Glucose의 Redox 반응에 의한 인슐린 방출 Device의 설계와 합성

정동준; Ito Y; Imanishi Y; 심정섭

Journal of the Korean Industrial and Engineering Chemistry, Vol.1, No.2, 107-115, December, 1990

Export Citation

Glucose의 Redox 반응에 의한 인슐린 방출 Device의 설계와 합성

Design and Synthesis of Devices Releasing Insulin in response to Redox Reaction of Glucose

정동준, Ito Y, Imanishi Y, 심정섭

초록

Glucose의 redox 반응에 의한 새로운 인슐린 방출계를 5, 5'-dithiobis(2-nitrobcnzoic acid)의 disulfide 결합을 이용해 인슐린을 pmma 막과 glucose oxidase에 고정화시켜 합성하였다. glucose와 glucose dehydrogenase 및 glucose oxidise와의 산화반응에 의해 disulfide 결합이 파괴되어 막과 효소로부터 인슐린이 방출된다. enzyme cofact들(nicotinamide adenin dinucleotide와 flavin adenin dinucleotide)을 coimmobilization시켜 membrane device에 대해 electron mediator로 작용하도록 하여 glucose의 농도 민감성을 향상시켰고 protein device에 대해서는 glucose oxidase에 인슐린을 직접 고정화시켜 민감성을 더욱 향상시켰다. 이 두 파지 계들은 glucose 특이성을 나타내며 방출된 인슐린은 생체인슐린과 구분되지 않았다. 방출인슐린의 생리활성은 생체인슐린의 81%였다.

New insulin-releasing system on the basis of the redox reaction of glucose was synthesized by immobilizing insulin through a disulfide bond(5, 5'-dithiobis(2-nitrobenzoic acid) to polymer membrane(poly(methyl methacrylate)) and enzyme(glucose oxidise). The disulfide bonds were cleaved upon oxidation of glucose with glucose dehydrogenase and glucose oxidase, releasing insulin from the membrane and enzyme. Sensitivity to glucose concentration was enhanced by coimmobilization of enzyme cofactors(nicotinamide adenin dinucleotide and flavin adenin dinucleotide) acting as electron mediator(for the membrane device), and further enhanced by direct immobilization of insulin on glucose oxidase(for the protein device). Both systems were specific to glucose, and the released insulin was indistinguishable from native insulin. The biological activity of released insulin was 81% of native insulin.

[References]

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[1] Spencer J, IEEE Trans. Biomed. Eng., 28, 37 (1981)

[2] Brwonlee M, Cerami A, Science, 206, 1190 (1979)

[3] Kim SW, Pai CM, Makino K, Seminoff LA, Holmberg DL, Gleeson JM, Wilson DE, Mack J, J. Control. Release, 11, 193 (1990)

[4] Ishihara K, Matsui K, J. Polym. Sci. C: Polym. Lett., 24, 413 (1986)

[5] Fischel-Ghodsian F, Brown L, Mathiowitz E, Brandenburg D, Langer R, Proc. Natl. Acad. Sci. U.S.A., 85, 2403 (1988)

[6] Ito Y, Casolaro M, Kono K, Imanishi Y, J. Control. Release, 10, 195 (1989)

[7] Ito Y, Kotera S, Inaba M, Kono K, Imanishi Y, Polymer, in press

[8] Ito Y, Casolaro M, Chung DJ, Imanishi Y, Drug Delivery System, 3, 391 (1988)

[9] Ito Y, Sisido M, Imanishi Y, J. Biomed. Mater. Res., 20, 1157 (1986)

[10] Liu LS, Ito Y, Imanishi Y, Biomaterials, in press

[11] Chung DJ, Ito Y, Imanishi Y, J. Control. Release, to be submitted

[12] Moore S, Stein WH, Methods Enzymology, 6, 819 (1963)

[13] Ito Y, Liu LS, Imanishi Y, J. Biomater. Sci.-Polym. Ed., accepted for publication

[14] Moody AJ, Stan MA, Stan M, Gliemann J, Horm. Metab. Res., 6, 12 (1974)

[15] Jeong SY, Kim SW, Holmberg DL, McRea JC, J. Control. Release, 2, 143 (1985)