Imparting bone mineral affinity to osteogenic proteins through heparin-bisphosphonate conjugates

Sébastien A. Gittens, Keith Bagnall, John R. Matyas, Raimar Löbenberg, Hasan Uludaǧ

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

Although numerous growth factors can promote the regeneration of bone upon parenteral administration, all exhibit undesirable side-effects that prevent their clinical utility. These side-effects arise due to the growth factors' inherent lack of bone affinity. The goal of this study was to develop a means to enhance the bone mineral affinity of osteogenic growth factors so as to minimize their extra-skeletal distribution. Heparin, a glycosaminoglycan that exhibits a high affinity to numerous growth factors, was modified with bisphosphonates to enhance its affinity to bone mineral (i.e. hydroxyapatite, HA). To this end, conjugation of 1-amino-1,1-diphosphonate methane (aminoBP) onto periodate-oxidized heparin using 4-(maleimidomethyl)cyclohexane-1-carboxyl- hydrazide was attempted. Using this chemistry, the number of aminoBPs conjugated onto heparin was modulated by varying the reacting reagent concentrations (to a maximum of 7 aminoBPs per heparin). Increasing the number of aminoBPs resulted in a more than twofold increase in heparin's affinity for HA in vitro. Subsequently, the ability of aminoBP-heparin conjugates to enhance the mineral affinity of basic fibroblast growth factor (bFGF) and bone morphogenetic protein-2 (BMP-2) was explored. The results revealed that the complexation between the conjugates and growth factors had occurred and that the conjugates increased the bone mineral affinity of bFGF and BMP-2 in an aminoBP-dependent manner. In conclusion, the conjugation of aminoBP onto heparin is a feasible approach to enhance the affinity of heparin-binding, osteogenic growth factors to HA.

Original languageEnglish
Pages (from-to)255-268
Number of pages14
JournalJournal of Controlled Release
Volume98
Issue number2
DOIs
Publication statusPublished - Aug 11 2004

Keywords

  • 1-amino-1,1-diphosphonate methane
  • BMP
  • BP
  • Basic fibroblast growth factor
  • Bisphosphonates
  • Bone affinity
  • Bone morphogenetic protein-2
  • DMF
  • Heparin
  • aminoBP
  • bFGF
  • basic fibroblast growth factor
  • bisphosphonates
  • bone morphogenetic protein-2,-4,-6,-7

ASJC Scopus subject areas

  • Pharmaceutical Science

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