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

J Control Release. 2004 Aug 11;98(2):255-68. doi: 10.1016/j.jconrel.2004.05.001.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins / chemistry
  • Bone Morphogenetic Proteins / metabolism*
  • Diphosphonates / chemistry*
  • Drug Carriers / chemical synthesis
  • Drug Carriers / chemistry
  • Drug Delivery Systems / methods*
  • Durapatite / chemistry
  • Durapatite / metabolism*
  • Fibroblast Growth Factor 2 / chemistry
  • Fibroblast Growth Factor 2 / metabolism*
  • Heparin / analogs & derivatives*
  • Heparin / chemistry
  • Heparin / pharmacology
  • Maleimides / chemistry
  • Periodic Acid / chemistry
  • Phosphates / chemistry
  • Protein Binding / drug effects
  • Transforming Growth Factor beta / chemistry
  • Transforming Growth Factor beta / metabolism*

Substances

  • 4-(4-N-maleimidomethyl)cyclohexane-1-carboxyl hydrazide
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins
  • Diphosphonates
  • Drug Carriers
  • Maleimides
  • Phosphates
  • Transforming Growth Factor beta
  • aminomethane diphosphonate
  • Fibroblast Growth Factor 2
  • Periodic Acid
  • Heparin
  • Durapatite
  • metaperiodate