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Autonomous Rhythmic Drug Delivery Systems Based on Chemical and Biochemomechanical Oscillators

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Chemomechanical Instabilities in Responsive Materials

Abstract

While many drug delivery systems target constant, or zero-order drug release, certain drugs and hormones must be delivered in rhythmic pulses in order to achieve their optimal effect. Here we describe studies with two model autonomous rhythmic delivery systems. The first system is driven by a pH oscillator that modulates the ionization state of a model drug, benzoic acid, which can permeate through a lipophilic membrane when the drug is uncharged. The second system is based on a nonlinear negative feedback instability that arises from coupling of swelling of a hydrogel membrane to an enzymatic reaction, with the hydrogel controlling access of substrate to the enzyme, and the enzyme's product controlling the hydrogel's swelling state. The latter system, whose autonomous oscillations are driven by glucose at constant external activity, is shown to deliver gonadotropin releasing hormone (GnRH) in rhythmic pulses, with periodicity of the same order as observed in sexually mature adult humans. Relevant experimental results and some mathematical models are reviewed.

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References

  1. T. G. J. Farmer, T. F. Edgar and N. A. Peppas, J. Pharm. Pharmacol. 60, 1–13 (2008).

    Article  Google Scholar 

  2. H. E. Koschwanez and W. M. Reichert, Biomaterials 28, 3687–3703 (2007).

    Article  Google Scholar 

  3. E. Renard, G. Costalat, H. Chevassus and J. Bringer, Diabet. Metab. 32, 497–502 (2006).

    Article  Google Scholar 

  4. G. M. Steil and K. Rebrin, Expert Opin. Drug Deliv. 2, 353–362 (2006).

    Article  Google Scholar 

  5. W. F. Crowley and J. G. Hofler, The Episodic Secretion of Hormones (Wiley, New York, 1987).

    Google Scholar 

  6. A. Goldbeter, Biochemical Oscillations and Cellular Rhythms (Cambridge University Press, Cambridge, U.K., 1996).

    Book  MATH  Google Scholar 

  7. G. Brabant, K. Prank and C. Schöfl, Trends Endocrinol. Metab. 3, 183–190 (1992).

    Article  Google Scholar 

  8. J. D. Veldhuis, M. L. Johnson and W. K. Bolton, Pediatr. Nephrol. 5, 522–528 (1991).

    Article  Google Scholar 

  9. C. H. Courtney, A. B. Atkinson, C. N. Ennis, B. Sheridan and P. M. Bell, Metabolism 52, 1050–1055 (2003).

    Article  Google Scholar 

  10. D. R. Matthews, B. A. Naylor, R. G. Jones, G. M. Ward and R. C. Turner, Diabetes 32, 617–621 (1983).

    Article  Google Scholar 

  11. P. E. Belchetz, T. M. Plant, Y. Nakai, E. J. Keogh, and E. Knobil, Science 202, 631–633 (1978).

    Article  ADS  Google Scholar 

  12. P. M. Conn and W. F. Crowley Jr., Ann. Rev. Med. 45, 391–405 (1994).

    Article  Google Scholar 

  13. N. Santoro, M. Filicori and W. F. Crowley Jr., Endocr. Revs. 7, 11–23 (1986).

    Article  Google Scholar 

  14. A. V. Schally, Science 202, 18–28 (1978).

    Article  ADS  Google Scholar 

  15. J. E. A. McIntosh and R. P. McIntosh, J. Endocr. 109, 155–161 (1986).

    Article  Google Scholar 

  16. G. L. Leyendecker, L. Wildt and M. Hansmann, J. Clin. Endocrinol. Metab. 51, 1214–1216 (1980).

    Article  Google Scholar 

  17. M. B. Southworth, A. M. Matsumoto, K. Gross, M. R. Soules and W. J. Bremner, J. Clin. Endocrin. Metab. 72, 1286–1289 (1991).

    Article  Google Scholar 

  18. J. O. Parker, M. H. Amies, R. W. Hawkinson, J. M. Heilman, A. J. Hougham, M. C. Vollmer and R. R. Wilson, Circulation 91, 1368–1374 (1995).

    Google Scholar 

  19. D. Stanislaus, J. H. Pinter, J. Janovick and P. M. Conn, Mol Cell Endocrinol 144, 1–10 (1998).

    Article  Google Scholar 

  20. Y.-X. Li and A. Goldbeter, Biophys. J. 55, 125–145 (1989).

    Article  Google Scholar 

  21. M. H. Smolensky and N. Peppas, Adv. Drug Del. Revs. 59, 828–851 (2007).

    Article  Google Scholar 

  22. B. Lemmer, J. Control. Release 16, 63–74 (1991).

    Article  Google Scholar 

  23. A. E. Reinberg, Ann. Rev. Pharmacol. Toxicol. 32, 51–66 (1992).

    Article  Google Scholar 

  24. B. Bruguerolle, A. Boulamery and N. Simon, J. Pharm. Sci. 97, 1099–1108 (2008).

    Article  Google Scholar 

  25. M. Baraldo, Expert. Opin. Drug Metabol. Toxicol. 4, 175–192 (2008).

    Article  Google Scholar 

  26. I. R. Epstein and J. A. Pojman, An Introduction to Nonlinear Chemical Dynamics, Oxford, New York, 1998.

    Google Scholar 

  27. P. Gray and S. K. Scott, Chemical Oscillations and Instabilities, Clarendon Press, Oxford, 1990.

    Google Scholar 

  28. G. Rábai, M. Orbán and I. R. Epstein, Acc. Chem. Res. 23, 258–263 (1990).

    Article  Google Scholar 

  29. S. A. Giannos, S. M. Dinh and B. Berner, J. Pharm. Sci. 84, 539–543 (1995).

    Article  Google Scholar 

  30. G. P. Misra and R. A. Siegel, J. Pharm. Sci. 91, 2003–2015 (2002).

    Article  Google Scholar 

  31. G. P. Misra and R. A. Siegel, J. Control. Release 79, 293–297 (2002).

    Article  Google Scholar 

  32. J. Crank, The Mathematics of Diffusion, Clarendon Press, Oxford, 1975.

    Google Scholar 

  33. E. L. Cussler, Diffusion, Cambridge University Press, Cambridge, 1997.

    Google Scholar 

  34. G. Rábai and I. Hanazaki, J. Phys. Chem. 100, 10615–10619 (1996).

    Article  Google Scholar 

  35. M. Dolnik, T. S. Gardner, I. R. Epstein and J. J. Collins, Phys. Rev. Lett. 82, 1582–1585 (1999).

    Article  ADS  Google Scholar 

  36. A. J. Ryan, C. J. Crook, J. R. Howse, P. Topham, M. Geoghegan, S. J. Martin, A. J. Parnell, L. Ruiz-Pèrez and R. A. L. Jones, J. Macromol. Sci. B Phys. 44, 1103–1121 (2005).

    Article  Google Scholar 

  37. R. Yoshida, H. Ichijo, T. Hakuta and T. Yamaguchi, Macromol. Rapid Commun. 16, 305–310 (1995).

    Article  Google Scholar 

  38. J. R. Howse, P. Topham, C. J. Crook, A. J. Gleeson, W. Bras, R. A. L. Jones and A. J. Ryan, Nano Lett. 6, 73–77 (2006).

    Article  ADS  Google Scholar 

  39. A. J. Ryan, C. J. Crook, J. R. Howse, P. Topham, R. A. L. Jones, M. Geoghegan, A. J. Parnell, L. Ruiz-Pèrez, S. J. Martin, A. Cadby, A. Menelle, J. R. P. Webster, A. J. Gleeson and W. Bras, Faraday Discuss 128, 55–74 (2005).

    Article  ADS  Google Scholar 

  40. C. J. Crook, A. Smith, R. A. L. Jones and A. J. Ryan, Phys. Chem. Chem. Phys. 4, 1367–1369 (2002).

    Article  Google Scholar 

  41. P. Topham, J. R. Howse, C. J. Crook, S. P. Armes, R. A. L. Jones and A. J. Ryan, Macromolecules 40, 4393–4395 (2007).

    Article  ADS  Google Scholar 

  42. I. Varga, I. Szalai, R. Meszaros and T. Gilanyi, J. Phys. Chem. B 110, 20297–20301 (2006).

    Article  Google Scholar 

  43. R. Yoshida, M. Tanaka, S. Onodera, T. Yamaguchi and E. Kokofuta, J. Phys. Chem. A 104, 7549–7555 (2000).

    Article  Google Scholar 

  44. S. Sasaki, S. Koga, R. Yoshida and T. Yamaguchi, Langmuir 19, 5595–5600 (2003).

    Article  Google Scholar 

  45. R. Yoshida and T. Sakai, Langmuir 20, 1036–1038 (2004).

    Article  Google Scholar 

  46. R. Yoshida, T. Takahashi, T. Yamaguchi and H. Ichijo, J. Am. Chem. Soc. 118, 5134–5135 (1996).

    Article  Google Scholar 

  47. P. Labrot, P. DeKepper, J. Boissonade, I. Szalai and F. Gauffre, J. Phys. Chem. B 109, 21476 (2005).

    Article  Google Scholar 

  48. J. Boissonade, P. DeKepper, F. Gauffre and I. Szalai, Chaos 16, 037110 (2006).

    Article  ADS  MathSciNet  Google Scholar 

  49. S. Villain, Comportement mécanique de gels soumis à des réactions autocatalytiques. Ph.D. Thesis, Université Paris 7 (2007).

    Google Scholar 

  50. J. Boissonade, Phys. Rev. Lett. 90, 188302 (2003).

    Article  ADS  Google Scholar 

  51. J. Boissonade, Chaos 15, 023703 (2005).

    Article  ADS  Google Scholar 

  52. R. A. Siegel and C. G. Pitt, J. Control Release 33, 173–186 (1995).

    Article  Google Scholar 

  53. R. A. Siegel, in: Controlled Release: Challenges and Strategies, edited by K. Park, American Chemical Society, Washington, DC, 1997, pp. 501–527.

    Google Scholar 

  54. J.-C. Leroux and R. A. Siegel, Chaos 9, 267–275 (1999).

    Article  ADS  Google Scholar 

  55. J.-C. Leroux and R. A. Siegel, in: Intelligent Materials and Novel Concepts for Controlled Release Technologies, edited by J. De Nuzzio, American Chemical Society, Washington, DC, 1999, pp. 98–112.

    Chapter  Google Scholar 

  56. X. Zou and R. A. Siegel, J. Chem. Phys. 110, 2267–2279 (1999).

    Article  ADS  Google Scholar 

  57. R. A. Siegel, G. P. Misra and A. P. Dhanarajan, in: Polymer Gels and Networks, edited by Y. Osada and A. R. Khokhlov, Marcel Dekker, New York, 2002, pp. 357–372.

    Google Scholar 

  58. G. P. Misra and R. A. Siegel, J. Control Release 81, 1–6 (2002).

    Article  Google Scholar 

  59. A. P. Dhanarajan, G. P. Misra and R. A. Siegel, J. Phys. Chem. 106, 8835–8838 (2002).

    Google Scholar 

  60. A. P. Dhanarajan, J. Urban and R. A. Siegel, in: Nonlinear Dynamics in Polymeric Systems, edited by P. J. Pojman and Q. Tran-Cong-Miyata, American Chemical Society, Washington, DC, 2003, pp. 44–57.

    Chapter  Google Scholar 

  61. A. S. Bhalla, S. K. Mujumdar and R. A. Siegel, Macromol. Symp. 254, 338–344 (2007).

    Google Scholar 

  62. A. Katchalsky and R. Spangler, Quart. Rev. Biophys. 2, 127–175 (1968).

    Article  Google Scholar 

  63. H.-S. Hahn, P. J. Ortoleva and J. Ross, J. Theoret. Biol. 41, 503–521 (1973).

    Article  Google Scholar 

  64. J.-F. Hervagault, M. C. Duban, J. P. Kernevez and D. Thomas, Proc. Natl. Acad. Sci. 80, 5455–5459 (1983).

    Article  ADS  Google Scholar 

  65. T. Teorell, J. Gen. Physiol. 42, 831–845 (1959).

    Article  Google Scholar 

  66. P. Meares and K. R. Page, Proc. R. Soc. Lond. A. 339, 513–532 (1974).

    Article  ADS  Google Scholar 

  67. R. Larter, Chem. Revs. 90, 355–381 (1990).

    Article  ADS  Google Scholar 

  68. P. E. Rapp, J. Math. Biol. 3, 203–224 (1976).

    MATH  MathSciNet  Google Scholar 

  69. T. Y.-C. Tsai, Y. S. Choi, W. Ma, J. R. Pomerening, C. Tang and J. E. Ferrell, Science 321, 126–129 (2008).

    Article  ADS  Google Scholar 

  70. K. Sekimoto, Phys. Rev. Lett. 70, 4154–4157 (1993).

    Article  ADS  Google Scholar 

  71. D. W. Urry, J. Phys. Chem. B. 101, 11007–11028 (1997).

    Article  Google Scholar 

  72. M. Shibayama, S. Mizutaini and S. Nomura, Macromolecules 29, 2019–2024 (1996).

    Article  ADS  Google Scholar 

  73. S. Sasaki and H. Maeda, Phys. Rev. E. 54, 2761–2765 (1996).

    Article  ADS  Google Scholar 

  74. S. Sasaki and F. J. M. Schipper, J. Chem. Phys. 115, 4349–4354 (2001).

    Article  ADS  Google Scholar 

  75. T. Tokuhiro and A. Tokuhiro, Polymer 49, 525–533 (2008).

    Article  Google Scholar 

  76. J. P. Baker and R. A. Siegel, Macromol. Rapid Commun. 17, 409–415 (1996).

    Article  Google Scholar 

  77. A. S. Bhalla, Physicochemical Investigations of a Drug Delivery Oscillator, Ph.D. Thesis, University of Minnesota, Minneapolis, MN, 2007.

    Google Scholar 

  78. A. Dhanarajan, Mechanistic Studies and Development of a Hydrogel/Enzyme Drug Delivery Oscillator, Ph.D. Thesis, University of Minnesota, Minneapolis, MN, 2004.

    Google Scholar 

  79. A. Dhanarajan and R. A. Siegel, Macromol. Symp. 227, 105–114 (2005).

    Article  Google Scholar 

  80. S. I. Kang and Y. H. Bae, Macromol. Chem. Symp. 14, 145–155 (2001).

    Google Scholar 

  81. S. I. Kang and Y. H. Bae, J. Control Release 80, 145–155 (2002).

    Article  Google Scholar 

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Authors and Affiliations

  1. Departments of Pharmaceutics and Biomedical Engineering, University of Minnesota, Minneapolis, MN, 55455, USA

    Ronald A. Siegel

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  1. Ronald A. Siegel
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Correspondence to Ronald A. Siegel .

Editor information

Editors and Affiliations

  1. Service de Chimie Physique et Biologie Théorique Université Libre de Bruxelles, Belgium

    P. Borckmans

  2. Centre de Recherche Paul Pascal Université de Bordeaux, France

    P. De Kepper

  3. Chair of Physics of Polymers and Crystals Moscow State University, Russia

    A. R. Khokhlov

  4. Matière et Systèmes Complexes Université Paris 7 — Denis Diderot, France

    S. Métens

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Siegel, R.A. (2009). Autonomous Rhythmic Drug Delivery Systems Based on Chemical and Biochemomechanical Oscillators. In: Borckmans, P., De Kepper, P., Khokhlov, A.R., Métens, S. (eds) Chemomechanical Instabilities in Responsive Materials. NATO Science for Peace and Security Series A: Chemistry and Biology. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-2993-5_7

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