title: Selectivity in bone targeting with multivalent dendritic polyanion dye conjugates.
abstract: Targeting bone with anionic macromolecules is a potent approach for the development of novel diagnostics and therapeutics for bone related diseases. A highly efficient modular synthesis of dendritic polyglycerol (dPG) polyanion dye conjugates, namely, sulfates, sulfonates, carboxylates, phosphates, phosphonates, and bisphosphonates via click chemistry is presented. By investigating the microarchitecture of stained bone sections with confocal laser scanning microscopy, the bisphosphonate, phosphonate, and phosphate functionalized polymers are identified as strongly penetrating compounds, whereas sulfates, sulfonates, and carboxylates reveal a weaker binding to hydroxyapatite (HA) but a more pronounced affinity toward collagen. In a quantitative HA binding assay, the affinity of the dPG sulfonate, sulfate, and carboxylate toward collagen and the exceptional high HA affinity of the phosphorous containing polyelectrolytes are validated. This shows the potential of dendritic polyphosphates and phosphonates as alternatives to the commonly employed bisphosphonate modification. In cytotoxicity studies with murine fibroblasts, the conjugates have no significant effect on the cell viability at 10(-5) m. All polyanions are taken up into the cells within 24 h. The presented synthetic approach allows versatile extensions for preparing conjugates for selective bone imaging applications, tissue engineering, and drug delivery.
authors.affiliation: Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustr. 3, D-14195, Berlin, Germany.
authors.forename: Dominic
authors.initials: D
authors.lastname: Gröger
authors.forename: Michael
authors.initials: M
authors.lastname: Kerschnitzki
authors.forename: Marie
authors.initials: M
authors.lastname: Weinhart
authors.forename: Sabine
authors.initials: S
authors.lastname: Reimann
authors.forename: Tobias
authors.initials: T
authors.lastname: Schneider
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kohl
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wagermaier
authors.forename: Gundula
authors.initials: G
authors.lastname: Schulze-Tanzil
authors.forename: Peter
authors.initials: P
authors.lastname: Fratzl
authors.forename: Rainer
authors.initials: R
authors.lastname: Haag
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000737:chemistry*; D002460:Cell Line; D004164:Diphosphonates / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D017886:Durapatite / Q000737:chemistry; D005347:Fibroblasts / Q000378:metabolism; D005990:Glycerol / Q000737:chemistry*; D051379:Mice; D000071228:Polyelectrolytes; D011108:Polymers / Q000737:chemistry*; D023822:Tissue Engineering
chemical_list: D004164:Diphosphonates; D017886:Durapatite; D005990:Glycerol; D000071228:Polyelectrolytes; D011108:Polymers; C043941:polyglycerol
keywords: bisphosphonates; bone targeting; conjugates; hydroxyapatite; inflammation