Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P30536 (PBS)
 9,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

6-Mercaptopurine (6-MP) is an orally administered, water-insoluble purine analog that is effective against acute lymphatic leukemia. Oral absorption of 6-MP, however, is quite erratic, with only 16-50% of the administered dose reaching the blood. In this report, water-soluble parenterally administered poly(ethylene glycol) (PEG) prodrugs of 6-MP were synthesized using several chemical approaches that enabled the protection of the thiol group through a modification of the benzyl elimination (BE) system. In our earlier work on antimetabolites, it was found that branching of the PEG allowed greater loading of the active drug. This approach was also utilized within this work to give multiloaded systems. The resulting conjugates were stable in pH 7.4 PBS buffer as well as in rat plasma for extended periods. However, these conjugates did act as prodrugs in vivo and a number of PEG-6-MP constructs had significant (P < 0.05) activity in murine leukemia, as well as certain solid tumors, compared with unconjugated 6-MP in a solubilizing vehicle. The fact that some PEG-6-MP conjugates were stable during in vitro plasma dissociation assays, but demonstrated in vivo anticancer activity, suggests extravascular cleavage of the linking group. This work demonstrates that PEG conjugation is an effective means of solubilizing 6-MP for parenteral administration.
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PMID:PEG prodrugs of 6-mercaptopurine for parenteral administration using benzyl elimination of thiols. 1549 Sep 77

Efficient and controlled gene delivery from biodegradable materials can be employed to stimulate cellular processes that lead to tissue regeneration. In this report, a substrate-mediated approach was developed to deliver DNA from hyaluronic acid-collagen hydrogels. The hydrogels were formed by crosslinking HA with poly(ethylene glycol) diglycidyl ether. Poly(ethylene imine)(PEI)/DNA complexes were immobilized to the substrate using either biotin/neutravidin or non-specific adsorption. Complexes were formed in the presence or absence of salt to regulate complex size, and resulted in complexes with z-average diameters of 1221.7 +/- 152.3 and 139.4 +/- 1.3 nm, respectively. During 48-h incubation in PBS or hyaluronidase, DNA was released slowly from the hydrogel substrate (<30% of immobilized DNA), which was enhanced by incubation with conditioned media (approximately 50% of immobilized DNA). Transgene expression mediated by immobilized, large diameter complexes was 3 to 7-fold greater than for small diameter complexes. However, the percentage of cells expressing the transgene was greater for small diameter complexes (48.7%) than for large diameter complexes (22.3%). Spatially controlled gene transfer was achieved by topographically patterning the hydrogel to pattern cell adhesion. Biomaterial-based gene delivery can be applicable to numerous tissue engineering applications, or as a tool to examine tissue formation.
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PMID:DNA delivery from hyaluronic acid-collagen hydrogels via a substrate-mediated approach. 1552 59

This work describes the development of a non-invasive means of simultaneously delivering insulin-like growth factor-1 (IGF-1) and transforming growth factor-beta1 (TGF-beta1) to injured cartilage tissue in a controlled manner. This novel delivery technology employs the water-soluble polymer, oligo(poly(ethylene glycol) fumarate) (OPF), in the fabrication of biodegradable hydrogels which encapsulate gelatin microparticles. Release studies first examined the effect of gelatin isoelectric point (IEP) and crosslinking extent on IGF-1 release from these microparticles. In the presence of collagenase, highly crosslinked, acidic gelatin (IEP=5.0) provided sustained release of IGF-1, 95.2+/-2.9% cumulative release at day 28, while less crosslinked microparticles and microparticles of alternate IEP exhibited similar release values after only 6 days. Encapsulation of these highly crosslinked microparticles in a network of OPF provided a means to further control release, reducing final cumulative release to 70.2+/-4.7% in collagenase-containing PBS. Final release values from OPF-gelatin microparticle composites could be altered by incorporating less crosslinked, non-loaded microparticles within these constructs. Finally, this technology was extended to the dual delivery of IGF-1 and TGF-beta1 by loading these growth factors into either the OPF hydrogel phase or gelatin microparticle phase of composites. Release profiles were successfully manipulated by altering the phase of growth factor loading and microparticle crosslinking extent. For instance, by loading TGF-beta1 into the gelatin microparticle phase, a burst release of 10.8+/-0.7% was achieved, while loading this growth factor into the OPF hydrogel phase resulted in a burst release of 25.2+/-1.5%. With either system, simultaneous, slow release of IGF-1 over a 4-week period was accomplished by selectively loading this protein into highly crosslinked, encapsulated microparticles. These results demonstrate the utility of these systems in future studies to assess the interplay and time course of multiple growth factors in cartilage repair.
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PMID:Dual growth factor delivery from degradable oligo(poly(ethylene glycol) fumarate) hydrogel scaffolds for cartilage tissue engineering. 1558 98

The encapsulation of biofunctional compounds, release properties and targetability of polymersomes of amphiphilic block-copolymers based on poly(ethylene glycol) (PEG) and biodegradable polyesters or polycarbonate are described. Carboxyfluorescein (CF), as a model for hydrophilic biofunctional compounds, could be readily incorporated in the polymersomes by adding the compound to the aqueous phase during polymersome preparation. The release of encapsulated material from the polymersomes can be adjusted by changing the copolymer composition, especially the molecular weight and type of hydrophobic block of the copolymer. The presence of plasma proteins other than albumin suppressed the release of CF. CF release in PBS both at room temperature and at 60 degrees C followed first order kinetics, confirming that the CF containing polymersome system is a membrane controlled reservoir system. These biodegradable polymersomes have the potential to be targeted to specific sites in the body as shown by the specific interaction of anti-human serum albumin immobilized polymersomes with a human serum albumin coated sensor surface.
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PMID:Biodegradable polymersomes as a basis for artificial cells: encapsulation, release and targeting. 1558 4

The results of a comprehensive in vivo study of a novel tumor-targeting modality are reported. The technique utilized in this study is based on the encapsulation of the chemotherapeutic agent within polymeric micelles in combination with a local ultrasonic irradiation of the tumor. A doxorubicin (DOX) biodistribution, a yield of the internal tumors and a growth rate of the subcutaneous (s.c.) tumors was compared for molecularly dissolved and micellar-encapsulated DOX. This was done with and without tumor sonication, using an ovarian carcinoma tumor model in nu/nu mice. Pure and mixed Pluronic P-105, PEG2000-diacylphospholipid, and poly(ethylene glycol)-co-poly(beta-benzyl-L-aspartate) micelles were used as drug carriers. DOX intracellular uptake was characterized by flow cytometry. A local ultrasonic irradiation of the tumor resulted in a substantially increased drug accumulation in the tumor cells. The effect of the ultrasound was dependent on the time between ultrasound application and drug injection. Ultrasound did not enhance micelle extravasation; the ultrasonic enhancement of drug internalization by the tumor cells required a preliminary passive drug accumulation in the tumor interstitium. Due to the ultrasound-enhanced drug intracellular uptake and cell killing, the yield of intraperitoneal (i.p.) ovarian carcinoma tumors decreased from 70% for DOX dissolved in PBS (positive control) to 36% for the same concentration of DOX encapsulated in Pluronic micelles combined with a 30-s sonication of the abdominal region of a mouse (3 mg/kg DOX, i.p. injection 1 day after inoculation, n>or=10). For s.c. tumors, micellar delivery combined with localized ultrasonic tumor irradiation resulted in a substantial decrease of the tumor growth rates compared to a positive control (3 mg/kg DOX, i.v. injections, n=7, p<0.05). Possible mechanisms of the ultrasound bioeffects on in vivo drug targeting are discussed.
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PMID:Controlled and targeted tumor chemotherapy by micellar-encapsulated drug and ultrasound. 1565 46

The creation of nonfouling surfaces is one of the major prerequisites for microdevices for biomedical and analytical applications. Poly(ethylene glycol) (PEG), a water soluble, nontoxic, and nonimmunogenic polymer has the unique ability of reducing nonspecific protein adsorption and cell adhesion and, therefore, is generally coupled with a wide variety of surfaces to improve their biocompatibility. The performance of these modified surfaces for long-term biomedical applications largely depends on the stability of these PEG films. To this end, we have investigated the stability of covalently coupled ultrathin PEG films on silicon in aqueous in vivo like conditions for a period of 4 weeks. The PEG-modified silicon substrates were incubated in PBS (37 degrees C, pH 7.4, 5% CO2) for different periods of time and then characterized using the techniques of ellipsometry, contact angle measurement, X-ray photoelectron spectroscopy, and atomic force microscopy. The ability of the PEG-modified surfaces to control protein fouling was examined by protein adsorption studies using fluorescein isothiocyanate labeled bovine serum albumin and ellipsometry. Furthermore, the ability of these films to control fibroblast adhesion was examined. Studies suggest that the PEG-modified surfaces retain their protein and cell repulsive nature even though the PEG film thickness decreases for the period of investigation.
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PMID:Evaluation of the stability of nonfouling ultrathin poly(ethylene glycol) films for silicon-based microdevices. 1574 77

Vitrification using open pulled straw (OPS) has provided encouraging results with embryos from other species. The aim of this study was to compare the survival of 6.5- and 6.75-day-old equine embryos after OPS vitrification and slow-cooling. Eighteen embryos were frozen using a slow-cooling method. Embryos were placed in modified PBS with increasing glycerol concentration (2.5%, 5%, 7.5% and 10% (v/v) 5 min each). Embryos were loaded into 0.25 ml straws then placed in a programmable freezer and subsequently plunged into liquid nitrogen. After thawing, cryoprotectant was removed by five steps with decreasing glycerol and sucrose concentrations. Twenty embryos were vitrified using the OPS method. Embryos were exposed to 7.5% dimethyl-sulfoxide (DMSO)+7.5% ethylene glycol (EG) for 3 min and in 18% DMSO+18% EG+0.4M sucrose for 1 min, loaded in OPS and plunged into liquid nitrogen. After warming, embryos were placed in decreasing sucrose concentrations. All embryos were cultured in synthetic oviduct fluid (SOF) medium for 3h and evaluated using 4',6-diamidino-2-phenylindole (DAPI) staining. The percentage of cells entering in S-phase (%SC) was evaluated by incorporation of BrdU. No significant differences were observed for mean diameter, morphological grade and percentage of degenerate embryos after 3h of culture for slow-cooling and OPS methods. The percentage of dead cells per embryo was similar for the two procedures (42+/-6 versus 46+/-9). The percentage of cells entering in S-phase did not differ significantly between the two procedures (27+/-5 versus 26+/-6). OPS vitrification may be as efficient as slow-cooling for the cryopreservation of equine embryos. However, these results should be confirmed by the transfer of OPS vitrified embryos to recipient mares.
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PMID:In vitro comparisons of two cryopreservation techniques for equine embryos: slow-cooling and open pulled straw (OPS) vitrification. 1590 92

A novel controlled release formulation has been developed with PEGylated human insulin encapsulated in PLGA microspheres that produces multi-day release in vivo. The insulin is specifically PEGylated at the amino terminus of the B chain with a relatively low molecular weight PEG (5000 Da). Insulin with this modification retains full biological activity, but has a limited serum half-life, making encapsulation necessary for sustained release beyond a few hours. PEGylated insulin can be co-dissolved with PLGA in methylene chloride and microspheres made by a single o/w emulsion process. Insulin conformation and biological activity are preserved after PEGylation and PLGA encapsulation. The monolithic microspheres have inherently low burst release, an important safety feature for an extended release injectable insulin product. In PBS at 37 degrees C, formulations with a drug content of approximately 14% show very low (< 1%) initial release of insulin over one day and near zero order drug release after a lag of 3-4 days. In animal studies, PEG-insulin microspheres administered subcutaneously as a single injection produced < 1% release of insulin in the first day but then lowered the serum glucose levels of diabetic rats to values < 200 mg/dL for approximately 9 days. When doses were given at 7-day intervals, steady state drug levels were achieved after only 2 doses. PEG-insulin PLGA microparticles show promise as a once-weekly dosed, sustained release basal insulin formulation.
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PMID:PEGylated insulin in PLGA microparticles. In vivo and in vitro analysis. 1591 Oct 45

An ideal gene carrier requires both safety and transfection efficiency. Polyethylenimine (PEI) is a well-known cationic polymer, which has high transfection efficiency owing to its buffering capacity. But it has been reported that PEI is cytotoxic in many cell lines and non-degradable. In this study, we synthesized degradable PEI-alt-poly(ethylene glycol) (PEG) copolymers using Michael-type addition reactions as a new gene carrier and characterized them. These copolymers were complexed with plasmid DNA and the resulting complexes were characterized by dynamic light scattering, gel retardation and atomic force microscopy to determine particle sizes, complex formation and complex shape, respectively. Cytotoxicity and transfection efficiency of the copolymers were also checked in cultured HeLa human cervix epithelial carcinoma cells, HepG2 human hepatoblastoma cell line and MG63 human osteosarcoma cells. PEG to PEI ratio in the copolymers was near 1 and the molecular weight of the copolymer ranged from around 8000 to 12,900. These copolymers degraded rapidly at 37 degrees C in 0.1 M phosphate buffered saline (PBS, pH 7.4). The complete copolymer/DNA complex was formed at an N/P ratio of 12, producing a complex resistant to DNase I. Particle sizes decreased with increasing N/P ratio and PEG molecular weight, exhibiting a minimum value of 75 nm at an N/P ratio of 45 with PEI-alt-PEG (700). Cytotoxicity study showed that copolymers exhibited no cytotoxic effects on cells even at high copolymer concentration. Also, transfection efficiency was influenced by PEG molecular weight and, in case of PEI-alt-PEG (258), the transfection efficiency was higher than that for PEI 25 K in HepG2 and MG63, whereas it was lower than that for PEI 25K in HeLa cells.
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PMID:Degradable polyethylenimine-alt-poly(ethylene glycol) copolymers as novel gene carriers. 1593 8

The occurrence of intracellular ice formation (IIF) during freezing, or the lack there of, is the single most important factor determining whether or not cells survive cryopreservation. One important determinant of IIF is the temperature at which a supercooled cell nucleates. To avoid intracellular ice formation, the cell must be cooled slowly enough so that osmotic dehydration eliminates nearly all cell supercooling before reaching that temperature. This report is concerned with factors that determine the nucleation temperature in mouse oocytes. Chief among these is the concentration of cryoprotective additive (here, glycerol or ethylene glycol). The temperature for IIF decreases from -14 degrees C in buffered isotonic saline (PBS) to -41 degrees C in 1M glycerol/PBS and 1.5M ethylene glycol/PBS. The latter rapidly permeates the oocyte; the former does not. The initial extracellular freezing at -3.9 to -7.8 degrees C, depending on the CPA concentration, deforms the cell. In PBS that deformation often leads to IIF; in CPA it does not. The oocytes are surrounded by a zona pellucida. That structure appears to impede the growth of external ice through it, but not to block it. In most cases, IIF is characterized by an abrupt blackening or flashing during cooling. But in some cases, especially with dezonated oocytes, a pale brown veil abruptly forms during cooling followed by slower blackening during warming. Above -30 degrees C, flashing occurs in a fraction of a second. Below -30 degrees C, it commonly occurs much more slowly. We have observed instances where flashing is accompanied by the abrupt ejection of cytoplasm. During freezing, cells lie in unfrozen channels between the growing external ice. From phase diagram data, we have computed the fraction of water and solution that remains unfrozen at the observed flash temperatures and the concentrations of salt and CPA in those channels. The results are somewhat ambiguous as to which of these characteristics best correlates with IIF.
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PMID:Extra- and intracellular ice formation in mouse oocytes. 1597 68


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