Succinimidyl Carbonates of Polyethylene Glycol

Zalipsky, Samuel; Seltzer, R.; Nho, Kwang

doi:10.1021/bk-1991-0469.ch010

Cited by 25 publications

(10 citation statements)

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“…To compare the novel protein-reactive PPEs with the gold standard PEG, commercially available poly(ethylene glycol) monomethyl ether (mPEG 5.0 kDa) was postmodified employing phosgene to produce the corresponding mPEG-chloroformate which was subsequently reacted with N -hydroxysuccinimide (NHS) to form a SC group . This activated mPEG-SC is used as a control to compare PPEylation with the established PEGylation remaining molecular weights constant (characterization detail of PEG-SC can be found in the Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

“…BSA, N -Hdroxysuccinimide (NHS), uric acid and uricase from Bacillus fastidiosus were purchased from Sigma-Aldrich (Germany) and used as received. Poly(ethylene glycol) mono methyl ether ( M n = 5000) was purchased from Fluka and postmodified following the procedure reported by Zalipski . Deuterated solvents were purchased from Deutero GmbH (Kastellaun, Germany) and used as received.…”

Section: Methodsmentioning

confidence: 99%

“…Poly(ethylene glycol) mono methyl ether (M n = 5000) was purchased from Fluka and postmodified following the procedure reported by Zalipski. 18 Deuterated solvents were purchased from Deutero GmbH (Kastellaun, Germany) and used as received. Ultrapure water with a resistivity of 18.2 MΩ cm −1 (Milli-Q, Millipore) was used to prepare buffers.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

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Degradable Polyphosphoester-Protein Conjugates: “PPEylation” of Proteins

Steinbach

Wurm

2016

Biomacromolecules

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Pharmacokinetic properties determine the efficacy of protein therapeutics. The covalent attachment of poly(ethylene glycol) (PEG) extends the half-life of such biologicals to maintain a therapeutically effective concentration over a prolonged period of time and improves administration and compliance. A major obstacle of these polymer-protein conjugates is the chemical stability of the PEG preventing its metabolism and leading to side effects. Instead, we propose the PPEylation, that is, the conjugation of degradable poly(phosphoester)s (PPE) to proteins, in order to generate fully biodegradable polymer-protein conjugates. The structure of the PPEylated protein conjugates was verified with mass spectrometry and size exclusion chromatography. They were compared to structural analogues, except classical, PEGylated proteins, and exhibit comparable bioactivity, but avoiding any nondegradable polymer in the conjugate. We proved the degradation of the protective polymer shell surrounding the conjugate in aqueous environments at physiological conditions by online triple detection size exclusion chromatography and gel electrophoresis. We believe that this research will provide an attractive alternative for future drug design with implications for the clinical use of biologicals.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: ■ Experimental Sectionmentioning

confidence: 99%

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Degradable Polyphosphoester-Protein Conjugates: “PPEylation” of Proteins

Steinbach

Wurm

2016

Biomacromolecules

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“…Human hemoglobin modified by covalent attachment of pyridoxal-5Ј-phosphate and surface conjugation to ␣-carboxymethyl, -carboxymethoxypolyoxyethylene (PHP, 7.7 g/dl, 4.8 mM heme) was supplied as a gift from Apex Biosciences, Inc. (11). Bovine hemoglobin surface conjugated to methoxypolyoxyethylene glycol (PEG-Hb, 5.5 g/dl, 3.4 mM heme) was supplied as a gift from Enzon, Inc. (12).…”

Section: Methodsmentioning

confidence: 99%

Arterial Blood Pressure Responses to Cell-free Hemoglobin Solutions and the Reaction with Nitric Oxide

Rohlfs

Bruner

Chiu

et al. 1998

Journal of Biological Chemistry

271

214

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Changes in mean arterial pressure were monitored in rats following 50% isovolemic exchange transfusion with solutions of chemically modified hemoglobins. Blood pressure responses fall into three categories: 1) an immediate and sustained increase, 2) an immediate yet transient increase, or 3) no significant change either during or subsequent to exchange transfusion. The reactivities of these hemoglobins with nitric monoxide ( ⅐ NO) were measured to test the hypothesis that different blood pressure responses to these solutions result from differences in ⅐ NO scavenging reactions. All hemoglobins studied exhibited a value of 30 M ؊1 s ؊1 for both ⅐ NO bimolecular association rate constants and the rate constants for ⅐ NO-induced oxidation in vitro. Only the ⅐ NO dissociation rate constants and, thus, the equilibrium dissociation constants varied. Values of equilibrium dissociation constants ranged from 2 to 14 pM and varied inversely with vasopressor response. Hemoglobin solutions that exhibited either transient or no significant increase in blood pressure showed tighter ⅐ NO binding affinities than hemoglobin solutions that exhibited sustained increases. These results suggest that blood pressure increases observed upon exchange transfusion with cell-free hemoglobin solutions can not be the result of ⅐ NO scavenging reactions at the heme, but rather must be due to alternative physiologic mechanisms.Control of blood pressure and resistance to blood flow is achieved by a dynamic constriction and relaxation of smooth muscle tissue which surrounds all blood vessels except capillaries. Vascular smooth muscle tension is continually adjusted by a complex system that causes either vasoconstriction or vasodilation, depending on metabolic need (1). Research performed over the last decade has established that endotheliumderived nitric oxide ( ⅐ NO) 1 can cause vasodilation. ⅐ NO is produced by endothelial cells that lie between the intravascular space and the surrounding smooth muscle. Among the findings was the demonstration that ⅐ NO donors (e.g. nitroprusside, nitroglycerin) lead to vasorelaxation through activation of guanylate cyclase, whereas inhibitors of ⅐ NO synthesis (e.g. N Gmonomethyl-L-arginine) or scavengers (e.g. hemoglobin) cause vasoconstriction (for reviews, see Refs. 2 and 3).Since cell-free hemoglobin is being developed as a red cell substitute (4), reactions between hemoglobin and ⅐ NO are of potential importance in maintenance of microvascular blood flow and O 2 delivery. Despite the wide variation that exists in the physical properties (O 2 affinity, molecular mass, and solution properties) of different cell-free hemoglobins, it appears vasoconstriction is a feature common to many hemoglobin solutions (for reviews, see Refs. 2, 3, and 5). It is tempting to conclude that ⅐ NO scavenging is the principal, if not sole mechanism for vasoconstriction associated with cell-free hemoglobin. However, it is well established that multiple factors contribute to the physiological control of vascular smooth muscle to...

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“…Although the reaction can be directed to some extent by the pH of the medium (for the reaction to proceed, the nucleophil must always be in the non-protonated form), this type of conjugation reactions always lead to complex PEGylation mixtures. The historical development of such "random" PEGylation reagents began in the 1970s with PEGchlorotriazine reagents [2,3] and continued with succinimidyl succinate (SS-PEG) [41] and succinimidyl carbonate PEG reagents (SC-PEGs) [42,43]. SS-PEG reagents produce stable amide bonds (-CO-NH-Protein) with the protein but due to another ester linkage in the 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 …”

Section: Random Pegylationmentioning

confidence: 99%

PEGylation of therapeutic proteins

Jevševar¹,

Kunstelj²,

Porekar

2010

Biotechnology Journal

638

481

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International audiencePEGylation has been widely used as a post-production modification methodology for improving biomedical efficacy and physicochemical properties of therapeutic proteins since the first PEGylated product was approved by Food and Drug Administration in 1990. Applicability and safety of this technology have been proven by use of various PEGylated pharmaceuticals for many years. It is expected that PEGylation as the most established technology for extension of drug residence in the body will play an important role in the next generation therapeutics, such as peptides, protein nanobodies and scaffolds, which due to their diminished molecular size need half-life extension. This review focuses on several factors important in the production of PEGylated biopharmaceuticals enabling efficient preparation of highly purified PEG-protein conjugates that have to meet stringent regulatory criteria for their use in human therapy. Areas addressed are PEG properties, the specificity of PEGylation reactions, separation and large-scale purification, the availability and analysis of PEG reagents, analysis of PEG-protein conjugates, the consistency of products and processes and approaches used for rapid screening of pharmacokinetic properties of PEG-protein conjugates

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Succinimidyl Carbonates of Polyethylene Glycol

Cited by 25 publications

References 0 publications

Degradable Polyphosphoester-Protein Conjugates: “PPEylation” of Proteins

Degradable Polyphosphoester-Protein Conjugates: “PPEylation” of Proteins

Arterial Blood Pressure Responses to Cell-free Hemoglobin Solutions and the Reaction with Nitric Oxide

PEGylation of therapeutic proteins

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