Advertisement

Nano Research

, Volume 10, Issue 4, pp 1393–1402 | Cite as

Ultrasound-triggered noninvasive regulation of blood glucose levels using microgels integrated with insulin nanocapsules

  • Jin Di
  • Jicheng Yu
  • Qun Wang
  • Shanshan Yao
  • Dingjie Suo
  • Yanqi Ye
  • Matthew Pless
  • Yong Zhu
  • Yun JingEmail author
  • Zhen GuEmail author
Research Article

Abstract

Diabetes is a serious public health problem affecting 422 million people worldwide. Traditional diabetes management often requires multiple daily insulin injections, associated with pain and inadequate glycemia control. Herein, we have developed an ultrasound-triggered insulin delivery system capable of pulsatile insulin release that can provide both long-term sustained and fast on-demand responses. In this system, insulin-loaded poly(lactic-co-glycolic acid) (PLGA) nanocapsules are encapsulated within chitosan microgels. The encapsulated insulin in nanocapsules can passively diffuse from the nanoparticle but remain restricted within the microgel. Upon ultrasound treatment, the stored insulin in microgels can be rapidly released to regulate blood glucose levels. In a chemically-induced type 1 diabetic mouse model, we demonstrated that this system, when activated by 30 s ultrasound administration, could effectively achieve glycemic control for up to one week in a noninvasive, localized, and pulsatile manner.

Keywords

controlled drug delivery focused ultrasound diabetes nanocapsule microgel 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Notes

Acknowledgements

This work was supported by the Junior Faculty Award of the American Diabetes Association (ADA), the NC State Faculty Research and Professional Development Award to Z. G. The authors thank Dr. John Buse at UNC-CH for helpful discussion and Dr. Elizabeth Loboa, Dr. Michael Gamcsik and Dr. Glenn Walker for assistance in equipment usage.

Supplementary material

12274_2017_1500_MOESM1_ESM.pdf (2 mb)
Ultrasound-triggered noninvasive regulation of blood glucose levels using microgels integrated with insulin nanocapsules

References

  1. [1]
    Whiting, D. R.; Guariguata, L.; Weil, C.; Shaw, J. IDF diabetes atlas: Global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res. Clin. Pract. 2011, 94, 311–321.CrossRefGoogle Scholar
  2. [2]
    W. H. O. (WHO). Global Report on Diabetes [Online]. http://apps.who.int/iris/bitstream/10665/204871/1/9789241 565257_eng.pdf?ua=1 (accessed Dec 10, 2016).Google Scholar
  3. [3]
    Herman, W. H. The economic costs of diabetes: Is it time for a new treatment paradigm? Diabetes Care 2013, 36, 775–776.CrossRefGoogle Scholar
  4. [4]
    Mead, V. P. A new model for understanding the role of environmental factors in the origins of chronic illness: A case study of type 1 diabetes mellitus. Med. Hypotheses 2004, 63, 1035–1046.CrossRefGoogle Scholar
  5. [5]
    Wood, J. R.; Miller, K. M.; Maahs, D. M.; Beck, R. W.; DiMeglio, L. A.; Libman, I. M.; Quinn, M.; Tamborlane, W. V.; Woerner, S. E. Most youth with type 1 diabetes in the T1D exchange clinic registry do not meet American diabetes association or international society for pediatric and adolescent diabetes clinical guidelines. Diabetes Care 2013, 36, 2035–2037.CrossRefGoogle Scholar
  6. [6]
    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
  7. [7]
    Ohkubo, Y.; Kishikawa, H.; Araki, E.; Miyata, T.; Isami, S.; Motoyoshi, S.; Kojima, Y.; Furuyoshi, N.; Shichiri, M. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with noninsulin- dependent diabetes mellitus: A randomized prospective 6-year study. Diabetes Res. Clin. Pract. 1995, 28, 103–117.CrossRefGoogle Scholar
  8. [8]
    The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med. 1993, 329, 977–986.Google Scholar
  9. [9]
    Barnett, A. H. The future of inhaled insulin and incretinmimetics in the management of diabetes. Prim. Care Diabetes 2008, 2, 59–61.CrossRefGoogle Scholar
  10. [10]
    Arbit, E.; Kidron, M. Oral insulin: The rationale for this approach and current developments. J. Diabetes Sci. Technol. 2009, 3, 562–567.CrossRefGoogle Scholar
  11. [11]
    Mitragotri, S.; Blankschtein, D.; Langer, R. Ultrasoundmediated transdermal protein delivery. Science 1995, 269, 850–853.CrossRefGoogle Scholar
  12. [12]
    Gu, Z.; Aimetti, A. A.; Wang, Q.; Dang, T. T.; Zhang, Y. L.; Veiseh, O.; Cheng, H.; Langer, R. S.; Anderson, D. G. Injectable nano-network for glucose-mediated insulin delivery. ACS Nano 2013, 7, 4194–4201.CrossRefGoogle Scholar
  13. [13]
    Fischel-Ghodsian, F.; Brown, L.; Mathiowitz, E.; Brandenburg, D.; Langer, R. Enzymatically controlled drug delivery. Proc. Natl. Acad. Sci. USA 1988, 85, 2403–2406.CrossRefGoogle Scholar
  14. [14]
    Gu, Z.; Dang, T. T.; Ma, M. L.; Tang, B. C.; Cheng, H.; Jiang, S.; Dong, Y. Z.; Zhang, Y. L.; Anderson, D. G. Glucose-responsive microgels integrated with enzyme nanocapsules for closed-loop insulin delivery. ACS Nano 2013, 7, 6758–6766.CrossRefGoogle Scholar
  15. [15]
    Yu, J. C.; Zhang, Y. Q.; Ye, Y. Q.; DiSanto, R.; Sun, W. J.; Ranson, D.; Ligler, F. S.; Buse, J. B.; Gu, Z. Microneedlearray patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery. Proc. Natl. Acad. Sci. USA 2015, 112, 8260–8265.CrossRefGoogle Scholar
  16. [16]
    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
  17. [17]
    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
  18. [18]
    Makino, K.; Mack, E. J.; Okano, T.; Kim, S. W. A microcapsule self-regulating delivery system for insulin. J. Control. Release 1990, 12, 235–239.CrossRefGoogle Scholar
  19. [19]
    Podual, K.; Doyle, F. J.; Peppas, N. A. Glucose-sensitivity of glucose oxidase-containing cationic copolymer hydrogels having poly (ethylene glycol) grafts. J. Control. Release 2000, 67, 9–17.CrossRefGoogle Scholar
  20. [20]
    Ng, K. Y.; Liu, Y. Therapeutic ultrasound: Its application in drug delivery. Med. Res. Rev. 2002, 22, 204–223.CrossRefGoogle Scholar
  21. [21]
    Zhang, Y. Q.; Yu, J. C.; Bomba, H. N.; Zhu, Y.; Gu, Z. Mechanical force-triggered drug delivery. Chem. Rev. 2016, 116, 12536–12563.CrossRefGoogle Scholar
  22. [22]
    Frinking, P. J. A.; Bouakaz, A.; de Jong, N.; Ten Cate, F. J.; Keating, S. Effect of ultrasound on the release of microencapsulated drugs. Ultrasonics 1998, 36, 709–712.CrossRefGoogle Scholar
  23. [23]
    Ferrara, K. W. Driving delivery vehicles with ultrasound. Adv. Drug Deliv. Rev. 2008, 60, 1097–1102.CrossRefGoogle Scholar
  24. [24]
    Timko, B. P.; Dvir, T.; Kohane, D. S. Remotely triggerable drug delivery systems. Adv. Mater. 2010, 22, 4925–4943.CrossRefGoogle Scholar
  25. [25]
    Di, J.; Price, J.; Gu, X.; Jiang, X. N.; Jing, Y.; Gu, Z. Ultrasound-triggered regulation of blood glucose levels using injectable nano-network. Adv. Healthc. Mater. 2014, 3, 811–816.CrossRefGoogle Scholar
  26. [26]
    Ferrara, K.; Pollard, R.; Borden, M. Ultrasound microbubble contrast agents: Fundamentals and application to gene and drug delivery. Annu. Rev. Biomed. Eng. 2007, 9, 415–447.CrossRefGoogle Scholar
  27. [27]
    Pavlin, C. J.; Harasiewicz, K.; Sherar, M. D.; Foster, F. S. Clinical use of ultrasound biomicroscopy. Ophthalmology 1991, 98, 287–295.CrossRefGoogle Scholar
  28. [28]
    Choi, W. I.; Lee, J. H.; Kim, J.-Y.; Kim, J.-C.; Kim, Y. H.; Tae, G. Efficient skin permeation of soluble proteins via flexible and functional nano-carrier. J. Control. Release 2012, 157, 272–278.CrossRefGoogle Scholar
  29. [29]
    Tinkov, S.; Bekeredjian, R.; Winter, G.; Coester, C. Microbubbles as ultrasound triggered drug carriers. J. Pharm. Sci. 2009, 98, 1935–1961.CrossRefGoogle Scholar
  30. [30]
    Schroeder, A.; Avnir, Y.; Weisman, S.; Najajreh, Y.; Gabizon, A.; Talmon, Y.; Kost, J.; Barenholz, Y. Controlling liposomal drug release with low frequency ultrasound: Mechanism and feasibility. Langmuir 2007, 23, 4019–4025.CrossRefGoogle Scholar
  31. [31]
    Epstein-Barash, H.; Orbey, G.; Polat, B. E.; Ewoldt, R. H.; Feshitan, J.; Langer, R.; Borden, M. A.; Kohane, D. S. A microcomposite hydrogel for repeated on-demand ultrasoundtriggered drug delivery. Biomaterials 2010, 31, 5208–5217.CrossRefGoogle Scholar
  32. [32]
    Tao, S. L.; Desai, T. A. Microfabricated drug delivery systems: From particles to pores. Adv. Drug Deliv. Rev. 2003, 55, 315–328.CrossRefGoogle Scholar
  33. [33]
    Di, J.; Yao, S. S.; Ye, Y. Q.; Cui, Z.; Yu, J. C.; Ghosh, T. K.; Zhu, Y.; Gu, Z. Stretch-triggered drug delivery from wearable elastomer films containing therapeutic depots. ACS Nano 2015, 9, 9407–9415.CrossRefGoogle Scholar

Copyright information

© Tsinghua University Press and Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Jin Di
    • 1
    • 2
  • Jicheng Yu
    • 1
    • 2
  • Qun Wang
    • 3
  • Shanshan Yao
    • 4
  • Dingjie Suo
    • 4
  • Yanqi Ye
    • 1
    • 2
  • Matthew Pless
    • 4
  • Yong Zhu
    • 4
  • Yun Jing
    • 4
    Email author
  • Zhen Gu
    • 1
    • 2
    • 5
    Email author
  1. 1.Joint Department of Biomedical EngineeringUniversity of North Carolina at Chapel Hill and North Carolina State UniversityRaleighUSA
  2. 2.Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, UNC Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillUSA
  3. 3.Department of Chemical and Biological EngineeringIowa State UniversityAmesUSA
  4. 4.Department of Mechanical and Aerospace EngineeringNorth Carolina State UniversityRaleighUSA
  5. 5.Department of MedicineUniversity of North Carolina at Chapel HillChapel HillUSA

Personalised recommendations