Transdermal delivery of a somatostatin receptor type 2 antagonist using microneedle patch technology for hypoglycemia prevention

Drug Delivery and Translational Research (2021)Cite this article

Abstract

Hypoglycemia is a serious and potentially fatal complication experienced by people with insulin-dependent diabetes. The complication is usually caused by insulin overdose, skipping meals, and/or excessive physical activities. In type 1 diabetes (T1D), on top of impaired pancreatic α-cells, excessive levels of somatostatin from δ-cells further inhibit glucagon secretion to counteract overdosed insulin. Herein, we aimed to develop a microneedle (MN) patch for transdermal delivery of a peptide (PRL-2903) that antagonizes somatostatin receptor type 2 (SSTR2) in α-cells. First, we investigated the efficacy of subcutaneously administered PRL-2903 and identified the optimal dose (i.e., the minimum effective dose) and treatment scheduling (i.e., the best administration time for hypoglycemia prevention) in a T1D rat model. We then designed an MN patch using a hyaluronic acid (HA)-based polymer. The possible effect of the polymer on stabilizing the native structure of PRL-2903 was studied by molecular dynamics (MD) simulations. The results showed that the HA-based polymer could stabilize the PRL-2903 structure by restricting water molecules, promoting intra-molecular H-bonding, and constraining torsional angles of important bonds. In vivo studies with an overdose insulin challenge revealed that the PRL-2903-loaded MN patch effectively increased the plasma glucagon level, restored the counter-regulation of blood glucose concentration, and prevented hypoglycemia. The proposed MN patch is the first demonstration of a transdermal microneedle patch designed to deliver an SSTR2 antagonist for the prevention of hypoglycemia. This counter-regulatory peptide delivery system may be applied alongside with insulin delivery systems to provide a more effective and safer treatment for people with insulin-dependent diabetes.

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Data availability

The authors confirm that the data supporting the findings of this study are available within the article [and/or] its supplementary materials.

References

  1. 1.

    Maahs DM, et al. Epidemiology of Type 1 Diabetes. Endocrinology and metabolism clinics of North America. 2010;39(3)481.

  2. 2.

    Miller KM, et al. Current state of type 1 diabetes treatment in the U.S.: updated data from the t1d exchange clinic registry. Diabetes Care. 2015;38(6):971–978.

  3. 3.

    GhavamiNejad A, et al. Glucose regulation by modified boronic acid-sulfobetaine zwitterionic nanogels - a non-hormonal strategy for the potential treatment of hyperglycemia. Nanoscale. 2019;11(21):10167–71.

    CAS  Article  Google Scholar 

  4. 4.

    Li J, et al. Enhancing thermal stability of a highly concentrated insulin formulation with Pluronic F-127 for long-term use in microfabricated implantable devices. Drug Deliv Transl Res. 2017;7(4):529–43.

    CAS  Article  Google Scholar 

  5. 5.

    Gupta J, Felner EI, Prausnitz MR. Minimally invasive insulin delivery in subjects with type 1 diabetes using hollow microneedles (vol 11, pg 329, 2009). Diabetes Technol Ther. 2009;11(7):471–471.

    CAS  Article  Google Scholar 

  6. 6.

    Chu MKL, et al. In Vivo Performance and biocompatibility of a subcutaneous implant for real-time glucose-responsive insulin delivery. Diabetes Technol Ther. 2015;17(4):255–67.

    CAS  Article  Google Scholar 

  7. 7.

    Maheandiran M, et al. Severe hypoglycemia in a juvenile diabetic rat model: Presence and severity of seizures are associated with mortality. PLoS One, 2013. 8(12).

  8. 8.

    Cryer PE. Minireview: glucagon in the pathogenesis of hypoglycemia and hyperglycemia in diabetes. Endocrinology. 2012;153(3):1039–48.

    CAS  Article  Google Scholar 

  9. 9.

    Leiter LA, et al. Assessment of the impact of fear of hypoglycemic episodes on glycemic and hypoglycemia management. Can J Diabetes. 2005;29(3):186–92.

    Google Scholar 

  10. 10.

    Zammitt NN, Frier BM. Hypoglycemia in type 2 diabetes - pathophysiology, frequency, and effects of different treatment modalities. Diabetes Care. 2005;28(12):2948–61.

    Article  Google Scholar 

  11. 11.

    Yue JTY, et al. Somatostatin receptor type 2 antagonism improves glucagon and corticosterone counterregulatory responses to hypoglycemia in streptozotocin-induced diabetic rats. Diabetes. 2012;61(1):197–207.

    CAS  Article  Google Scholar 

  12. 12.

    Gaisano HY, MacDonald PE, Vranic M. Glucagon secretion and signaling in the development of diabetes. Front Physiol. 2012. 3 Sep.

  13. 13.

    Strowski MZ, et al. Somatostatin inhibits insulin and glucagon secretion via two receptor subtypes: an in vitro study of pancreatic islets from somatostatin receptor 2 knockout mice. Endocrinology. 2000;141(1):111–7.

    CAS  Article  Google Scholar 

  14. 14.

    Leclair E, et al. Glucagon responses to exercise-induced hypoglycaemia are improved by somatostatin receptor type 2 antagonism in a rat model of diabetes. Diabetologia. 2016;59(8):1724–31.

    CAS  Article  Google Scholar 

  15. 15.

    Karimian N, et al. Somatostatin receptor type 2 antagonism improves glucagon counterregulation in biobreeding diabetic rats. Diabetes. 2013;62(8):2968–77.

    CAS  Article  Google Scholar 

  16. 16.

    Yue JT, et al. Amelioration of hypoglycemia via somatostatin receptor type 2 antagonism in recurrently hypoglycemic diabetic rats. Diabetes. 2013;62(7):2215–22.

    CAS  Article  Google Scholar 

  17. 17.

    GhavamiNejad A, et al. Glucose-responsive composite microneedle patch for hypoglycemia-triggered delivery of native glucagon. Adv Mater. 2019;31(30).

  18. 18.

    GhavamiNejad A, Lu B, Wu XY. Transdermal drug delivery via microneedle patches. Biomimetic Nanoengineered Materials for Advanced Drug Delivery. 2019.

  19. 19.

    Wang JQ, et al. Glucose-responsive insulin and delivery systems: innovation and translation. Adv Mater. 2020;32(13).

  20. 20.

    Kolluru C, Gomaa Y, Prausnitz MR. Development of a thermostable microneedle patch for polio vaccination. Drug Deliv Transl Res. 2019;9(1):192–203.

    CAS  Article  Google Scholar 

  21. 21.

    Donnelly RF, et al. Hydrogel-forming microneedle arrays for enhanced transdermal drug delivery. Adv Func Mater. 2012;22(23):4879–90.

    CAS  Article  Google Scholar 

  22. 22.

    Fukushima K, et al. Pharmacokinetic and pharmacodynamic evaluation of insulin dissolving microneedles in dogs. Diabetes Technol Ther. 2010;12(6):465–74.

    CAS  Article  Google Scholar 

  23. 23.

    Zhang SJ, et al. Microneedles improve the immunogenicity of DNA vaccines. Hum Gene Ther. 2018;29(9):1004–10.

    CAS  Article  Google Scholar 

  24. 24.

    Ripolin A, et al. Successful application of large microneedle patches by human volunteers. Int J Pharm. 2017;521(1–2):92–101.

    CAS  Article  Google Scholar 

  25. 25.

    Al-Kasasbeh R, et al. Evaluation of the clinical impact of repeat application of hydrogel-forming microneedle array patches. Drug Deliv Transl Res. 2020;10(3):690–705.

    CAS  Article  Google Scholar 

  26. 26.

    Larraneta E, et al. Microneedle arrays as transdermal and intradermal drug delivery systems: materials science, manufacture and commercial development. Maters Sci Eng R Rep. 2016;104:1–32.

    Article  Google Scholar 

  27. 27.

    Chang H, et al. A swellable microneedle patch to rapidly extract skin interstitial fluid for timely metabolic analysis. Adv Mater. 2017;29(37).

  28. 28.

    Yu JC, et al. Hypoxia and H2O2 dual-sensitive vesicles for enhanced glucose-responsive insulin delivery. Nano Lett. 2017;17(2):733–9.

    CAS  Article  Google Scholar 

  29. 29.

    Neves-Petersen MT, et al. High probability of disrupting a disulphide bridge mediated by an endogenous excited tryptophan residue. Protein Sci. 2002;11(3):588–600.

    CAS  Article  Google Scholar 

  30. 30.

    Choudhury CK, et al. Designing highly thermostable lysozyme-copolymer conjugates: focus on effect of polymer concentration. Biomacromol. 2018;19(4):1175–88.

    CAS  Article  Google Scholar 

  31. 31.

    Frisch M, et al. GAUSSIAN16. Revision C. 01. Gaussian Inc., Wallingford, CT, USA; 2016.

  32. 32.

    Case DA, Belfon K, Ben-Shalom IY, Brozell SR, Cerutti DS, Cheatham III TE, Cruzeiro VWD, Darden TA, Duke RE, Giambasu G, Gilson MK, Gohlke H, Goetz AW, Harris R, Izadi S, Izmailov SA, Kasavajhala K, Kovalenko A, Krasny R, Kurtzman T, Lee TS, LeGrand S, Li P, Lin C, Liu J, Luchko T, Luo R, Man V, Merz KM, Miao Y, Mikhailovskii O, Monard G, Nguyen H, Onufriev A, Pan F, Pantano S, Qi R, Roe DR, Roitberg A, Sagui C, Schott-Verdugo S, Shen J, Simmerling C, Skrynnikov NR, Smith J, Swails J, Walker RC, Wang J, Wilson L, Wolf RM, Wu X, Xiong Y, Xue Y, York DM, Kollman PA. AMBER 2020. University of California, San Francisco; 2020.

  33. 33.

    Van Der Spoel D, et al. GROMACS: fast, flexible, and free. J Comput Chem. 2005;26(16):1701–18.

    Article  Google Scholar 

  34. 34.

    Release S. 3: Desmond molecular dynamics system, DE Shaw research, New York, NY, 2017. Schrödinger, New York, NY: Maestro-Desmond Interoperability Tools; 2017.

    Google Scholar 

  35. 35.

    Banks JL, et al. Integrated modeling program, applied chemical theory (IMPACT). J Comput Chem. 2005;26(16):1752–80.

    CAS  Article  Google Scholar 

  36. 36.

    Toukmaji AY, Board JA Jr. Ewald summation techniques in perspective: a survey. Comput Phys Commun. 1996;95(2–3):73–92.

    CAS  Article  Google Scholar 

  37. 37.

    Mark P, Nilsson L. Structure and dynamics of the TIP3P, SPC, and SPC/E water models at 298 K. J Phys Chem A. 2001;105(43):9954–60.

    CAS  Article  Google Scholar 

  38. 38.

    Martyna GJ, et al. Explicit reversible integrators for extended systems dynamics. Mol Phys. 1996;87(5):1117–57.

    CAS  Article  Google Scholar 

  39. 39.

    Martyna GJ, Klein ML, Tuckerman M. Nosé-Hoover chains: the canonical ensemble via continuous dynamics. J Chem Phys. 1992;97(4):2635–43.

    Article  Google Scholar 

  40. 40.

    Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graph. 1996;14(1):33–8.

    CAS  Article  Google Scholar 

  41. 41.

    Hirobe S, et al. Clinical study of a retinoic acid-loaded microneedle patch for seborrheic keratosis or senile lentigo. Life Sci. 2017;168:24–7.

    CAS  Article  Google Scholar 

  42. 42.

    Yu WJ, et al. Polymer microneedles fabricated from alginate and hyaluronate for transdermal delivery of insulin. Mater Sci Eng C Mater Biol Appl. 2017;80:187–96.

    CAS  Article  Google Scholar 

  43. 43.

    Lee J, et al. Rapid and repeatable fabrication of high A/R silk fibroin microneedles using thermally-drawn micromolds. Eur J Pharm Biopharm. 2015;94:11–9.

    CAS  Article  Google Scholar 

  44. 44.

    Gittard SD, et al. The effects of geometry on skin penetration and failure of polymer microneedles. J Adhes Sci Technol. 2013;27(3):227–43.

    CAS  Article  Google Scholar 

  45. 45.

    Zhou Y, Wu XY. Theoretical analyses of dispersed-drug release from planar matrices with a boundary layer in a finite medium. J Control Release. 2002;84(1–2):1–13.

    CAS  Article  Google Scholar 

  46. 46.

    Fornaro T, et al. Hydrogen-bonding effects on infrared spectra from anharmonic computations: uracil–water complexes and uracil dimers. J Phys Chem A. 2015;119(18):4224–36.

    CAS  Article  Google Scholar 

  47. 47.

    Kumar K, Anbarasu A, Ramaiah S. Molecular docking and molecular dynamics studies on β-lactamases and penicillin binding proteins. Mol BioSyst. 2014;10(4):891–900.

    CAS  Article  Google Scholar 

  48. 48.

    Hamed E, Xu T, Keten S. Poly (ethylene glycol) conjugation stabilizes the secondary structure of α-helices by reducing peptide solvent accessible surface area. Biomacromol. 2013;14(11):4053–60.

    CAS  Article  Google Scholar 

  49. 49.

    Keefe AJ, Jiang S. Poly (zwitterionic) protein conjugates offer increased stability without sacrificing binding affinity or bioactivity. Nat Chem. 2012;4(1):59–63.

    CAS  Article  Google Scholar 

  50. 50.

    Childs BP, et al. Defining and reporting hypoglycemia in diabetes - a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care. 2005;28(5):1245–9.

    Article  Google Scholar 

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Acknowledgements

The authors would also like to thank the Banting and Best Diabetes Centre (BBDC) Seller Fellowship to A.GN., Ontario Graduate Scholarship and BBDC Travel Award to B.L., Graduate Department of Pharmaceutical Sciences scholarship to B.L. and F.L., and the staff of the DCM facility at the University of Toronto for help with certain experiments.

Funding

The work was supported through funding from JDRF (2-SRA-2016-268-A-N) to X.Y.W. and A.G. and the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery (RGPIN 170460-13) and Equipment grants (EQPEQ 374799-09; EQPEQ 440689-13) to X.Y.W.

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Affiliations

  1. Advanced Pharmaceutics and Drug Delivery Laboratory, Leslie L. Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, M5S 3M2, Canada

    Amin GhavamiNejad, Brian Lu, Jackie Fule Liu, Sako Mirzaie & Xiao Yu Wu

  2. Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada

    Melisa Samarikhalaj, Sandra Pereira, Liwei Zhou & Adria Giacca

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  1. Amin GhavamiNejad
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  2. Brian Lu
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  3. Melisa Samarikhalaj
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  9. Xiao Yu Wu
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Contributions

A.GN., B.L., A.G., and X.Y.W. designed the in vitro and in vivo experiments. A.GN. synthesized the materials and fabricated the MN patches. A.GN., B.L., M.S., J.F.L., and L.Z. performed the experiments. A.GN., B.L., and S.M. wrote the manuscript. S.M. designed and performed the simulation studies. S.P. performed the statistical analysis. A.G. and X.Y.W. provided resources and supervised the project. The manuscript was edited through contributions of all authors.

Corresponding author

Correspondence to Xiao Yu Wu.

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GhavamiNejad, A., Lu, B., Samarikhalaj, M. et al. Transdermal delivery of a somatostatin receptor type 2 antagonist using microneedle patch technology for hypoglycemia prevention. Drug Deliv. and Transl. Res. (2021). https://doi.org/10.1007/s13346-021-00944-3

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Keywords

  • Hypoglycemia prevention
  • Drug delivery systems
  • Microneedle patch
  • Somatostatin receptor type 2 antagonist
  • Molecular dynamics simulation