A novel drug delivery system for type 1 diabetes:: Insulin-mimetic vanadyl-poly(γ-glutamic acid) complex

Insulin-mimetic vanadyl-poly(gamma-glutamic acid) complex, VO-gamma-PGA, is proposed as a novel drug delivery system for treating type I diabetic animals. The structure of VO-gamma-PGA in solution as well as in solid state was analyzed by electronic absorption, infra-red, and electron spin resonance spectra, and proposed that the equatorial coordination mode of VO2+ is in either carboxylate(O)-VO-(OH2)(3) or 2 carboxylate(O-2)-VO-(OH2)(2), In vitro insulin-mimetic activity, metallokinetic feature in the blood of healthy rats, and in vivo normoglycemic effect of the complex prepared in solution were evaluated in streptozotocin(STZ) -induced type 1 diabetic mice, and these effects were compared with those of a solution containing only VOSO4 as a positive control. The in vitro insulin-mimetic activity of VO-gamma-PGA was examined by determining both inhibition of free fatty acid (FFA) release and glucose uptake in isolated rat adipocytes, in which the concentration of VO-gamma-PGA for 50% inhibition of FFA release was significantly lower than that of VOSO4. Metallokinetic study suggested that the bioavailability of VO-gamma-PGA complex was much higher than that of VOSO4. The complex showed a significant hypoglycemic activity within at least 4 h after a single oral administration, the effect being sustained for at least 24 h. Furthermore, VO-gamma-PGA normalized the hyperglycemia in STZ-mice within 3 days when it was given orally at doses of 5-10 mg V kg(-1) body mass for 16 days. The improvement in diabetes was also supported by the results on oral glucose tolerance test, MbA(1c) levels, and blood pressure. (c) 2006 Elsevier Inc. All rights reserved.