SYNTHESIS OF SULFONYLUREA CONJUGATED COPOLYMER VIA PEO SPACER AND ITSIN-VITRO SHORT-TERM BIOACTIVITY IN INSULIN-SECRETION FROM ISLETS OF LANGERHANS

In order to reduce the number of immunoprotected islets required in xe no- or allogenic transplants for reversing diabetes, analogues of glyb uride (a sulfonylurea), an extremely hydrophobic insulin secretagogue, were synthesized and used in an attempt to produce water soluble sulf onylurea (SU) grafted polymers. After synthesizing various polymers co ntaining glyburide analogues, a poly(N-vinyl-2-pyrrolidone-co-sulfonyl urea succinyl PEO (M-w = 3000) acrylate) was found to be soluble in a cell culture medium at pH 7.4. However, solubility was only obtained b y decreasing solution pH from 11 to 7.4. When the copolymer was added to the islet cell culture media at a concentration of 5 mu g ml(-1) (b ased on the theoretical SU content of the copolymer), insulin secretio n was enhanced by about 30% at low glucose concentrations of 50 and 10 0 mg dl(-1) compared to the control. This is equivalent to 40-60% bioa ctivity of glyburide. The polymer's effect on insulin secretion at a h igher glucose concentration of 200 mg dl(-1) was not significant. Cons idering the previous results where a similar but insoluble polymer wit hout 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. (C) 1998 Publish ed by Elsevier Science Ltd. All rights reserved.