Journal Home > Volume 12 , Issue 7
Nano Research 2019, 12(7): 1539-1545 https://doi.org/10.1007/s12274-018-2264-9
Research Article | Issue | Published: 18 December 2018

Glucose-responsive oral insulin delivery for postprandial glycemic regulation

Show Author's Information Jicheng Yu1,  Yuqi Zhang1,  Jinqiang Wang1,2,  Di Wen1,2,  Anna R. Kahkoska3,  John B. Buse3,  Zhen Gu1,2,3,4( )
Joint Department of Biomedical Engineering,University of North Carolina at Chapel Hill and North Carolina State University,Raleigh, NC,27695,USA;
Department of Bioengineering,University of California,Los Angeles, Los Angeles, CA,90095,USA;
Department of Medicine,University of North Carolina at Chapel Hill,Chapel Hill, NC,27599,USA;
California NanoSystems Institute (CNSI), Jonsson Comprehensive Cancer Center, Center for Minimally Invasive Therapeutics,University of California,Los Angeles, Los Angeles, CA,90095,USA;
Keywords:
drug delivery, nanomedicine, diabetes, glucose-responsive, insulin
Topics:
Controlled drug deliveryDrug deliveryInsulinLiposomesMammalsMedical nanotechnologyMedical problemsOrganic acids Targeted drug delivery
Cite this article:
Yu J, Zhang Y, Wang J, et al. Glucose-responsive oral insulin delivery for postprandial glycemic regulation. Nano Research, 2019, 12(7): 1539-1545. https://doi.org/10.1007/s12274-018-2264-9
Download citation
EndNote(RIS)
BibTeX

676

Views

45

Downloads

Citations

62

Crossref

N/A

WoS

52

Scopus

5

CSCD

Abstract Full text Electronic supplementary material About this 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.


menu
Abstract
Full text
Outline
Electronic supplementary material
About this article

Glucose-responsive oral insulin delivery for postprandial glycemic regulation

Show Author's information Jicheng Yu1, Yuqi Zhang1, Jinqiang Wang1,2, Di Wen1,2, Anna R. Kahkoska3, John B. Buse3, Zhen Gu1,2,3,4( )
Joint Department of Biomedical Engineering,University of North Carolina at Chapel Hill and North Carolina State University,Raleigh, NC,27695,USA;
Department of Bioengineering,University of California,Los Angeles, Los Angeles, CA,90095,USA;
Department of Medicine,University of North Carolina at Chapel Hill,Chapel Hill, NC,27599,USA;
California NanoSystems Institute (CNSI), Jonsson Comprehensive Cancer Center, Center for Minimally Invasive Therapeutics,University of California,Los Angeles, Los Angeles, CA,90095,USA;

Abstract

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.

Keywords: drug delivery, nanomedicine, diabetes, glucose-responsive, insulin

References(41)

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.
DOI Google Scholar
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.
DOI Google Scholar
3

Owens, D. R.; Zinman, B.; Bolli, G. B. Insulins today and beyond. Lancet 2001, 358, 739–746.
DOI Google Scholar
4

Owens, D. R. New horizons—Alternative routes for insulin therapy. Nat. Rev. Drug Discov. 2002, 1, 529–540.
DOI Google Scholar
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.
DOI Google Scholar
6

Ravaine, V.; Ancla, C.; Catargi, B. Chemically controlled closed-loop insulin delivery. J. Control. Release 2008, 132, 2–11.
DOI Google Scholar
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.
DOI Google Scholar
8

Owens, D. R.; Zinman, B.; Bolli, G. Alternative routes of insulin delivery. Diabet. Med. 2003, 20, 886–898.
DOI Google Scholar
9

Carino, G. P.; Mathiowitz, E. Oral insulin delivery. Adv. Drug Deliv. Rev. 1999, 35, 249–257.
DOI Google Scholar
10

Cefalu, W. T. Concept, strategies, and feasibility of noninvasive insulin delivery. Diabetes Care 2004, 27, 239–246.
DOI Google Scholar
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.
DOI Google Scholar
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.
DOI Google Scholar
13

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.
DOI Google Scholar
14

Iyer, H.; Khedkar, A.; Verma, M. Oral insulin—A review of current status. Diabetes Obes. Metab. 2010, 12, 179–185.
DOI Google Scholar
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.
DOI Google Scholar
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.
DOI Google Scholar
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.
DOI Google Scholar
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.
DOI Google Scholar
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.
DOI Google Scholar
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.
DOI Google Scholar
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.
DOI Google Scholar
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.
DOI Google Scholar
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.
DOI Google Scholar
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.
DOI Google Scholar
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.
DOI Google Scholar
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.
DOI Google Scholar
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.
DOI Google Scholar
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.
DOI Google Scholar
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.
DOI Google Scholar
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.
DOI Google Scholar
31

Lu, Y.; Aimetti, A. A.; Langer, R.; Gu, Z. Bioresponsive materials. Nat. Rev. Mater. 2016, 2, 16075.
DOI Google Scholar
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.
DOI Google Scholar
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.
DOI Google Scholar
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.
DOI Google Scholar
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.
DOI Google Scholar
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

American Diabetes Association, A. D. Standards of medical care in diabetes—2017: Summary of revisions. Diabetes Care 2017, 40, S4–S5.
DOI Google Scholar
38

Roopenian, D. C.; Akilesh, S. FcRn: The neonatal Fc receptor comes of age. Nat. Rev. Immunol. 2007, 7, 715–725.
DOI Google Scholar
39

Wang, Y. F.; Kohane, D. S. External triggering and triggered targeting strategies for drug delivery. Nat. Rev. Mater. 2017, 2, 17020.
DOI Google Scholar
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.
DOI Google Scholar
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.
DOI Google Scholar
File
12274_2018_2264_MOESM1_ESM.pdf (1.6 MB)
Publication history
Copyright
Acknowledgements

Publication history

Received: 12 October 2018
Revised: 03 December 2018
Accepted: 04 December 2018
Published: 18 December 2018
Issue date: July 2019

Copyright

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

Acknowledgements

Acknowledgements

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).

Return