Polymer Gels pp 127-140 | Cite as

Silica-Based Polymeric Gels as Platforms for Delivery of Phosphonate Pharmaceutics

  • Konstantinos E. Papathanasiou
  • Maria Vassaki
  • Argyro Spinthaki
  • Argyri Moschona
  • Konstantinos D. DemadisEmail author
Part of the Gels Horizons: From Science to Smart Materials book series (GHFSSM)


This chapter focuses on polymeric gel drug delivery systems used for initial immobilization and subsequent controlled release of active pharmaceutical ingredients. The primary focus is on phosphonate-based drugs, which are extensively used for a variety of medicinal applications and pathological conditions. Their most recognizable use is for osteoporosis drugs with the common names: medronate, chlodronate, etidronate, alendronate, zoledronate, obadronate, ibandronate, neridronate, etc. Herein, we present a concise literature overview of this research field, presenting research results on immobilization of phosphonates onto silica-based polymeric gels, with the goal to achieve controlled release of these ingredients into biological fluids.


Silica Gels Controlled release Phosphonates Osteoporosis 



K. E. Papathanasiou thanks the Onassis Foundation for a doctoral scholarship. K. D. Demadis thanks the EU for funding the Research Program SILICAMPS-153, under the ERA.NET-RUS Pilot Joint Call for Collaborative S&T projects.


  1. Balas F, Manzano M, Horcajada P, Vallet-Regí M (2006) Confinement and controlled release of bisphosphonates on ordered mesoporous silica-based materials. J Am Chem Soc 128:8116–8117CrossRefPubMedGoogle Scholar
  2. Belton DJ, Patwardhan SV, Perry CC (2005) Spermine, spermidine and their analogues generate tailored silicas. J Mater Chem 15:4629–4638CrossRefGoogle Scholar
  3. Belton DJ, Patwardhan SV, Annenkov VV, Danilovtseva EN, Perry CC (2008) From biosilicification to tailored materials: optimizing hydrophobic domains and resistance to protonation of polyamines. Proc Natl Acad Sci USA 105:5963–5968CrossRefPubMedGoogle Scholar
  4. Binauld S, Stenzel MH (2013) Acid-degradable polymers for drug delivery: a decade of innovation. Chem Commun 49:2082–2102CrossRefGoogle Scholar
  5. Chen T, Berenson J, Vescio R, Swift R, Gilchick A, Goodin S, LoRusso P, Ma P, Ravera C, Deckert F, Schran H, Seaman J, Skerjanec A (2002) Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with bone metastases. J Clin Pharmacol 42:1228–1236CrossRefPubMedGoogle Scholar
  6. Chong ASM, Zhao XS (2003) Functionalization of SBA-15 with APTES and characterization of functionalized materials. J Phys Chem B 107:12650–12657CrossRefGoogle Scholar
  7. Coradin T, Eglin D, Livage J (2004) The silicomolybdic acid spectrophotometric method and its application to silicate/biopolymer interaction studies. Spectroscopy 18:567–576CrossRefGoogle Scholar
  8. Cremers SC, Pillai G, Papapoulos SE (2005) Pharmacokinetics/pharmacodynamics of bisphosphonates: use for optimisation of intermittent therapy for osteoporosis. Clin Pharmacokinet 44:551–570CrossRefPubMedGoogle Scholar
  9. Demadis KD (2008) Silica scale inhibition relevant to desalination technologies: progress and recent developments. In: Delgado DJ, Moreno P (eds) Desalination research progress. Nova Science Publishers, Inc., New York, pp 249–259Google Scholar
  10. Dunford JE, Thomspson K, Coxon FP, Luckman SP, Hahn FM, Poulter CD, Ebetino FH, Rogers MJ (2001) Structure-activity relationships for inhibition of farnesyl disphosphate syntase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharm Exp Ther 296:235–242Google Scholar
  11. Ehrlich H, Demadis KD, Koutsoukos PG, Pokrovsky O (2010) Modern views on desilicification: biosilica and abiotic silica dissolution in natural and artificial environments. Chem Rev 110:4656–4689CrossRefPubMedGoogle Scholar
  12. Fisher JE, Rogers MJ, Halasy JM, Luckman SP, Hughes DE, Masarachia PJ, Wesolowski G, Russell RG, Rodan GA, Reszka AA (1999) Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption and kinase activation in vitro. Proc Natl Acad Sci USA 96:133–138CrossRefPubMedGoogle Scholar
  13. Fleisch H, Reszka A, Rodan G, Rogers G (2002) Bisphosphonates: mechanisms of action. In: Bilezikian JP, Raisz LG, Rodan GA (eds) Principles of bone biology. Academic Press, San Diego, pp 1361–1385Google Scholar
  14. Francis MD, Fogelman I (1987) 99 mTc diphosphonate uptake mechanism on bone. In: Fogelman I (ed) Bone scanning in clinical practice. Springer, New York, pp 7–17CrossRefGoogle Scholar
  15. Francis MD, Graham R, Russell RGG, Fleisch H (1969) Diphosphonates inhibit formation of calcium phosphate crystals in vitro and pathological calcification in vivo. Science 165:1264–1266CrossRefPubMedGoogle Scholar
  16. Frith JC, Mönkkönen J, Blackburn GM, Russell RGG, Rogers MJ (1997) Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5′-(β, γ-dichloromethylene) triphosphate, by mammalian cells in vitro. J Bone Miner Res 12:1358–1367CrossRefPubMedGoogle Scholar
  17. Fujisaki J, Tokunaga Y, Takahashi T, Hirose T, Shimojo F, Kagayama A, Hata T (1995) Osteotropic drug delivery system (ODDS) based on bisphosphonic prodrug. I: synthesis and in vivo characterization of osteotropic carboxyfluorescein. J Drug Target 3:273–282CrossRefPubMedGoogle Scholar
  18. Fujisaki J, Tokunaga Y, Sawamoto T, Takahashi T, Kimura S, Shimojo F, Hata T (1996a) Osteotropic drug delivery system (ODDS) based on bisphosphonic prodrug. III: pharmacokinetics and targeting characteristics of osteotropic carboxyfluorescein. J Drug Target 4:117–123CrossRefPubMedGoogle Scholar
  19. Fujisaki J, Tokunaga Y, Takahashi T, Murata S, Shimojo F, Hata T (1996b) Physicochemical characterization of bisphosphonic carboxyfluorescein for osteotropic drug delivery. J Pharm Pharmacol 48:798–800CrossRefPubMedGoogle Scholar
  20. Giger EV, Castagner B, Leroux J-C (2013) Biomedical applications of bisphosphonates. J Control Release 167:175–188CrossRefPubMedGoogle Scholar
  21. Gil L, Han Y, Opas EE, Rodan GA, Ruel R, Seedor JG, Tyler PC, Young RN (1999) Prostaglandin E2–bisphosphonate conjugates: potential agents for treatment of osteoporosis. Bioorg Med Chem 7:901–919CrossRefPubMedGoogle Scholar
  22. Gittens SA, Bansal G, Zernicke RF, Uludag H (2005) Designing proteins for bone targeting. Adv Drug Deliv Rev 57:1011–1036CrossRefPubMedGoogle Scholar
  23. Golomb G, Dixon M, Smith MS, Schoen FJ, Levy RJ (1987) Controlled-release drug delivery of diphosphonates to inhibit bioprosthetic heart valve calcification: release rate modulation with silicone matrices via drug solubility and membrane coating. J Pharm Sci 76:271–276CrossRefPubMedGoogle Scholar
  24. Gommes C, Blacher S, Goderis B, Pirard R, Heinrichs B, Alie C, Pirard JP (2004) In situ SAXS analysis of silica gel formation with an additive. J Phys Chem B 108:8983–8991CrossRefGoogle Scholar
  25. Hengst V, Oussoren C, Kissel T, Storm G (2007) Bone targeting potential of bisphosphonate-targeted liposomes. Preparation, characterization and hydroxyapatite binding in vitro. Int J Pharm 331:224–227CrossRefPubMedGoogle Scholar
  26. Hildebrand M (2008) Diatoms, biomineralization processes, and genomics. Chem Rev 108:4855–4874CrossRefPubMedGoogle Scholar
  27. Hirabayashi H, Takahashi T, Fujisaki J, Masunaga T, Sato S, Hiroi J, Tokunaga Y, Kimura S, Hata T (2001) Bone specific delivery and sustained release of diclofenac, a non- steroidal anti-inflammatory drug, via bisphosphonic prodrug based on osteotropic drug delivery system (ODDS). J Control Release 70:183–191CrossRefPubMedGoogle Scholar
  28. Hosain F, Spencer RP, Couthon HM, Sturtz GL (1996) Targeted delivery of antineoplastic agent to bone: biodistribution studies of technetium-99m-labeled gembisphosphonate conjugate of methotrexate. J Nucl Med 37:105–107PubMedGoogle Scholar
  29. Hughes LG, Vick TA, Wang JH (2004) Coated Implants. European Patent 1250164Google Scholar
  30. Kennedy JH (1997) HPLC purification of pergolide using silica gel. Org Process Res Dev 1:68–71CrossRefGoogle Scholar
  31. Lamb HM, Faulds D (1997) Samarium 153Sm lexidronam. Drugs Aging 11:413–418CrossRefPubMedGoogle Scholar
  32. Lehenkari PP, Kellinsalmi M, Näpänkangas JP, Ylitalo KV, Mönkkönen J, Rogers MJ, Azhayev A, Väänänen HK, Hassinen IE (2002) Further insight into mechanism of action of clodronate: inhibition of mitochondrial ADP/ATP translocase by a nonhydrolyzable, adenine-containing metabolite. Mol Pharmacol 61:1255–1262CrossRefPubMedGoogle Scholar
  33. Levy RJ, Wolfrum J, Schoen FJ, Hawley MA, Lund SA, Langer R (1985) Inhibition of calcification of bioprosthetic heart valves by local controlled-release diphosphonate. Science 228:190–192CrossRefPubMedGoogle Scholar
  34. Levy RJ, Johnson TP, Sintov A, Golomb G (1990) Controlled release implants for cardiovascular disease. J Control Release 11:245–254CrossRefGoogle Scholar
  35. Levy RJ, Qu X, Underwood T, Trachy J, Schoen FJ (1995) Calcification of valved aortic allografts in rats: effects of age, crosslinking, and inhibitors. J Biomed Mater Res 29:217–226CrossRefPubMedGoogle Scholar
  36. Liu X, Wiswall AT, Rutledge JE, Akhter MP, Cullen DM, Reinhardt RA, Wang D (2008) Osteotropic β-cyclodextrin for local bone regeneration. Biomaterials 29:1686–1692CrossRefPubMedPubMedCentralGoogle Scholar
  37. Lopez PJ, Gautier C, Livage J, Coradin T (2005) Mimicking biogenic silica nanostructures formation. Curr Nanosci 1:73–83CrossRefGoogle Scholar
  38. Luckman SP, Hughes DE, Coxon FP, Graham R, Russell RG, Rogers MJ (1998) Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res 13:581–589CrossRefPubMedGoogle Scholar
  39. Mann S, Perry CC, Williams RJP, Fyfe CA, Gobbi GC, Kennedy GJ (1983) The characterisation of the nature of silica in biological systems. J Chem Soc Chem Commun 4:168–170CrossRefGoogle Scholar
  40. Martin del Valle EM, Galan MA, Carbonell RG (2009) Drug delivery technologies: the way forward in the new decade. Ind Eng Chem Res 48:2475–2486CrossRefGoogle Scholar
  41. Mashkevich BO (ed) (2007) Drug delivery research advances. Nova Science Publishers Inc., New YorkGoogle Scholar
  42. Mestiri M, Benoit JP, Hernigou P, Devissaguet JP, Puisieux F (1995) Cisplatin-loaded poly(methyl methacrylate) implants: a sustained drug delivery system. J Control Release 33:107–113CrossRefGoogle Scholar
  43. Morse DE (1999) Silicon biotechnology: harnessing biological silica production to construct new materials. Trends Biotechnol 17:230–232CrossRefGoogle Scholar
  44. Mundy GR (1997) Mechanisms of bone metastasis. Cancer 80:1546–1556CrossRefPubMedGoogle Scholar
  45. Ning RY (2010) Reactive silica in natural waters—a review. Des Wat Treat 21:79–86CrossRefGoogle Scholar
  46. Patwardhan SV (2011) Biomimetic and bioinspired silica: recent developments and applications. Chem Commun 47:7567–7582CrossRefGoogle Scholar
  47. Patwardhan SV, Clarson SJ, Perry CC (2005) On the role(s) of additives in bioinspired silicification. Chem Commun 1113–1121Google Scholar
  48. Perry CC, Keeling-Tucker T (1998) Aspects of the bioinorganic chemistry of silicon in conjunction with the biometals calcium, iron and aluminium. J Inorg Biochem 69:181–191CrossRefPubMedGoogle Scholar
  49. Ramakrishna S, Mayer J, Wintermantel E, Leong KW (2001) Biomedical applications of polymer-composite materials: a review. Compos Sci Technol 61:1189–1224CrossRefGoogle Scholar
  50. Rodan GA, Reszka AA (2002) Bisphophonate mechanism of action. Curr Mol Med 2:571–577CrossRefPubMedGoogle Scholar
  51. Russell RGG, Watts N, Ebetino F, Rogers M (2008) Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 19:733–759CrossRefPubMedGoogle Scholar
  52. Shakespeare WC, Metcalf CA III, Wang Y, Sundaramoorthi R, Keenan T, Weigele M, Bohacek RS, Dalgarno DC, Sawyer TK (2003) Novel bone-targeted Src tyrosine kinase inhibitor drug discovery. Curr Opin Drug Discov Devel 6:729–741PubMedGoogle Scholar
  53. Shane E (2010) Evolving data about subtrochanteric fractures and bisphosphonates. N Engl J Med 362:1825–1827CrossRefPubMedGoogle Scholar
  54. Siegel RA, Rathbone MJ (2012) Overview of controlled release mechanisms. In: Siepmann J, Siegel RA, Rathbone MJ (eds) Fundamentals and applications of controlled release drug delivery. Springer, New York, pp 19–43CrossRefGoogle Scholar
  55. Soppimath KS, Aminabhavi TM, Kulkarni AR, Rudzinski WE (2001) Biodegradable polymeric nanoparticles as drug delivery devices. J Control Release 70:1–20CrossRefPubMedPubMedCentralGoogle Scholar
  56. Steven CR, Busby GA, Mather C, Tariq B, Lucia Briuglia M, Lamprou DA, Urquhart AJ, Grant MH, Patwardhan SV (2014) Bioinspired silica as drug delivery systems and their biocompatibility. J Mater Chem B 2:5028–5042CrossRefGoogle Scholar
  57. Szymura-Oleksiak J, Slosarczyk A, Cios A, Mycek B, Paszkiewicz Z, Szklarczyk S, Stankiewicz D (2001) The kinetics of pentoxifyllinerelease in vivo from drug-loaded hydroxyapatite implants. Ceram Int 27:767–772CrossRefGoogle Scholar
  58. Thomas JM, Johnson BFG, Raja R, Samkar G, Midgley PA (2003) High-performance nanocatalysts for single-step hydrogenations. Acc Chem Res 36:20–30CrossRefPubMedGoogle Scholar
  59. Thompson WJ, Thompson DD, Anderson PS, Rodan GA (1989) Polymalonic acids as bone affinity agents. European Patent 0341961Google Scholar
  60. Uhrich KE, Cannizzaro SM, Langer RS, Shakesheff KM (1999) Polymeric systems for controlled drug release. Chem Rev 99:3181–3198CrossRefGoogle Scholar
  61. Van Beek E, Pieterman E, Cohen L, Lowik C, Papapoulos S (1999) Nitrogen-containing bisphosphonates inhibit isopentenyl pyrophosphate isomerase/farnesyl pyrophosphate synthase activity with relative potencies corresponding to their antiresorptive potencies in vitro and in vivo. Biochem Biophys Res Commun 255:491–494CrossRefPubMedGoogle Scholar
  62. Walcarius A, Etienne M, Lebeau B (2003) Rate of access to the binding sites in organically modified silicates. 2. Ordered mesoporous silicas grafted with amine or thiol groups. Chem Mater 15:2161–2173CrossRefGoogle Scholar
  63. Walter KA, Tamargo R, Olivi A, Burger PC, Brem H (1995) Intratumoral chemotherapy. Neurosurgery 37:1129–1145CrossRefGoogle Scholar
  64. Wang GH, Zhang LM (2007) Manipulating formation and drug-release behavior of new sol-gel silica matrix by hydroxypropyl guar gum. J Phys Chem B 111:10665–10670CrossRefPubMedGoogle Scholar
  65. Weinstein RS, Robertson PK, Manolagas SC (2009) Giant osteoclast formation and long-term oral bisphosphonate therapy. N Engl J Med 360:53–62CrossRefPubMedPubMedCentralGoogle Scholar
  66. Zhao Z-G (1992) Adsorption of phenylalanine from aqueous solution onto active carbon and silica gel. Chin J Chem 10:325–330CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Konstantinos E. Papathanasiou
    • 1
  • Maria Vassaki
    • 1
  • Argyro Spinthaki
    • 1
  • Argyri Moschona
    • 1
  • Konstantinos D. Demadis
    • 1
    Email author
  1. 1.Crystal Engineering, Growth and Design Laboratory, Department of ChemistryUniversity of CreteHeraklion, CreteGreece

Personalised recommendations