Glucose-responsive oral insulin delivery for postprandial glycemic regulation

  • Jicheng Yu
  • Yuqi Zhang
  • Jinqiang Wang
  • Di Wen
  • Anna R. Kahkoska
  • John B. Buse
  • Zhen GuEmail author
Research Article


Controlling postprandial glucose levels for diabetic patients is critical to achieve the tight glycemic control that decreases the risk for developing long-term micro- and macrovascular complications. Herein, we report a glucose-responsive oral insulin delivery system based on Fc receptor (FcRn)-targeted liposomes with glucose-sensitive hyaluronic acid (HA) shell for postprandial glycemic regulation. After oral administration, the HA shell can quickly detach in the presence of increasing intestinal glucose concentration due to the competitive binding of glucose with the phenylboronic acid groups conjugated with HA. The exposed Fc groups on the surface of liposomes then facilitate enhanced intestinal absorption in an FcRn-mediated transport pathway. In vivo studies on chemically-induced type 1 diabetic mice show this oral glucose-responsive delivery approach can effectively reduce postprandial blood glucose excursions. This work is the first demonstration of an oral insulin delivery system directly triggered by increasing postprandial glucose concentrations in the intestine to provide an on-demand insulin release with ease of administration.


diabetes drug delivery glucose-responsive insulin nanomedicine 


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This work was supported by the grants from NC TraCS, NIH’s Clinical and Translational Science Awards (CTSA, NIH grant 1UL1TR001111) at UNC-CH and Sloan Research Fellowship. We acknowledge the use of the Analytical Instrumentation Facility (AIF) at NC State, which is supported by the State of North Carolina and the National Science Foundation (NSF).

Supplementary material

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Glucose-responsive oral insulin delivery for postprandial glycemic regulation


  1. [1]
    Mo, R.; Jiang, T. Y.; Di, J.; Tai, W. Y.; Gu, Z. Emerging micro- and nanotechnology based synthetic approaches for insulin delivery. Chem. Soc. Rev. 2014, 43, 3595–3629.CrossRefGoogle Scholar
  2. [2]
    Veiseh, O.; Tang, B. C.; Whitehead, K. A.; Anderson, D. G.; Langer, R. Managing diabetes with nanomedicine: Challenges and opportunities. Nat. Rev. Drug Discov. 2015, 14, 45–57.CrossRefGoogle Scholar
  3. [3]
    Owens, D. R.; Zinman, B.; Bolli, G. B. Insulins today and beyond. Lancet 2001, 358, 739–746.CrossRefGoogle Scholar
  4. [4]
    Owens, D. R. New horizons—Alternative routes for insulin therapy. Nat. Rev. Drug Discov. 2002, 1, 529–540.CrossRefGoogle Scholar
  5. [5]
    Bratlie, K. M.; York, R. L.; Invernale, M. A.; Langer, R.; Anderson, D. G. Materials for diabetes therapeutics. Adv. Healthc. Mater. 2012, 1, 267–284.CrossRefGoogle Scholar
  6. [6]
    Ravaine, V.; Ancla, C.; Catargi, B. Chemically controlled closed-loop insulin delivery. J. Control. Release 2008, 132, 2–11.CrossRefGoogle Scholar
  7. [7]
    Heinemann, L.; Pfutzner, A.; Heise, T. Alternative routes of administration as an approach to improve insulin therapy: Update on dermal, oral, nasal and pulmonary insulin delivery. Curr. Pharm. Des. 2001, 7, 1327–1351.CrossRefGoogle Scholar
  8. [8]
    Owens, D. R.; Zinman, B.; Bolli, G. Alternative routes of insulin delivery. Diabet. Med. 2003, 20, 886–898.CrossRefGoogle Scholar
  9. [9]
    Carino, G. P.; Mathiowitz, E. Oral insulin delivery. Adv. Drug Deliv. Rev. 1999, 35, 249–257.CrossRefGoogle Scholar
  10. [10]
    Cefalu, W. T. Concept, strategies, and feasibility of noninvasive insulin delivery. Diabetes Care 2004, 27, 239–246.CrossRefGoogle Scholar
  11. [11]
    Yu, J. C.; Zhang, Y. Q.; Ye, Y. Q.; DiSanto, R.; Sun, W. J.; Ranson, D.; Ligler, F. S.; Buse, J. B.; Gu, Z. Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery. Proc. Natl. Acad. Sci. USA 2015, 112, 8260–8265.CrossRefGoogle Scholar
  12. [12]
    Yu, J. C.; Zhang, Y. Q.; Bomba, H.; Gu, Z. Stimuli-responsive delivery of therapeutics for diabetes treatment. Bioeng. Transl. Med. 2016, 1, 323–337.Google Scholar
  13. [13]
    Makino, K.; Mack, E. J.; Okano, T.; Kim, S. W. A microcapsule selfregulating delivery system for insulin. J. Control. Release 1990, 12, 235–239.CrossRefGoogle Scholar
  14. [14]
    Iyer, H.; Khedkar, A.; Verma, M. Oral insulin—A review of current status. Diabetes Obes. Metab. 2010, 12, 179–185.CrossRefGoogle Scholar
  15. [15]
    Mitragotri, S.; Burke, P. A.; Langer, R. Overcoming the challenges in administering biopharmaceuticals: Formulation and delivery strategies. Nat. Rev. Drug Discov. 2014, 13, 655–672.CrossRefGoogle Scholar
  16. [16]
    Moroz, E.; Matoori, S.; Leroux, J. C. Oral delivery of macromolecular drugs: Where we are after almost 100 years of attempts. Adv. Drug Deliv. Rev. 2016, 101, 108–121.CrossRefGoogle Scholar
  17. [17]
    Lowman, A. M.; Morishita, M.; Kajita, M.; Nagai, T.; Peppas, N. A. Oral delivery of insulin using pH-responsive complexation gels. J. Pharm. Sci. 1999, 88, 933–937.CrossRefGoogle Scholar
  18. [18]
    Sonaje, K.; Lin, K. J.; Wang, J. J.; Mi, F. L.; Chen, C. T.; Juang, J. H.; Sung, H. W. Self-assembled pH-sensitive nanoparticles: A platform for oral delivery of protein drugs. Adv. Funct. Mater. 2010, 20, 3695–3700.CrossRefGoogle Scholar
  19. [19]
    Yin, L. C.; Ding, J. Y.; He, C. B.; Cui, L. M.; Tang, C.; Yin, C. H. Drug permeability and mucoadhesion properties of thiolated trimethyl chitosan nanoparticles in oral insulin delivery. Biomaterials 2009, 30, 5691–5700.CrossRefGoogle Scholar
  20. [20]
    Pridgen, E. M.; Alexis, F.; Kuo, T. T.; Levy-Nissenbaum, E.; Karnik, R.; Blumberg, R. S.; Langer, R.; Farokhzad, O. C. Transepithelial transport of Fc-targeted nanoparticles by the neonatal fc receptor for oral delivery. Sci. Transl. Med. 2013, 5, 213ra167.CrossRefGoogle Scholar
  21. [21]
    Raghavan, M.; Gastinel, L. N.; Bjorkman, P. J. The class I major histocompatibility complex related Fc receptor shows pH-dependent stability differences correlating with immunoglobulin binding and release. Biochemistry 1993, 32, 8654–8660.CrossRefGoogle Scholar
  22. [22]
    Qin, J. J.; Wang, W.; Sarkar, S.; Zhang, R. W. Oral delivery of anti-MDM2 inhibitor SP141-loaded FcRn-targeted nanoparticles to treat breast cancer and metastasis. J. Control. Release 2016, 237, 101–114.CrossRefGoogle Scholar
  23. [23]
    He, W. Z.; Ladinsky, M. S.; Huey-Tubman, K. E.; Jensen, G. J.; McIntosh, J. R.; Björkman, P. J. FcRn-mediated antibody transport across epithelial cells revealed by electron tomography. Nature 2008, 455, 542–546.CrossRefGoogle Scholar
  24. [24]
    Shi, Y. N.; Sun, X. F.; Zhang, L. P.; Sun, K. X.; Li, K. K.; Li, Y. X.; Zhang, Q. Fc-modified exenatide-loaded nanoparticles for oral delivery to improve hypoglycemic effects in mice. Sci. Rep. 2018, 8, 726.CrossRefGoogle Scholar
  25. [25]
    Deng, C. C.; Brooks, W. L. A.; Abboud, K. A.; Sumerlin, B. S. Boronic acid-based hydrogels undergo self-healing at neutral and acidic pH. ACS Macro Lett. 2015, 4, 220–224.CrossRefGoogle Scholar
  26. [26]
    Brooks, W. L. A.; Sumerlin, B. S. Synthesis and applications of boronic acid-containing polymers: From materials to medicine. Chem. Rev. 2015, 116, 1375–1397.CrossRefGoogle Scholar
  27. [27]
    Kataoka, K.; Miyazaki, H.; Bunya, M.; Okano, T.; Sakurai, Y. Totally synthetic polymer gels responding to external glucose concentration: Their preparation and application to on–off regulation of insulin release. J. Am. Chem. Soc. 1998, 120, 12694–12695.CrossRefGoogle Scholar
  28. [28]
    Chou, D. H. C.; Webber, M. J.; Tang, B. C.; Lin, A. B.; Thapa, L. S.; Deng, D.; Truong, J. V.; Cortinas, A. B.; Langer, R.; Anderson, D. G. Glucose-responsive insulin activity by covalent modification with aliphatic phenylboronic acid conjugates. Proc. Natl. Acad. Sci. USA 2015, 112, 2401–2406.CrossRefGoogle Scholar
  29. [29]
    Mo, R.; Jiang, T. Y.; Gu, Z. Enhanced anticancer efficacy by ATP-mediated liposomal drug delivery. Angew. Chem., Int. Ed. 2014, 53, 5815–5820.CrossRefGoogle Scholar
  30. [30]
    Zhan, C. Y.; Wang, W. P.; Santamaria, C.; Wang, B.; Rwei, A.; Timko, B. P.; Kohane, D. S. Ultrasensitive phototriggered local anesthesia. Nano Lett. 2017, 17, 660–665.CrossRefGoogle Scholar
  31. [31]
    Lu, Y.; Aimetti, A. A.; Langer, R.; Gu, Z. Bioresponsive materials. Nat. Rev. Mater. 2016, 2, 16075.CrossRefGoogle Scholar
  32. [32]
    Jin, Y.; Song, Y. P.; Zhu, X.; Zhou, D.; Chen, C. H.; Zhang, Z. R.; Huang, Y. Goblet cell-targeting nanoparticles for oral insulin delivery and the influence of mucus on insulin transport. Biomaterials 2012, 33, 1573–1582.CrossRefGoogle Scholar
  33. [33]
    Li, Y. H.; Wen, S. P.; Kota, B. P.; Peng, G.; Li, G. Q.; Yamahara, J.; Roufogalis, B. D. Punica granatum flower extract, a potent α-glucosidase inhibitor, improves postprandial hyperglycemia in Zucker diabetic fatty rats. J. Ethnopharmacol. 2005, 99, 239–244.CrossRefGoogle Scholar
  34. [34]
    Kim, J. H.; Kang, M. J.; Choi, H. N.; Jeong, S. M.; Lee, Y. M.; Kim, J. I. Quercetin attenuates fasting and postprandial hyperglycemia in animal models of diabetes mellitus. Nutr. Res. Pract. 2011, 5, 107–111.CrossRefGoogle Scholar
  35. [35]
    Bell, K. J.; King, B. R.; Shafat, A.; Smart, C. E. The relationship between carbohydrate and the mealtime insulin dose in type 1 diabetes. J. Diabetes Complications 2015, 29, 1323–1329.CrossRefGoogle Scholar
  36. [36]
    Wolever, T. M.; Bolognesi, C. Source and amount of carbohydrate affect postprandial glucose and insulin in normal subjects. J. Nutr. 1996, 126, 2798–2806.Google Scholar
  37. [37]
    American Diabetes Association, A. D. Standards of medical care in diabetes—2017: Summary of revisions. Diabetes Care 2017, 40, S4–S5.CrossRefGoogle Scholar
  38. [38]
    Roopenian, D. C.; Akilesh, S. FcRn: The neonatal Fc receptor comes of age. Nat. Rev. Immunol. 2007, 7, 715–725.CrossRefGoogle Scholar
  39. [39]
    Wang, Y. F.; Kohane, D. S. External triggering and triggered targeting strategies for drug delivery. Nat. Rev. Mater. 2017, 2, 17020.CrossRefGoogle Scholar
  40. [40]
    Di, J.; Yu, J. C.; Ye, Y. Q.; Ranson, D.; Jindal, A.; Gu, Z. Engineering synthetic insulin-secreting cells using hyaluronic acid microgels integrated with glucose-responsive nanoparticles. Cell. Mol. Bioeng. 2015, 8, 445–454.CrossRefGoogle Scholar
  41. [41]
    Zhang, Y. Q.; Yu, J. C.; Wang, J. Q.; Hanne, N. J.; Cui, Z.; Qian, C. G.; Wang, C.; Xin, H. L.; Cole, J. H.; Gallippi, C. M. et al. Thrombin-responsive transcutaneous patch for auto-anticoagulant regulation. Adv. Mater. 2017, 29, 1604043.CrossRefGoogle Scholar

Copyright information

© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Jicheng Yu
    • 1
  • Yuqi Zhang
    • 1
  • Jinqiang Wang
    • 1
    • 2
  • Di Wen
    • 1
    • 2
  • Anna R. Kahkoska
    • 3
  • John B. Buse
    • 3
  • Zhen Gu
    • 1
    • 2
    • 3
    • 4
  1. 1.Joint Department of Biomedical EngineeringUniversity of North Carolina at Chapel Hill and North Carolina State UniversityRaleighUSA
  2. 2.Department of BioengineeringUniversity of California, Los AngelesLos AngelesUSA
  3. 3.Department of MedicineUniversity of North Carolina at Chapel HillChapel HillUSA
  4. 4.California NanoSystems Institute (CNSI), Jonsson Comprehensive Cancer Center, Center for Minimally Invasive TherapeuticsUniversity of California, Los AngelesLos AngelesUSA

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