TY - JOUR
T1 - Imparting bone mineral affinity to osteogenic proteins through heparin-bisphosphonate conjugates
AU - Gittens, Sébastien A.
AU - Bagnall, Keith
AU - Matyas, John R.
AU - Löbenberg, Raimar
AU - Uludaǧ, Hasan
N1 - Funding Information:
This work was financially supported by a Biomedical Engineering Grant from the Whitaker Foundation, an Operating Grant from the Canadian Institutes of Health Research and Infrastructure Grants from the Alberta Heritage Foundation for Medical Research and the Canadian Foundation for Innovation. SAG was funded by an Izaak Walton Killam Memorial Scholarship provided by the University of Alberta and the Killam Trust.
PY - 2004/8/11
Y1 - 2004/8/11
N2 - 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.
AB - 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.
KW - 1-amino-1,1-diphosphonate methane
KW - BMP
KW - BP
KW - Basic fibroblast growth factor
KW - Bisphosphonates
KW - Bone affinity
KW - Bone morphogenetic protein-2
KW - DMF
KW - Heparin
KW - aminoBP
KW - bFGF
KW - basic fibroblast growth factor
KW - bisphosphonates
KW - bone morphogenetic protein-2,-4,-6,-7
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U2 - 10.1016/j.jconrel.2004.05.001
DO - 10.1016/j.jconrel.2004.05.001
M3 - Article
C2 - 15262417
AN - SCOPUS:3242700510
SN - 0168-3659
VL - 98
SP - 255
EP - 268
JO - Journal of Controlled Release
JF - Journal of Controlled Release
IS - 2
ER -