“…Reaction of mPEG succinimidyl carbonates 4.31 and PEG bis(succinimidyl carbonates) 4.32 (Chart ) with lysine residues allowed formation of rather stable urethane linkages (eq 4.9) , (section IV.D). …”
Section: Acylation Reactionsmentioning
confidence: 99%
“…647 The ester linkage between the PEG strand and the succinic residue had, however, limited stability under physiological conditions. 648 The negatively charged monofunctional sulfosuccinimidyl acetate 4.33 and difunctional bis(sulfosuccinimidyl) suberate 4.34a and sebacate 4.34b were reported to selectively acylate and cross-link in the case of the difunctional esters (except in the case of ) has been used for establishing structure/ function relations in Hb, including determination of the residues involved in the Bohr effect, the role of the terminal NH 2 groups in CO 2 binding, the mechanism of the CO 2 -mediated reduction of O 2 affinity, and for increasing the O 2 affinity of HbS. 584,610,[649][650][651][652][653][654] When performed on deoxyHb at a pH ca.…”
Pharmaceutical Corporation in San Diego; however, the opinion expressed here are solely his and not necessarily those of the Corporation. Jean G. Riess received his chemical engineer and doctorat-e `s-sciences degrees (the latter with Professor Guy Ourisson in 1963) from the University of Strasbourg. He then spent two years with John Van Wazer at Monsanto in Saint-Louis, MO, learning some phosphorus and transitionmetal chemistry. In 1968 he became Professor at the University of Nice, France, where he founded, directed, and eventually became honorary director of the Unite ´de Chimie Mole ´culaire (associated with the Centre National de la Recherche Scientifique). His research successively involved phosphorus chemistry, transition-metal chemistry, organometallics, and eventually perfluorochemicals. His present interests are in fluorocarbons, fluorinated amphiphiles, and their colloid chemistry, including fluorocarbon emulsions for in vivo O 2 delivery, fluorinated self-assemblies, and drug delivery systems. Professor Riess has published about 360 papers and holds ca. 25 patents. He has served on numerous councils and committees and has chaired or co-chaired international conferences on phosphorus chemistry and blood substitutes. He has won awards from the French Academy of Sciences, French Chemical Society, Alexander von Humboldt Stifftung, City of Nice and Controlled Release Society, as well as Alliance's first Distinguished Contribution Award. He holds an honorary Research Associate position at the University of California at San Diego and sits on the Board of Directors of Alliance Pharmaceutical Corp.
“…Reaction of mPEG succinimidyl carbonates 4.31 and PEG bis(succinimidyl carbonates) 4.32 (Chart ) with lysine residues allowed formation of rather stable urethane linkages (eq 4.9) , (section IV.D). …”
Section: Acylation Reactionsmentioning
confidence: 99%
“…647 The ester linkage between the PEG strand and the succinic residue had, however, limited stability under physiological conditions. 648 The negatively charged monofunctional sulfosuccinimidyl acetate 4.33 and difunctional bis(sulfosuccinimidyl) suberate 4.34a and sebacate 4.34b were reported to selectively acylate and cross-link in the case of the difunctional esters (except in the case of ) has been used for establishing structure/ function relations in Hb, including determination of the residues involved in the Bohr effect, the role of the terminal NH 2 groups in CO 2 binding, the mechanism of the CO 2 -mediated reduction of O 2 affinity, and for increasing the O 2 affinity of HbS. 584,610,[649][650][651][652][653][654] When performed on deoxyHb at a pH ca.…”
Pharmaceutical Corporation in San Diego; however, the opinion expressed here are solely his and not necessarily those of the Corporation. Jean G. Riess received his chemical engineer and doctorat-e `s-sciences degrees (the latter with Professor Guy Ourisson in 1963) from the University of Strasbourg. He then spent two years with John Van Wazer at Monsanto in Saint-Louis, MO, learning some phosphorus and transitionmetal chemistry. In 1968 he became Professor at the University of Nice, France, where he founded, directed, and eventually became honorary director of the Unite ´de Chimie Mole ´culaire (associated with the Centre National de la Recherche Scientifique). His research successively involved phosphorus chemistry, transition-metal chemistry, organometallics, and eventually perfluorochemicals. His present interests are in fluorocarbons, fluorinated amphiphiles, and their colloid chemistry, including fluorocarbon emulsions for in vivo O 2 delivery, fluorinated self-assemblies, and drug delivery systems. Professor Riess has published about 360 papers and holds ca. 25 patents. He has served on numerous councils and committees and has chaired or co-chaired international conferences on phosphorus chemistry and blood substitutes. He has won awards from the French Academy of Sciences, French Chemical Society, Alexander von Humboldt Stifftung, City of Nice and Controlled Release Society, as well as Alliance's first Distinguished Contribution Award. He holds an honorary Research Associate position at the University of California at San Diego and sits on the Board of Directors of Alliance Pharmaceutical Corp.
“…In addition, the Bohr effect is more pronounced in bovine Hb, which allows an enhanced delivery of oxygen at a lower pH (14). When 1 to 10 monofunctional mPEGs (α‐hydroxy‐ω‐methypoly‐[oxy‐1,2‐ethanediyl]) are bound to the bovine hemoglobin surface, the intrinsic ability of bovine hemoglobin to deliver oxygen is retained and circulation time prolonged as the molecular weight of the adduct increases (15). PEG‐Hb, with its high colloidal osmotic pressure and long circulating half‐life, is exemplary for plasma expansion.…”
This study was designed to determine the advantages of using the hemoglobin-based oxygen carrier, polyethylene glycol conjugated bovine hemoglobin (PEG-Hb), as an additive to Ringer's lactate solution (RLS) for the treatment of acute hemorrhage in anesthetized female rats. Different compositions of PEG-Hb and RLS were administered intravenously in a paradigm that provided 30 ml/kg of resuscitation fluid following an episode of 15 min of hypotension. Hypotension was achieved by the removal of blood (1 ml/min) from the femoral vein until the mean arterial pressure was lowered to or below 50 mmHg and subsequently maintained until resuscitation. Short-term cardiovascular assessment showed that resuscitation fluids containing PEG-Hb resulted in higher mean arterial pressure, aortic blood flow, renal blood flow, and less dramatic shifts in arterial base excess and respiratory blood gases than plain RLS. The long-term survival experiment showed lower lactate dehydrogenase, alkaline phosphatase, and serum glutamic pyruvic transaminase levels in most groups resuscitated with solutions containing PEG-Hb, but no differences in survival (100%) were observed. The data suggest that the addition of PEG-Hb to RLS improves its resuscitative effects. Specifically, a solution of 50% RLS:50% PEG-Hb appeared to have the most favorable cardiovascular and metabolic effects in this anesthetized rat hypovolemic shock resuscitation model. Presumably, the improved effects seen with the addition of PEG-Hb were due to its innate plasma expansion and oxygen-delivery capabilities.
“…PEGs represent fairly high MW polymers and they tend to increase the viscosities of aqueous solutions. They non-specifically adsorb to surfaces and in so doing affect the physical and other properties of such surfaces including charge group pKa's and protein adsorption (Harris, 1992b;Harris and Zalipsky, 1997 Chapman, 2002;Harris, 1992b;Harris and Zalipsky, 1997;Nho et al, 1992). In many cases the methods listed in Table 1 Given the above, plus the great variation in proteins which are PEGylated and their degree of PEGylation, it may not be possible to identify a generic separation process for PEG-proteins.…”
Poly(ethylene glycol)-conjugated (or PEGylated) proteins are an increasingly important class of therapeutic proteins that offer improved in vivo circulation half lives over their corresponding native forms. Their production involves covalent attachment of one or more poly(ethylene glycol) molecules to a native protein, followed by purification. Because of the extremely high costs involved in producing native therapeutic proteins it is important that subsequent PEGylation processes are as efficient as possible. In this paper, reaction engineering and purification issues for PEGylated proteins are reviewed. Paramount considerations for PEGylation reactions are specificity with respect to the conjugation site and overall yield. Batch PEGylation reaction methods are discussed, along with innovative methods using packed bed or "on-column" approaches to improve specificity and yield. Purification methods are currently dominated by ion exchange and size exclusion chromatography. Other methods in common use for protein separations, including hydrophobic interaction chromatography, affinity chromatography and membrane separations, are rarely used in PEGylated protein purification schemes. A better understanding of the effects of PEGylation on the physicochemical properties of proteins (isoelectric point, surface charge density and distribution, molecular size and relative hydrophobicity) and interactions between PEGylated proteins and surfaces is needed for the future development of optimal purification processes and media.
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