads to apoptosis. When PEG-ASNase is combined with antimetabolite drugs such as ara-C, or combinations of 6-MP followed by ara-C, it augments the cytotoxic effect synergistically against human T-leukemia cells. MATERIALS AND METHODS: Synergism studies with two- or three-drug combination regimens in the human leukemia cell lines, CEM/0 and CEM/ara-C/7A have been investigated along with its effect in inducing apoptosis. RESULTS: The IC50 (approximately Dm) values of ara-C were 0.032 microM and 0.11 microM, and that of PEG-ASNase were 0.002 IU/ml and 1.52 IU/ml against CEM/0 and CEM/ara-C/7A cells, respectively. Thus, CEM/ara-C/7A cell line that is partially resistant to ara-C exhibited 681-fold cross-resistant to PEG-ASNase as compared to CEM/0. The concurrent drug exposure of ara-C and PEG-ASNase for 48 hours resulted in IC50 values of 0.56 nM for ara-C and 0.56 mIU/ml for PEG-ASNase respectively, in CEM/0 cells which represents a 57.4-fold synergism compared to ara-C alone. In the CEM/ara-C/7A cell line, the co-incubation with these two drugs resulted in IC50 value of 0.015 microM for ara-C and 0.015 IU/ml for PEG-ASNase respectively, or a 7.25-fold synergism as compared to ara-C and 101.1-fold synergism in comparison with PEG-ASNase alone. Pre-clinical studies involving three-drug combination consisting of 6-MP, ara-C and PEG-ASNase in a sequence-specific manner showed a 15.6-fold synergism against CEM/0 cell line over the two-drug combination of 6-MP followed by ara-C or approximately 160-fold syneryism over ara-C alone. CONCLUSION: The two-drug combination of ara-C and PEG-ASNase or the three-drug combination of 6-MP, ara-C and PEG-ASNase in the ara-C sensitive and resistant cell line showed significant drug synergism and CEM/ara-C/7A cells exhibited collateral sensitivity to PEG-ASNase. The three-drug combination also induced dose-dependent apoptotic DNA fragmentation which was higher than the two-drug combination of 6-MP and ara-C. We also conclude that the sequence specific use of PEG-ASNase in combination with the nucleoside analog drugs may benefit leukemia patients in early relapse.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2001

Ocular tolerability and in vivo bioavailability of poly(ethylene glycol) (PEG)-coated polyethyl-2-cyanoacrylate nanosphere-encapsulated acyclovir.

Acyclovir-loaded polyethyl-2-cyanoacrylate (PECA) nanospheres were prepared by an emulsion polymerization process in the micellar phase and characterized. The influence of the presence of nonionic surfactant as well as other substances [i.e., 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) and poly(ethylene glycol) (PEG)], on formulation parameters and loading capacity was investigated. In particular, the presence of PEG resulted in an increase of mean size and size distribution. To obtain PEG-coated PECA nanospheres with a mean size of < 200 nm, Pluronic F68 at concentrations > 1.5% (w/v) should be used during preparation. The presence of PEG also resulted in a change in zeta potential, from -25.9 mV for uncoated nanospheres to -12.2 mV for PEG-coated PECA nanospheres. The presence of HP-beta-CyD elicited an increase of nanosphere size and size distribution, but zeta potential was not influenced. In vitro drug release from nanospheres was determined in both phosphate buffer (pH 7.4) and plasma. The presence of HP-beta-CyD and PEG did not influence the acyclovir release rate in plasma. In the case of release in phosphate buffer, PEG-coated nanospheres showed a slower release. Ocular tolerability of PEG-coated PECA nanospheres was evaluated by the in vivo Draize test. This colloidal carrier was well tolerated, eliciting no particular inflammation at the level of the various ocular structures. In vivo ocular bioavailability was evaluated by instilling 50 microL of the acyclovir-loaded nanospheres only once in the conjunctival sac of rabbit eyes. At various time intervals, aqueous humour acyclovir content was determined by high-performance liquid chromatography. Acyclovir-loaded PEG-coated PECA nanospheres were compared with an aqueous solution of the drug and a physical mixture of acyclovir nanospheres. The acyclovir-loaded PEG-coated PECA nanospheres showed a significant (p < 0.001) increase of drug levels (25-fold) in aqueous humor compared with the free drug or the physical mixture. This finding is probably due to an improved ocular mucoadhesion of PEG-coated PECA nanospheres.

Acyclovir↗

PubMed2006

Pharmacodynamics of PEG-IFN alpha differentiate HIV/HCV coinfected sustained virological responders from nonresponders.

Pegylated interferon (PEG-IFN) has become standard therapy for hepatitis C virus (HCV) infection. We evaluated whether PEG-IFN pharmacodynamics and pharmacokinetics account for differences in treatment outcome and whether these parameters might be predictors of therapeutic outcome. Twenty-four IFN-naïve, HCV/human immunodeficiency virus-coinfected patients received PEG-IFN alpha-2b (1.5 microg/kg) once weekly plus daily ribavirin (1000 or 1200 mg) for up to 48 weeks. HCV RNA and PEG-IFN alpha concentrations were obtained from samples collected frequently after the first 3 PEG-IFN doses. We modeled HCV kinetics incorporating pharmacokinetic and pharmacodynamic parameters. Although PEG-IFN concentrations and pharmacokinetic parameters were similar in sustained virological responders (SVRs) and nonresponders (NRs), the PEG-IFN alpha-2b concentration that decreases HCV production by 50% (EC50) was lower in SVRs compared with NRs (0.04 vs. 0.45 microg/L [P = .014]). Additionally, the median therapeutic quotient (i.e., the ratio between average PEG-IFN concentration and EC50 [C/EC50]), and the PEG-IFN concentration at day 7 divided by EC50 (C(7)/EC50) were significantly increased in SVRs compared with NRs after the first (10.1 vs. 1.0 [P = .012], 2.8 vs. 0.3 [P = .007], respectively) and second (14.0 vs. 1.1 [P = .016], 5.4 vs. 0.4 [P = .02], respectively) PEG-IFN doses. All 3 parameters may be used to identify NRs. In conclusion, PEG-IFN concentrations and pharmacokinetic parameters do not differ between SVRs and NRs. In contrast, pharmacodynamic measurements-namely EC50, the therapeutic quotient, and C(7)/EC50--are different in coinfected SVRs and NRs. These parameters might be useful predictors of treatment outcome during the first month of therapy.

Antiviral Agents↗

PubMed1998

[Long-term experience with percutaneous endoscopic controlled gastrostomy (PEG) in ENT tumor patients].

Percutaneous endoscopically controlled gastrostomy (PEG) enables patients suffering from a tumor of the upper aerodigestive tract to receive direct gastric feedings. The procedure also avoids the social stigma of a nasal feeding tube. The results of 630 PEG procedures used in 555 patients suffering from various head and neck cancers are reported. The mean age of the patients was 58.0 years with a range from 11 to 92 years. The PEG procedure was carried out under local anesthesia in 60% of the cases and with general anesthesia in 40%. In 512 patients the initial PEG procedure was successful while 43 of the patients require a second PEG procedure after loss of the PEG. In 19 patients the PEG procedure was not successful because of tumor obstruction or it was not possible to perform endoscopy. Twenty-four patients were successfully treated in a second or third session. Although 97% (n = 563) of all 555 patients and 92% (n = 579) of all PEG procedures were successful. The mean duration of PEG use was 243 (range: 0-2271 days). In 66 patients (10.5%) complications occurred but severe complications developed in only 8 patients (1.3%). Operative interventions were necessary in two cases. No deaths resulted from the PEG. These findings show that the PEG technique is safe to do with only few complications when performed by a skilled team.

Adolescent↗

PubMed2003

In vitro and in vivo study of 99mTc-MIBI encapsulated in PEG-liposomes: a promising radiotracer for tumour imaging.

Encapsulation of technetium-99m sestamibi ((99m)Tc-MIBI) in polyethyleneglycol-liposomes ((99m)Tc-MIBI-PEG-liposomes) could extend the duration of its circulation in blood and alter its biodistribution, enabling its concentration in tumours to be increased. An original method to encapsulate (99m)Tc-MIBI in PEG-liposomes is described. The (99m)Tc-MIBI-PEG-liposomes were compared with free (99m)Tc-MIBI with respect to (a) tumour availability (b) ability to distinguish between chemotherapy-sensitive and -resistant cells and (c) uptake ratio in tumour imaging. PEG-liposomal systems composed of distearoylphosphatidylcholine/cholesterol/PEG(2000)-distearoyl phosphatidylethanolamine and lissamine-rhodamine B-labelled liposomes were used. The encapsulation of (99m)Tc-MIBI in liposomes was achieved using the K(+) diffusion potential method. We compared the uptake of free versus encapsulated (99m)Tc-MIBI by sensitive and resistant erythroleukaemia (K562) and breast tumour (MCF-7ras) cells. To assess the internalisation of these liposomes into cells, rhodamine B-labelled PEG-liposomes were used and visualised by fluorescence microscopy. Biodistribution and imaging characteristics of encapsulated and free radiotracer were determined in rats and tumour-bearing nude mice. The efficiency of (99m)Tc-MIBI encapsulation in PEG-liposomes was 50+/-5%. Use of (99m)Tc-MIBI-PEG-liposomes did not impair the ability of this tracer to distinguish between chemotherapy-sensitive and -resistant tumour cells; the percentage of radioactivity accumulated in the sensitive K562 cells was 1.24+/-0.04%, as compared with 0.41+/-0.04% in the resistant K562 cells. One hour post injection in rats, PEG-liposomes showed a ten times higher activity in blood than free (99m)Tc-MIBI, whereas activity of free (99m)Tc-MIBI in kidneys and bladder was markedly higher than that of encapsulated (99m)Tc-MIBI, indicating faster clearance of the free radiotracer. In the (MCF7-ras)-bearing nude mice, PEG-liposome uptake in tumour was two times that of free (99m)Tc-MIBI. Summarising, the (99m)Tc-MIBI-PEG-liposomes demonstrated a longer blood circulation time, enabled distinction between chemotherapy-sensitive and -resistant cells and improved tumour to background contrast in in vivo imaging. (99m)Tc-MIBI-PEG-liposomes therefore show promising potential for tumour imaging.

Animals↗

PubMed2005

Preparation of a PLA-PEG block copolymer using a PLA derivative with a formyl terminal group and its application to nanoparticulate formulation.

A novel poly(DL-lactic acid) (PLA) derivative with a diethoxy propanol ester at the end, named PLA-acetal, was synthesized by ring opening polymerization using DL-lactide and 3,3-diethoxy propanol. PLA-acetal was hydrolyzed to a PLA derivative with a formyl group, named PLA-aldehyde, by acid treatment. Reductive amination between PLA-aldehyde and methoxypolyethylene glycol amine (MeO-PEG(N)) gave the block copolymer (PLA-(MeO-PEG(N))). Nanoparticles were prepared by emulsification-solvent evaporation or solvent diffusion using PLA-(MeO-PEG(N)) or a conventional methoxypolyethylene glycol-PLA block copolymer, PLA-(MeO-PEG(O)). PLA-(MeO-PEG(N)) nanoparticles had a particle size of 60-340 nm, dependent on the preparative procedure, while PLA-(MeO-PEG(O)) nanoparticles prepared by solvent diffusion showed a particle size of 60 nm. The PLA-(MeO-PEG) nanoparticles with a smaller PEG introduction degree exhibited a more negative zeta potential. 1,1'-Dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine perchlorate (DiD) could be incorporated efficiently in PLA-(MeO-PEG(N)) nanoparticles. It is suggested that PLA-aldehyde should be useful as a functional intermediate for derivatization of PLA, and PLA-(MeO-PEG(N)) can be used for the preparation of PEG-coated PLA nanoparticles.

Chemistry, Pharmaceutical↗

PubMed2002

Effects of cloud-point grafting, chain length, and density of PEG layers on competitive adsorption of ocular proteins.

The effects of pinning density, chain length, and 'cloud point' (CP) versus non-CP grafting conditions have been studied on the ability of polyethylene glycol (PEG) layers to minimize adsorption from a multicomponent (lysozyme, human serum albumin (HSA), IgG and lactoferrin) protein solution. Methoxy-terminated aldehyde-PEG (M-PEG, MW 5000) and dialdehyde-PEG (PEG(ald)2, MW 3400) were grafted by reductive amination onto two surfaces of different amine group density, generated by radiofrequency glow discharge (r.f.g.d.) deposition of n-heptylamine (HA) (low density) or allylamine (AlA) (high density) r.f.g.d. polymer layers. The PEG graft density was varied also by increasing the temperature and salt (K2SO4) content of the grafting solution; it reached a maximum at the CP of the PEGs. The CP reaction conditions were critical for producing PEG layers capable of minimizing protein adsorption. X-ray photoelectron spectroscopy (XPS) showed that under these conditions, PEG(ald)2 produced a thick linear PEG layer, most likely by aldol condensation. Protein adsorption was assessed using XPS and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-ToF-MS) in the surface mode (Surface-MALDI-MS). Coatings grafted at non-CP conditions showed some protein adsorption, as did the HA/M-PEG layer grafted at the CP. On the other hand, no protein adsorption was detected on the HA/PEG(ald)2, AlA/M-PEG, and AlA/PEG(ald)2 surfaces when grafted at the CP. Thus, the effects of pinning density and chain length are interrelated, but the key factor is optimization of PEG chain density by use of the CP conditions, provided that a sufficient density of pinning sites exists.

Adsorption↗

PubMed2001

POE-PEG-POE triblock copolymeric microspheres containing protein. I. Preparation and characterization.

Poly(ortho ester) (POE)-poly (ethylene glycol) (PEG) triblock copolymers (POE-PEG-POE) with different PEG contents were synthesised as carriers for controlled protein delivery. POE-PEG-POE microspheres containing bovine serum albumin (BSA) were prepared using a double-emulsion (water-in-oil-in-water) process. In this first paper of a two-part series, we report the fundamentals of the fabrication and characterization of POE-PEG-POE microspheres. Because the triblock copolymer is more hydrophilic than neat poly(ortho ester), the triblock copolymer yields a more stable first emulsion (water-in-oil) and a greater BSA encapsulation efficiency (90% vs. 30%). No BSA is found on POE-PEG-POE microsphere surfaces measured by X-ray photoelectron spectroscopy, while uniform BSA distributions are observed within the microspheres by confocal microscopy. SEM pictures show that an increase in PEG content results in microspheres with a denser cross-section because of a more stable first emulsion and better affinity between the copolymer and water. POE-PEG(20%)-POE suffers significant swelling during the fabrication process and yields the biggest microspheres. However, the POE-PEG(30%)-POE microspheres are much smaller since the dissolution loss of POE-PEG(30%)-POE in the external water phase may be much higher than that of POE-PEG(20%)-POE. The salt concentration in the external water phase significantly affects the morphology of the resultant microspheres. Microspheres with a dense wall are produced when using pure water as the external water phase. Polymer concentration has less impact on BSA encapsulation efficiency but has a considerable effect on microsphere size and morphology. Increasing the concentration of the polyvinyl alcohol emulsifier does not cause an obvious decrease in microsphere size. However, increased BSA loading results in bigger microspheres.

Algorithms↗