The ability of glucagon-like peptide-1 analogs to enhance glucose-dependent insulin secretion and to inhibit β cell apoptosis could be of potential benefit for islet transplantation. In this study, we investigated the effect of sustained local delivery of exenatide, a synthetic exendin-4, on the in vitro viability and function of encapsulated porcine islets. Prior to encapsulation, we fabricated exenatide-loaded poly(latic-co-glycolic acid) microspheres, and investigated their release behavior with different initial drug-loading amounts. Exenatide-loaded microspheres, exhibiting a sustained release over 21 days, were subsequently chosen and co-encapsulated with porcine islets in alginate microcapsules. During the 21-day period, the islets co-encapsulated with the exenatide-loaded microspheres exhibited improved survival and glucose-stimulated insulin secretion, compared to those without. This suggested that the intracapsular sustained delivery of exenatide via microspheres could be a promising strategy for improving survival and function of microencapsulated porcine islets for islet xenotransplantation.
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de Groot M, Schuurs TA, van Schilfgaarde R. Causes of limited survival of microencapsulated pancreatic islet grafts. J Surg Res. 2004;121(1):141–50. https://doi.org/10.1016/j.jss.2004.02.018.
Gaba RC, Garcia-Roca R, Oberholzer J. Pancreatic islet cell transplantation: an update for interventional radiologists. J Vasc Interv Radiol. 2012;23(5):583–94; quiz 594. https://doi.org/10.1016/j.jvir.2012.01.057.
Qi M. Transplantation of encapsulated pancreatic islets as a treatment for patients with type 1 diabetes mellitus. Adv Med. 2014;2014:429710.
Lim F, Sun AM. Microencapsulated islets as bioartificial endocrine pancreas. Science. 1980;210(4472):908–10. https://doi.org/10.1126/science.6776628.
Potter KJ, Abedini A, Marek P, Klimek AM, Butterworth S, Driscoll M, et al. Islet amyloid deposition limits the viability of human islet grafts but not porcine islet grafts. Proc Natl Acad Sci U S A. 2010;107(9):4305–10. https://doi.org/10.1073/pnas.0909024107.
Wynyard S, Nathu D, Garkavenko O, Denner J, Elliott R. Microbiological safety of the first clinical pig islet xenotransplantation trial in New Zealand. Xenotransplantation. 2014;21(4):309–23. https://doi.org/10.1111/xen.12102.
Zhu HT, et al. Pig-islet xenotransplantation: recent progress and current perspectives. Front Surg. 2014;1:7.
Mineo D, Pileggi A, Alejandro R, Ricordi C. Point: steady progress and current challenges in clinical islet transplantation. Diabetes Care. 2009;32(8):1563–9. https://doi.org/10.2337/dc09-0490.
Sakata N, Sumi S, Yoshimatsu G, Goto M, Egawa S, Unno M. Encapsulated islets transplantation: past, present and future. World J Gastrointest Pathophysiol. 2012;3(1):19–26. https://doi.org/10.4291/wjgp.v3.i1.19.
Yang HK, Yoon KH. Current status of encapsulated islet transplantation. J Diabetes Complicat. 2015;29(5):737–43. https://doi.org/10.1016/j.jdiacomp.2015.03.017.
Sato Y, Endo H, Okuyama H, Takeda T, Iwahashi H, Imagawa A, et al. Cellular hypoxia of pancreatic beta-cells due to high levels of oxygen consumption for insulin secretion in vitro. J Biol Chem. 2011;286(14):12524–32. https://doi.org/10.1074/jbc.M110.194738.
Pileggi A, Ricordi C, Alessiani M, Inverardi L. Factors influencing Islet of Langerhans graft function and monitoring. Clin Chim Acta. 2001;310(1):3–16. https://doi.org/10.1016/S0009-8981(01)00503-4.
Padmasekar M, Lingwal N, Samikannu B, Chen C, Sauer H, Linn T. Exendin-4 protects hypoxic islets from oxidative stress and improves islet transplantation outcome. Endocrinology. 2013;154(4):1424–33. https://doi.org/10.1210/en.2012-1983.
Jeong JH, Yook S, Jung Y, Im BH, Lee M, Ahn CH, et al. Functional enhancement of beta cells in transplanted pancreatic islets by secretion signal peptide-linked exendin-4 gene transduction. J Control Release. 2012;159(3):368–75. https://doi.org/10.1016/j.jconrel.2012.01.029.
Berkland C, Kim K, Pack DW. Fabrication of PLG microspheres with precisely controlled and monodisperse size distributions. J Control Release. 2001;73(1):59–74. https://doi.org/10.1016/S0168-3659(01)00289-9.
Berkland C, King M, Cox A, Kim KK, Pack DW. Precise control of PLG microsphere size provides enhanced control of drug release rate. J Control Release. 2002;82(1):137–47. https://doi.org/10.1016/S0168-3659(02)00136-0.
Cheng F, Choy YB, Choi H, Kim KK. Modeling of small-molecule release from crosslinked hydrogel microspheres: effect of crosslinking and enzymatic degradation of hydrogel matrix. Int J Pharm. 2011;403(1–2):90–5. https://doi.org/10.1016/j.ijpharm.2010.10.029.
Liu B, Dong Q, Wang M, Shi L, Wu Y, Yu X, et al. Preparation, characterization, and pharmacodynamics of exenatide-loaded poly(DL-lactic-co-glycolic acid) microspheres. Chem Pharm Bull (Tokyo). 2010;58(11):1474–9. https://doi.org/10.1248/cpb.58.1474.
Meinel L, Illi OE, Zapf J, Malfanti M, Peter Merkle H, Gander B. Stabilizing insulin-like growth factor-I in poly(D,L-lactide-co-glycolide) microspheres. J Control Release. 2001;70(1–2):193–202. https://doi.org/10.1016/S0168-3659(00)00352-7.
Geng Y, et al. Formulating erythropoietin-loaded sustained-release PLGA microspheres without protein aggregation. J Control Release. 2008;130(3):259–65. https://doi.org/10.1016/j.jconrel.2008.06.011.
Ricordi C, Finke EH, Lacy PE. A method for the mass isolation of islets from the adult pig pancreas. Diabetes. 1986;35(6):649–53. https://doi.org/10.2337/diab.35.6.649.
Brandhorst H, Brandhorst D, Hering BJ, Bretzel RG. Significant progress in porcine islet mass isolation utilizing liberase HI for enzymatic low-temperature pancreas digestion. Transplantation. 1999;68(3):355–61. https://doi.org/10.1097/00007890-199908150-00006.
Shimoda M, Noguchi H, Fujita Y, Takita M, Ikemoto T, Chujo D, et al. Improvement of porcine islet isolation by inhibition of trypsin activity during pancreas preservation and digestion using alpha1-antitrypsin. Cell Transplant. 2012;21(2–3):465–71. https://doi.org/10.3727/096368911X605376.
Kim IY, Pusey PL, Zhao Y, Korban SS, Choi H, Kim KK. Controlled release of Pantoea agglomerans E325 for biocontrol of fire blight disease of apple. J Control Release. 2012;161(1):109–15. https://doi.org/10.1016/j.jconrel.2012.03.028.
Qi M, Strand BL, Mørch Y, Lacík I, Wang Y, Salehi P, et al. Encapsulation of human islets in novel inhomogeneous alginate-ca2+/ba2+ microbeads: in vitro and in vivo function. Artif Cells Blood Substit Immobil Biotechnol. 2008;36(5):403–20. https://doi.org/10.1080/10731190802369755.
Strand BL, Mørch YA, Espevik T, Skjåk-Braek G. Visualization of alginate-poly-L-lysine-alginate microcapsules by confocal laser scanning microscopy. Biotechnol Bioeng. 2003;82(4):386–94. https://doi.org/10.1002/bit.10577.
Ricordi C, Gray DWR, Hering BJ, Kaufman DB, Warnock GL, Kneteman NM, et al. Islet isolation assessment in man and large animals. Acta Diabetol Lat. 1990;27(3):185–95. https://doi.org/10.1007/BF02581331.
Korbutt GS, Mallett AG, Ao Z, Flashner M, Rajotte RV. Improved survival of microencapsulated islets during in vitro culture and enhanced metabolic function following transplantation. Diabetologia. 2004;47(10):1810–8. https://doi.org/10.1007/s00125-004-1531-3.
Shive MS, Anderson JM. Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv Drug Deliv Rev. 1997;28(1):5–24.
Ma G. Microencapsulation of protein drugs for drug delivery: strategy, preparation, and applications. J Control Release. 2014;193:324–40. https://doi.org/10.1016/j.jconrel.2014.09.003.
Ramazani F, Chen W, van Nostrum CF, Storm G, Kiessling F, Lammers T, et al. Strategies for encapsulation of small hydrophilic and amphiphilic drugs in PLGA microspheres: state-of-the-art and challenges. Int J Pharm. 2016;499(1–2):358–67. https://doi.org/10.1016/j.ijpharm.2016.01.020.
Zhu C, Huang Y, Zhang X, Mei L, Pan X, Li G, et al. Comparative studies on exenatide-loaded poly (D,L-lactic-co-glycolic acid) microparticles prepared by a novel ultra-fine particle processing system and spray drying. Colloids Surf B Biointerfaces. 2015;132:103–10. https://doi.org/10.1016/j.colsurfb.2015.05.001.
Qi F, Wu J, Fan Q, He F, Tian G, Yang T, et al. Preparation of uniform-sized exenatide-loaded PLGA microspheres as long-effective release system with high encapsulation efficiency and bio-stability. Colloids Surf B Biointerfaces. 2013;112:492–8. https://doi.org/10.1016/j.colsurfb.2013.08.048.
Prentki M, Nolan CJ. Islet beta cell failure in type 2 diabetes. J Clin Invest. 2006;116(7):1802–12. https://doi.org/10.1172/JCI29103.
This work was carried out in part in the Frederick Seitz Materials Research Laboratory Central Facilities and Beckman Institute for Advanced Science and Technology, University of Illinois.
Financial support for this work was partially provided by the Research Board and Kim-Fund of the University of Illinois.
All institutional and national guidelines for the care and use of laboratory animals were followed.
Conflict of interest
The authors declare that they have no conflict of interest.
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Lew, B., Kim, IY., Choi, H. et al. Sustained exenatide delivery via intracapsular microspheres for improved survival and function of microencapsulated porcine islets. Drug Deliv. and Transl. Res. 8, 857–862 (2018). https://doi.org/10.1007/s13346-018-0484-x
- Porcine islets
- Islet encapsulation
- Islet xenotransplantation