Carboxymethyl dextran lactone: A preactivated polymer for amine conjugations

Heindel, Ned D.; Kauffman, Michael A.; Akyea, Eric; Engel, Stephanie A.; Frey, Michael F.; Lacey, C. Jeffrey; Egolf, Roger A.

doi:10.1021/bc00025a013

Cited by 5 publications

(1 citation statement)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Others took advantage of functional carboxyl groups on CMD to prepare stable enzyme conjugates by using water-soluble carbodiimide as the activating agent (7)(8)(9). The use of carbodiimide activation is, however, problematic because of the wellrecognized tendency of the activated intermediate to undergo an O-to N-acyl shift to form more stable nonreactive N-acyl urea derivatives (10).…”

Section: Introductionmentioning

confidence: 99%

Extending Insulin Action in Vivo by Conjugation to Carboxymethyl Dextran

et al. 1998

View full text Add to dashboard Cite

The biochemical and pharmacological properties of bioactive peptides and proteins can be altered by conjugation with polymers. This report describes site-specific attachment of insulin to activated carboxyl groups of carboxymethyl dextran (CMD, MW=51000) through the GlyA1 insulin amino group. On average, three or four insulin molecules were grafted to a CMD linear chain. Coupled insulin molecules were properly folded, and the bioactivity of conjugated insulin in the blood glucose depression assay was 9.6 IU/mg, which was only 2.6 times less than that for native insulin. The cell growth study indicated that the CMD-insulin conjugate was as mitogenic as insulin on vascular smooth muscle cells, whereas the starting CMD polymer was not. The insulin receptor binding constant of the conjugate (3.6 x 10[9] M[-1]) compared well with that of native insulin (7.6 x 10[9] M[-1]), indicating that the CMD chain does not present any major constraints to binding. Plasma clearance of CMD-insulin obeyed a two-compartment pharmacokinetic (PK) model with a CMD-insulin conjugate plasma elimination half-life of 114.1 min, which was significantly longer than that of soluble Zn-insulin (12.4 min). In contrast, pharmacodynamic (PD) profiles (blood glucose lowering effects) after intravenous (iv) administration of the conjugate or insulin in rats were not different. Subcutaneous (sc) administration of the conjugate resulted in a significantly prolonged plasma profile with a noncompartmental PK parameter mean residence time (MRT) of 103.5 min which was significantly longer than that of soluble Zn-insulin (40.5 min). This was reflected in the protracted PD effect of sc administered conjugate with time needed to reach minimum glucose concentration Tnadir of 95.7 min, which was significantly longer than that of insulin (62 min). We conclude that the conjugation of insulin to CMD leads to a bioactive conjugate with a delayed sc PD profile showing prolonged response, resembling intermediate acting insulin preparations.

show abstract

Section: Introductionmentioning

confidence: 99%

Extending Insulin Action in Vivo by Conjugation to Carboxymethyl Dextran

et al. 1998

View full text Add to dashboard Cite

show abstract

References

2008

Bioconjugate Techniques

View full text Add to dashboard Cite

A new cleavable reagent for cross-linking and reversible immobilization of proteins . Biochem. Biophys. Res. Comm. 87 , 734 -742 . Abou-Samra , A.B. , Freeman , M. , Juppner , H. , Uneno , S. , and Segre , G.V. ( 1990 ) Characterization of fully active biotinylated parathyroid hormone analogs. Applications to fl uorescence activated cell sorting of parathyroid hormone receptor bearing cells . Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase . Alteration of immunological properties of bovine serum albumin by covalent attachment of polyethylene glycol . Solid phase DNA amplifi cation: Characterisation of primer attachment and amplifi cation mechanisms . Nucleic Acids Res. 28 , e87 . Adolfson , R. , and Moudrianokis , E.N. ( 1976 ) Molecular polymorphism and mechanisms of activation and deactivation of the hydrolytic function of the coupling factor of oxidative phosphorylation . A strain-promoted [3 ϩ 2] azide-alkyne cycloaddition for covalent modifi cation of biomolecules in living systems . Interaction of fl uorescently labelled myosin subfragment 1 with nucleotide and actin . Biochemistry 25 , 6827 .

show abstract

References

2013

Bioconjugate Techniques

View full text Add to dashboard Cite

Carboxymethyl dextran lactone: A preactivated polymer for amine conjugations

Cited by 5 publications

References 12 publications

Extending Insulin Action in Vivo by Conjugation to Carboxymethyl Dextran

Extending Insulin Action in Vivo by Conjugation to Carboxymethyl Dextran

References

References

Contact Info

Product

Resources

About