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Drug Delivery and Translational Research

, Volume 8, Issue 3, pp 857–862 | Cite as

Sustained exenatide delivery via intracapsular microspheres for improved survival and function of microencapsulated porcine islets

Short Communication

Abstract

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.

Keywords

Porcine islets Exenatide Microspheres Microcapsules Islet encapsulation Islet xenotransplantation 

Notes

Acknowledgements

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.

Funding

Financial support for this work was partially provided by the Research Board and Kim-Fund of the University of Illinois.

Compliance with ethical standards

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.

References

  1. 1.
    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.CrossRefPubMedGoogle Scholar
  2. 2.
    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.CrossRefPubMedGoogle Scholar
  3. 3.
    Qi M. Transplantation of encapsulated pancreatic islets as a treatment for patients with type 1 diabetes mellitus. Adv Med. 2014;2014:429710.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Lim F, Sun AM. Microencapsulated islets as bioartificial endocrine pancreas. Science. 1980;210(4472):908–10.  https://doi.org/10.1126/science.6776628.CrossRefPubMedGoogle Scholar
  5. 5.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    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.CrossRefPubMedGoogle Scholar
  7. 7.
    Zhu HT, et al. Pig-islet xenotransplantation: recent progress and current perspectives. Front Surg. 2014;1:7.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    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.CrossRefPubMedGoogle Scholar
  11. 11.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    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.CrossRefPubMedGoogle Scholar
  13. 13.
    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.CrossRefPubMedGoogle Scholar
  14. 14.
    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.CrossRefPubMedGoogle Scholar
  15. 15.
    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.CrossRefPubMedGoogle Scholar
  16. 16.
    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.CrossRefPubMedGoogle Scholar
  17. 17.
    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.CrossRefPubMedGoogle Scholar
  18. 18.
    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.CrossRefGoogle Scholar
  19. 19.
    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.CrossRefPubMedGoogle Scholar
  20. 20.
    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.CrossRefPubMedGoogle Scholar
  21. 21.
    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.CrossRefPubMedGoogle Scholar
  22. 22.
    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.CrossRefPubMedGoogle Scholar
  23. 23.
    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.CrossRefPubMedGoogle Scholar
  24. 24.
    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.CrossRefPubMedGoogle Scholar
  25. 25.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    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.CrossRefPubMedGoogle Scholar
  27. 27.
    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.CrossRefPubMedGoogle Scholar
  28. 28.
    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.CrossRefPubMedGoogle Scholar
  29. 29.
    Shive MS, Anderson JM. Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv Drug Deliv Rev. 1997;28(1):5–24.CrossRefPubMedGoogle Scholar
  30. 30.
    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.CrossRefPubMedGoogle Scholar
  31. 31.
    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.CrossRefPubMedGoogle Scholar
  32. 32.
    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.CrossRefPubMedGoogle Scholar
  33. 33.
    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.CrossRefPubMedGoogle Scholar
  34. 34.
    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.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Controlled Release Society 2018

Authors and Affiliations

  1. 1.Department of Electrical and Computer EngineeringUniversity of IllinoisUrbanaUSA
  2. 2.Department of Biotechnology, College of Life Sciences and BiotechnologyKorea UniversitySeoulSouth Korea
  3. 3.Micro and Nanotechnology LaboratoryUniversity of IllinoisUrbanaUSA
  4. 4.Department of BioengineeringUniversity of IllinoisUrbanaUSA
  5. 5.Department of Materials Science and EngineeringUniversity of IllinoisUrbanaUSA

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