Synthesis of sulfonylurea conjugated copolymer via PEO spacer and its in vitro short-term bioactivity in insulin secretion from islets of Langerhans.
In order to reduce the number of immunoprotected islets required in xeno- or allogenic transplants for reversing diabetes, analogues of glyburide (a sulfonylurea), an extremely hydrophobic insulin secretagogue, were synthesized and used in an attempt to produce water soluble sulfonylurea (SU) grafted polymers. After synthesizing various polymers containing glyburide analogues, a poly(N-vinyl-2-pyrrolidone-co-sulfonylurea succinyl PEO (Mw = 3000) acrylate) was found to be soluble in a cell culture medium at pH 7.4. However, solubility was only obtained by decreasing solution pH from 11 to 7.4. When the copolymer was added to the islet cell culture media at a concentration of 5 microg ml(-1) (based on the theoretical SU content of the copolymer), insulin secretion was enhanced by about 30% at low glucose concentrations of 50 and 100 mg dl(-1) compared to the control. This is equivalent to 40-60% bioactivity of glyburide. The polymer's effect on insulin secretion at a higher glucose concentration of 200 mg dl(-1) was not significant. Considering the previous results where a similar but insoluble polymer without a PEO spacer was used and the polymer showed SU bioactivity only at a glucose concentration of 50 mg dl(-1), the observations from this study indicates that the solubility of SU-grafted polymers may affect the binding of SU groups to SU receptors on the pancreatic beta-cells, resulting in improved pharmacodynamic effect of SU.
Hwang
J S
JS
Department of Materials Science and Engineering, Kwangju Institute of Science and Technology, South Korea.
Chae
S Y
SY
Lee
M K
MK
Bae
Y H
YH
D018528:ATP-Binding Cassette Transporters; D000818:Animals; D001672:Biocompatible Materials / Q000138:chemical synthesis* / Q000494:pharmacology; D002478:Cells, Cultured; D005905:Glyburide / Q000031:analogs & derivatives* / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D007328:Insulin / Q000032:analysis*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008970:Molecular Weight; D019397:Pancreas, Artificial; D011092:Polyethylene Glycols / Q000737:chemistry; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism; D012995:Solubility; D064233:Sulfonylurea Receptors
D018528:ATP-Binding Cassette Transporters; D001672:Biocompatible Materials; D007004:Hypoglycemic Agents; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D011092:Polyethylene Glycols; D005905:Glyburide