Dose Optimization of Tacrolimus for Improving Survival Time of PEGylated Islets in a Rat-to-Mouse Xenograft Model

Jee-Heon Jeong; Simmyung Yook; Youngro Byun

Macromolecular Research, Vol.24, No.12, 1047-1054, December, 2016

DOI10.1007/s13233-016-4110-9 Export Citation

Dose Optimization of Tacrolimus for Improving Survival Time of PEGylated Islets in a Rat-to-Mouse Xenograft Model

Jee-Heon Jeong¹, Simmyung Yook^{2, 3}, and Youngro Byun^{2, 4, †}

¹College of Pharmacy, Yeungnam University, Gyeongsan 38541, Korea
²Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea
³College of Pharmacy, Keimyung University, Daegu 42601, Korea
⁴Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Korea

E-mail:

Improvements in preventing pancreatic islet rejection are needed for successful treatment of type 1 diabetes. Our objective was to develop an optimized protocol combining modification of islets with polyethyleneglycol (PEG) chains and administration of tacrolimus (FK506, Prograf), an immunosuppressive drug for preventing rejection following transplantation. Freshly isolated islets were incubated with different concentrations (0.25, 1.00, 10.00, and 25.00%) of FITC-labeled mPEG-SCM (MW. 20 KDa) for various incubation times. 1% mPEG-SCM incubated with islets for 1 h is optimized surface coverage condition without cell toxicity. In addition, in order to optimize the concentration of tacrolimus (FK506, Prograf), different concentrations (0.1, 0.5 or 2.0 mg/kg) were injected into the diabetic mice following transplantation of PEGylated islets. The PEGylated islet survival time in mice injected daily with 0.1 mg/kg and 0.5 mg/kg of tacrolimus was significantly better than in the group without tacrolimus injection. The graft survival time in mice injected daily with 2.00 mg/kg of exhibited no prolonged survival time. Finally, immunohistochemical staining of left kidney containing PEGylated islets (injected with 0.1 mg/kg of tacrolimus) demonstrated strong staining for insulin, glucagon, and somatostatin but very weak CD20 staining was observed in the islet transplanted area. In conclusion, 1% mPEG-SCM incubated with islets for 1 h was the optimal condition for PEGylation without affecting the cell viability. A dose of tacrolimus between 0.1-0.5 mg/kg was highly effective for inhibiting immune cell activation. These results are promising for their application in developing a novel immunosuppressive protocol for successful pancreatic islet transplantation in the treatment of type 1 diabetes.

Keywords:islet transplantation;FK506;PEGylation;surface modification

[References]

Pellegrini S, Cantarelli E, Sordi V, Nano R, Piemonti L, Acta Diabetol., DOI:10.1007/s00592-016-0847-z (2016)
Shapiro AM, Nanji SA, Lakey JR, Immunol. Rev., 196, 219 (2003)
Bastaki S, Int. J. Diabetes Metab., 13, 111 (2005)
The Diabetes Control and Complications Trial Research Group, N. Engl. J. Med., 329, 977 (1993).
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, Heller SR, Rodriguez H, Rosenzweig J, Vigersky R, Diabetes Care, 36, 1384 (2013)
Fiorina P, Shapiro AM, Ricordi C, Secchi A, Am. J. Transplant., 8, 1990 (2008)
Davalli AM, Scaglia L, Zangen DH, Hollister J, Bonner-Weir S, Weir GC, Diabetes, 45, 1161 (1996)
Fox A, Koulmanda M, Mandel TE, van Rooijen N, Harrison LC, Transplantation, 66, 1407 (1998)
Kourtzelis I, Magnusson PU, Kotlabova K, Lambris JD, Chavakis T, Adv. Exp. Med. Biol., 865, 171 (2015)
MacGregor RR, Williams SJ, Tong PY, Kover K, Moore WV, Stehno-Bitte L, Am. J. Physiol. Endocrinol. Metab., 290, E771 (2006)
Gibly RF, Graham JG, Luo X, Lowe WL, Hering BJ, Shea LD, Diabetologia, 54, 2494 (2011)
Shahaf G, Moser H, Ozeri E, Mizrahi M, Abecassis A, Lewis EC, Mol. Med., 17, 1000 (2011)
Beck J, Angus R, Madsen B, Britt D, Vernon B, Nguyen KT, Tissue Eng., 13, 589 (2007)
Shapiro AM, Ricordi C, Hering BJ, Auchincloss H, Lindblad R, Robertson RP, Secchi A, Brendel MD, Berney T, Brennan DC, Cagliero E, Alejandro R, Ryan EA, DiMercurio B, Morel P, Polonsky KS, Reems JA, Bretzel RG, Bertuzzi F, Froud T, Kandaswamy R, Sutherlan, N. Engl. J. Med., 355, 1318 (2006)
Brennan DC, Kopetskie HA, Sayre PH, Alejandro R, Cagliero E, Shapiro AM, Goldstein JS, DesMarais MR, Booher S, Bianchine PJ, Am. J. Transplant., 16, 509 (2016)
Ryan EA, Paty BW, Senior PA, Bigam D, Alfadhli E, Kneteman NM, Lakey JR, Shapiro AM, Diabetes, 54, 2060 (2005)
Jeong JH, Yook S, Lee H, Ahn CH, Lee DY, Byun Y, Biochem. Biophys. Res. Commun., 433(4), 513 (2013)
Jeong JH, Yook S, Hwang JW, Jung MJ, Moon HT, Lee DY, Byun Y, Transplant. Proc., 45, 585 (2013)
Im BH, Jeong JH, Haque MR, Lee DY, Ahn CH, Kim JE, Byun Y, Biomaterials, 34, 2098 (2013)
Jeong JH, Hong SW, Hong S, Yook S, Jung Y, Park JB, Khue CD, Im BH, Seo J, Lee H, Ahn CH, Lee DY, Byun Y, Biomaterials, 32, 7961 (2011)
Liu XY, Nothias JM, Scavone A, Garfinkel M, Millis JM, ASAIO J., 56, 241 (2010)
Yang H, O'Hali W, Kearns H, Wright JR, Transplantation, 64, 28 (1997)
Lee DY, Park SJ, Nam JH, Byun Y, Tissue Eng., 12, 615 (2006)
Jeong JH, Arch. Pharmacal Res., 38, 785 (2015)
Jung YS, Jeong JH, Yook S, Im BH, Seo J, Hong SW, Park JB, Yang VC, Lee DY, Byun Y, Biomaterials, 33, 295 (2012)
Lee DY, Nam JH, Byun Y, J. Biomater. Sci.-Polym. Ed., 15, 753 (2004)
Lee DY, Lee S, Nam JH, Byun Y, Am. J. Transplant., 6, 1820 (2006)
Chang JY, Sehgal SN, Bansbach CC, Trends Pharmacol. Sci., 12, 218 (1991)
Haque MR, Lee DY, Ahn CH, Jeong JH, Byun Y, Pharm. Res., 31, 2453 (2014)
Jeong JH, Yook S, Jung Y, Im BH, Lee M, Ahn CH, Lee DY, Byun Y, J. Control. Release, 159, 368 (2012)
Yook S, Jeong JH, Jung YS, Hong SW, Im BH, Seo JW, Park JB, Lee M, Ahn CH, Lee H, Lee DY, Byun Y, Cell Transplant., 21, 1775 (2012)
Hsu SM, Raine L, Fanger H, J. Histochem. Cytochem., 29, 577 (1981)
Lee DY, Park SJ, Nam JH, Byun Y, J. Control. Release, 110, 290 (2006)
Ochiai M, Arita S, Nagai T, Sakamoto Y, Smith CV, Shevlin L, Mullen Y, Transplant. Proc., 30, 663 (1998)
Johnson JD, Ao Z, Ao P, Li H, Dai LJ, He Z, Tee M, Potter KJ, Klimek AM, Meloche RM, Thompson DM, Verchere CB, Warnock GL, Cell Transplant., 18, 883 (2009)

[1] Pellegrini S, Cantarelli E, Sordi V, Nano R, Piemonti L, Acta Diabetol., DOI:10.1007/s00592-016-0847-z (2016)

[2] Shapiro AM, Nanji SA, Lakey JR, Immunol. Rev., 196, 219 (2003)

[3] Bastaki S, Int. J. Diabetes Metab., 13, 111 (2005)

[4] The Diabetes Control and Complications Trial Research Group, N. Engl. J. Med., 329, 977 (1993).

[5] Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, Heller SR, Rodriguez H, Rosenzweig J, Vigersky R, Diabetes Care, 36, 1384 (2013)

[6] Fiorina P, Shapiro AM, Ricordi C, Secchi A, Am. J. Transplant., 8, 1990 (2008)

[7] Davalli AM, Scaglia L, Zangen DH, Hollister J, Bonner-Weir S, Weir GC, Diabetes, 45, 1161 (1996)

[8] Fox A, Koulmanda M, Mandel TE, van Rooijen N, Harrison LC, Transplantation, 66, 1407 (1998)

[9] Kourtzelis I, Magnusson PU, Kotlabova K, Lambris JD, Chavakis T, Adv. Exp. Med. Biol., 865, 171 (2015)

[10] MacGregor RR, Williams SJ, Tong PY, Kover K, Moore WV, Stehno-Bitte L, Am. J. Physiol. Endocrinol. Metab., 290, E771 (2006)

[11] Gibly RF, Graham JG, Luo X, Lowe WL, Hering BJ, Shea LD, Diabetologia, 54, 2494 (2011)

[12] Shahaf G, Moser H, Ozeri E, Mizrahi M, Abecassis A, Lewis EC, Mol. Med., 17, 1000 (2011)

[13] Beck J, Angus R, Madsen B, Britt D, Vernon B, Nguyen KT, Tissue Eng., 13, 589 (2007)

[14] Shapiro AM, Ricordi C, Hering BJ, Auchincloss H, Lindblad R, Robertson RP, Secchi A, Brendel MD, Berney T, Brennan DC, Cagliero E, Alejandro R, Ryan EA, DiMercurio B, Morel P, Polonsky KS, Reems JA, Bretzel RG, Bertuzzi F, Froud T, Kandaswamy R, Sutherlan, N. Engl. J. Med., 355, 1318 (2006)

[15] Brennan DC, Kopetskie HA, Sayre PH, Alejandro R, Cagliero E, Shapiro AM, Goldstein JS, DesMarais MR, Booher S, Bianchine PJ, Am. J. Transplant., 16, 509 (2016)

[16] Ryan EA, Paty BW, Senior PA, Bigam D, Alfadhli E, Kneteman NM, Lakey JR, Shapiro AM, Diabetes, 54, 2060 (2005)

[17] Jeong JH, Yook S, Lee H, Ahn CH, Lee DY, Byun Y, Biochem. Biophys. Res. Commun., 433(4), 513 (2013)

[18] Jeong JH, Yook S, Hwang JW, Jung MJ, Moon HT, Lee DY, Byun Y, Transplant. Proc., 45, 585 (2013)

[19] Im BH, Jeong JH, Haque MR, Lee DY, Ahn CH, Kim JE, Byun Y, Biomaterials, 34, 2098 (2013)

[20] Jeong JH, Hong SW, Hong S, Yook S, Jung Y, Park JB, Khue CD, Im BH, Seo J, Lee H, Ahn CH, Lee DY, Byun Y, Biomaterials, 32, 7961 (2011)

[21] Liu XY, Nothias JM, Scavone A, Garfinkel M, Millis JM, ASAIO J., 56, 241 (2010)

[22] Yang H, O'Hali W, Kearns H, Wright JR, Transplantation, 64, 28 (1997)

[23] Lee DY, Park SJ, Nam JH, Byun Y, Tissue Eng., 12, 615 (2006)

[24] Jeong JH, Arch. Pharmacal Res., 38, 785 (2015)

[25] Jung YS, Jeong JH, Yook S, Im BH, Seo J, Hong SW, Park JB, Yang VC, Lee DY, Byun Y, Biomaterials, 33, 295 (2012)

[26] Lee DY, Nam JH, Byun Y, J. Biomater. Sci.-Polym. Ed., 15, 753 (2004)

[27] Lee DY, Lee S, Nam JH, Byun Y, Am. J. Transplant., 6, 1820 (2006)

[28] Chang JY, Sehgal SN, Bansbach CC, Trends Pharmacol. Sci., 12, 218 (1991)

[29] Haque MR, Lee DY, Ahn CH, Jeong JH, Byun Y, Pharm. Res., 31, 2453 (2014)

[30] Jeong JH, Yook S, Jung Y, Im BH, Lee M, Ahn CH, Lee DY, Byun Y, J. Control. Release, 159, 368 (2012)

[31] Yook S, Jeong JH, Jung YS, Hong SW, Im BH, Seo JW, Park JB, Lee M, Ahn CH, Lee H, Lee DY, Byun Y, Cell Transplant., 21, 1775 (2012)

[32] Hsu SM, Raine L, Fanger H, J. Histochem. Cytochem., 29, 577 (1981)

[33] Lee DY, Park SJ, Nam JH, Byun Y, J. Control. Release, 110, 290 (2006)

[34] Ochiai M, Arita S, Nagai T, Sakamoto Y, Smith CV, Shevlin L, Mullen Y, Transplant. Proc., 30, 663 (1998)

[35] Johnson JD, Ao Z, Ao P, Li H, Dai LJ, He Z, Tee M, Potter KJ, Klimek AM, Meloche RM, Thompson DM, Verchere CB, Warnock GL, Cell Transplant., 18, 883 (2009)