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Journal of Nanoparticle Research

, Volume 10, Issue 1, pp 141–150 | Cite as

Exploiting the high-affinity phosphonate–hydroxyapatite nanoparticle interaction for delivery of radiation and drugs

  • Hooi Tin Ong
  • Joachim S. C. Loo
  • Freddy Y. C. Boey
  • Stephen J. Russell
  • Jan Ma
  • Kah-Whye PengEmail author
Research Paper

Abstract

Hydroxyapatite is biocompatible and used in various biomedical applications. Here, we generated hydroxyapatite nanoparticles (HNPs) of various sizes (40–200 nm) and demonstrated that they can be stably loaded with drugs or radioisotopes by exploiting the high-affinity HA–(poly)phosphonate interaction. Clinically available phosphonates, clodronate, and Tc-99m-methylene-diphosphonate (Tc-99m-MDP), were efficiently loaded onto HNPs within 15 min. Biodistribution of radiolabeled HNP-MDP-Tc99m in mice was monitored non-invasively using microSPECT-CT. Imaging and dosimetry studies indicated that the HNPs, regardless of size, were quickly taken up by Kupffer cells in the liver after systemic administration into mice. Clodronate loaded onto HNPs remained biologically active and were able to result in selective depletion of Kupffer cells. This method of drug or isotope loading on HA is fast and easy as it eliminates the need for additional surface modifications of the nanoparticles.

Keywords

Hydroxyapatite nanoparticles SPECT-CT imaging Bisphosphonate Biodistribution Clodronate Radioactive Nanoparticle synthesis Nanomedicine Diagnostics Radioisotopes Drug delivery 

Notes

Acknowledgments

This work was supported by funds from the Fraternal Order of Eagles, Mayo Clinic Cancer Center, Mayo Foundation and the School of Materials Engineering, Nanyang Technological University.

References

  1. Barroug A, Glimcher MJ (2002) Hydroxyapatite crystals as a local delivery system for cisplatin: adsorption and release of cisplatin in vitro. J Orthop Res 20:274–280CrossRefGoogle Scholar
  2. Bernardi G (1973) Chromatography of proteins on hydroxyapatite. Methods Enzymol 27:471–479Google Scholar
  3. Chuah MK, Schiedner G, Thorrez L, Brown B, Johnston M, Gillijns V, Hertel S, Van Rooijen N, Lillicrap D, Collen D, VandenDriessche T, Kochanek S (2003) Therapeutic factor VIII levels and negligible toxicity in mouse and dog models of hemophilia A following gene therapy with high-capacity adenoviral vectors. Blood 101:1734–1743CrossRefGoogle Scholar
  4. Coleman RE (2001) Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 27:165–176CrossRefGoogle Scholar
  5. Doonan S (2004) Chromatography on hydroxyapatite. Methods Mol Biol 244:191–194Google Scholar
  6. Dumbleton J, Manley MT (2004) Hydroxyapatite-coated prostheses in total hip and knee arthroplasty. J Bone Joint Surg Am 86A:2526–2540Google Scholar
  7. Fleisch H, Russell RG, Bisaz S, Casey PA, Muhlbauer RC (1968) The influence of pyrophosphate analogues (diphosphonates) on the precipitation and dissolution. Calcif Tissue Res 2 (Suppl 1):10–10aCrossRefGoogle Scholar
  8. Fleisch H, Russell RG, Francis MD (1969) Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo. Science 165:1262–1264CrossRefGoogle Scholar
  9. Gorbunoff MJ (1985) Protein chromatography on hydroxyapatite columns. Methods Enzymol 117:370–380CrossRefGoogle Scholar
  10. Grillenberger KG, Glatz S, Reske SN (1997) Rhenium-188 labeled hydroxyapatite and rhenium-188 sulfur colloid. In vitro comparison of two agents for radiation synovectomy. Nuklearmedizin 36:71–75Google Scholar
  11. Grimes JS, Bocklage TJ, Pitcher JD (2006) Collagen and biphasic calcium phosphate bone graft in large osseous defects. Orthopedics 29:145–148Google Scholar
  12. Itokazu M, Sugiyama T, Ohno T, Wada E, Katagiri Y (1998) Development of porous apatite ceramic for local delivery of chemotherapeutic agents. J Biomed Mater Res 39:536–538CrossRefGoogle Scholar
  13. Jung A, Bisaz S, Fleisch H (1973) The binding of pyrophosphate and two diphosphonates by hydroxyapatite crystals. Calcif Tissue Res 11:269–280CrossRefGoogle Scholar
  14. Lewandrowski KU, Bondre SP, Wise DL, Trantolo DJ (2003) Enhanced bioactivity of a poly (propylene fumarate) bone graft substitute by augmentation with nano-hydroxyapatite. Biomed Mater Eng 13:115–124Google Scholar
  15. Matsumoto T, Okazaki M, Inoue M, Yamaguchi S, Kusunose T, Toyonaga T, Hamada Y, Takahashi J (2004) Hydroxyapatite particles as a controlled release carrier of protein. Biomaterials 25:3807–3812CrossRefGoogle Scholar
  16. McEwan AJ (2000) Use of radionuclides for the palliation of bone metastases. Semin Radiat Oncol 10:103–114CrossRefGoogle Scholar
  17. Mizushima Y, Ikoma T, Tanaka J, Hoshi K, Ishihara T, Ogawa Y, Ueno A (2006) Injectable porous hydroxyapatite microparticles as a new carrier for protein and lipophilic drugs. J Control Release 110:260–265CrossRefGoogle Scholar
  18. Moghimi SM, Szebeni J (2003) Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties. Prog Lipid Res 42:463–478CrossRefGoogle Scholar
  19. O’Duffy EK, Clunie GP, Lui D, Edwards JC, Ell PJ (1999) Double blind glucocorticoid controlled trial of samarium-153 particulate hydroxyapatite radiation synovectomy for chronic knee synovitis. Ann Rheum Dis 58:554–558CrossRefGoogle Scholar
  20. Ostovic D, Stelmach C, Hulshizer B (1993) Formation of a chromophoric complex between alendronate and copper(II) ions. Pharm Res 10:470–472CrossRefGoogle Scholar
  21. Pandey U, Mukherjee A, Chaudhary PR, Pillai MR, Venkates M (2001) Preparation and studies with 90Y-labelled particles for use in radiation synovectomy. Appl Radiat Isot 55:471–475CrossRefGoogle Scholar
  22. Paul W, Sharma CP (2003) Ceramic drug delivery: a perspective. J Biomater Appl 17:253–264CrossRefGoogle Scholar
  23. Pratten MK, Lloyd JB (1986) Pinocytosis and phagocytosis: the effect of size of a particulate substrate on its mode of capture by rat peritoneal macrophages cultured in vitro. Biochim Biophys Acta 881:307–313Google Scholar
  24. van Rooijen N, van Kesteren-Hendrikx E (2003) In vivo depletion of macrophages by liposome-mediated “suicide”. Methods Enzymol 373:3–16Google Scholar
  25. Russell RG (2006) Bisphosphonates: from bench to bedside. Ann NY Acad Sci 1068:367–401CrossRefGoogle Scholar
  26. Saag KG (2003) Glucocorticoid-induced osteoporosis. Endocrinol Metab Clin North Am 32:135–157, viiCrossRefGoogle Scholar
  27. Schiedner G, Hertel S, Johnston M, Dries V, van Rooijen N, Kochanek S (2003) Selective depletion or blockade of Kupffer cells leads to enhanced and prolonged hepatic transgene expression using high-capacity adenoviral vectors. Mol Ther 7:35–43CrossRefGoogle Scholar
  28. Selby PL, Davie MW, Ralston SH, Stone MD (2002) Guidelines on the management of Paget’s disease of bone. Bone 31:366–373CrossRefGoogle Scholar
  29. Senior JH (1987) Fate and behavior of liposomes in vivo: a review of controlling factors. Crit Rev Ther Drug Carrier Syst 3:123–193Google Scholar
  30. Shinto Y, Uchida A, Korkusuz F, Araki N, Ono K (1992) Calcium hydroxyapatite ceramic used as a delivery system for antibiotics. J Bone Joint Surg Br 74:600–604Google Scholar
  31. Uchida A, Shinto Y, Araki N, Ono K (1992) Slow release of anticancer drugs from porous calcium hydroxyapatite ceramic. J Orthop Res 10:440–445CrossRefGoogle Scholar
  32. Uchtman V (1972) Structural investigations of calcium binding molecules. II. The crystal and molecular structures of calcium dihydrogen ethane-1-hydroxy-1,1-diphosphonate dihydrate, CaC(CH3)(OH)(PO3H)2.2H2O; implications for polynuclear complex formation. J Phys Chem 76:1304–1310CrossRefGoogle Scholar
  33. Unni PR, Chaudhari PR, Venkatesh M, Ramamoorthy N, Pillai MR (2002) Preparation and bioevaluation of 166Ho labelled hydroxyapatite (HA) particles for radiosynovectomy. Nucl Med Biol 29:199–209CrossRefGoogle Scholar
  34. Wahl DA, Czernuszka JT (2006) Collagen-hydroxyapatite composites for hard tissue repair. Eur Cell Mater 11:43–56Google Scholar
  35. Wolff G, Worgall S, van Rooijen N, Song WR, Harvey BG, Crystal RG (1997) Enhancement of in vivo adenovirus-mediated gene transfer and expression by prior depletion of tissue macrophages in the target organ. J Virol 71:624–629Google Scholar
  36. Worgall S, Leopold PL, Wolff G, Ferris B, Van Roijen N, Crystal RG (1997) Role of alveolar macrophages in rapid elimination of adenovirus vectors administered to the epithelial surface of the respiratory tract. Hum Gene Ther 8:1675–1684Google Scholar
  37. Yeh HS, Berenson JR (2006) Treatment for myeloma bone disease. Clin Cancer Res 12:6279s–6284sCrossRefGoogle Scholar
  38. Zhang S, Gonsalves KE (1997) Preparation and characterization of thermally stable nanohydroxyapatite. J Mater Sci Mater Med 8:25–28CrossRefGoogle Scholar
  39. Zhang YF, Cheng XR, Chen Y, Shi B, Chen XH, Xu DX, Ke J (2007) Three-dimensional nanohydroxyapatite/chitosan scaffolds as potential tissue engineered periodontal tissue. J Biomater Appl 21:333–349CrossRefGoogle Scholar
  40. Zhu SH, Huang BY, Zhou KC, Huang SP, Liu F, Li YM, Xue ZG, Long ZG (2004) Hydroxyapatite Nanoparticles as a Novel Gene Carrier. J Nanopart Res 6:307–311CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2007

Authors and Affiliations

  • Hooi Tin Ong
    • 1
  • Joachim S. C. Loo
    • 2
  • Freddy Y. C. Boey
    • 2
  • Stephen J. Russell
    • 1
  • Jan Ma
    • 2
  • Kah-Whye Peng
    • 1
    Email author
  1. 1.Guggenheim 18, Molecular Medicine ProgramMayo Clinic College of MedicineRochesterUSA
  2. 2.School of Materials Science and EngineeringNanyang Technological UniversitySingaporeSingapore

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