Extending insulin action in vivo by conjugation to carboxymethyl dextran

Bioconjugate Chemistry
M BaudysS W Kim

Abstract

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 gluc...Continue Reading

References

Nov 15, 1977·FEBS Letters·J J MarshallS L Abramson
Oct 17, 1983·European Journal of Biochemistry·M Baudys, V Kostka
Jan 1, 1994·Bioconjugate Chemistry·N D HeindelR A Egolf
Jan 1, 1995·Journal of Pharmaceutical Sciences·M BaudysS W Kim

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Citations

Oct 6, 2000·Journal of Controlled Release : Official Journal of the Controlled Release Society·R Mehvar
Mar 4, 2000·Journal of Controlled Release : Official Journal of the Controlled Release Society·D LetourneurM Cansell
Feb 21, 2009·Molecular Pharmaceutics·Leena N PatelWei-Chiang Shen
Oct 12, 2011·Journal of Controlled Release : Official Journal of the Controlled Release Society·Gul ShahnazAndreas Bernkop-Schnürch
May 19, 2009·International Journal of Pharmaceutics·Taishi HigashiKaneto Uekama
Oct 13, 2006·Journal of Controlled Release : Official Journal of the Controlled Release Society·Yu-Qing ZhangRen-Yu Xue
Mar 26, 2014·Biomacromolecules·Alice W Du, Martina H Stenzel
Feb 6, 2017·Journal of Controlled Release : Official Journal of the Controlled Release Society·Jianhai Yang, Zhiqiang Cao
Jun 13, 2006·Journal of Biomedical Materials Research. Part B, Applied Biomaterials·Yu-Qing ZhangKenji Kiguchi
Apr 23, 2014·Advanced Healthcare Materials·Thavasyappan ThambiJae Hyung Park
Oct 25, 2016·ChemMedChem·Søren B van WitteloostuijnKnud J Jensen
Jul 9, 1999·Journal of Biomedical Materials Research·M CansellD Letourneur

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