title: Role of Polymer Architecture on the Activity of Polymer-Protein Conjugates for the Treatment of Accelerated Bone Loss Disorders.
abstract: Polymers of similar molecular weights and chemical constitution but varying in their macromolecular architectures were conjugated to osteoprotegerin (OPG) to determine the effect of polymer topology on protein activity in vitro and in vivo. OPG is a protein that inhibits bone resorption by preventing the formation of mature osteoclasts from the osteoclast precursor cell. Accelerated bone loss disorders, such as osteoporosis, rheumatoid arthritis, and metastatic bone disease, occur as a result of increased osteoclastogenesis, leading to the severe weakening of the bone. OPG has shown promise as a treatment in bone disorders; however, it is rapidly cleared from circulation through rapid liver uptake, and frequent, high doses of the protein are necessary to achieve a therapeutic benefit. We aimed to improve the effectiveness of OPG by creating OPG-polymer bioconjugates, employing reversible addition-fragmentation chain transfer polymerization to create well-defined polymers with branching densities varying from linear, loosely branched to densely branched. Polymers with each of these architectures were conjugated to OPG using a "grafting-to" approach, and the bioconjugates were characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis. The OPG-polymer bioconjugates showed retention of activity in vitro against osteoclasts, and each bioconjugate was shown to be nontoxic. Preliminary in vivo studies further supported the nontoxic characteristics of the bioconjugates, and measurement of the bone mineral density in rats 7 days post-treatment via peripheral quantitative computed tomography suggested a slight increase in bone mineral density after administration of the loosely branched OPG-polymer bioconjugate.
authors.affiliation: †Department of Chemistry, ‡George and Josephine Butler Polymer Research Laboratory, and §Center for Macromolecular Science and Engineering, University of Florida, Gainesville, Florida 32611, United States.|⊥Department of Physiological Sciences, College of Veterinary Medicine and ¶Department of Orthodontics, College of Dentistry, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Bryan S
authors.initials: BS
authors.lastname: Tucker
authors.affiliation: †Department of Chemistry, ‡George and Josephine Butler Polymer Research Laboratory, and §Center for Macromolecular Science and Engineering, University of Florida, Gainesville, Florida 32611, United States.|⊥Department of Physiological Sciences, College of Veterinary Medicine and ¶Department of Orthodontics, College of Dentistry, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Jon D
authors.initials: JD
authors.lastname: Stewart
authors.affiliation: †Department of Chemistry, ‡George and Josephine Butler Polymer Research Laboratory, and §Center for Macromolecular Science and Engineering, University of Florida, Gainesville, Florida 32611, United States.|⊥Department of Physiological Sciences, College of Veterinary Medicine and ¶Department of Orthodontics, College of Dentistry, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: J Ignacio
authors.initials: JI
authors.lastname: Aguirre
authors.affiliation: †Department of Chemistry, ‡George and Josephine Butler Polymer Research Laboratory, and §Center for Macromolecular Science and Engineering, University of Florida, Gainesville, Florida 32611, United States.|⊥Department of Physiological Sciences, College of Veterinary Medicine and ¶Department of Orthodontics, College of Dentistry, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: L Shannon
authors.initials: LS
authors.lastname: Holliday
authors.affiliation: †Department of Chemistry, ‡George and Josephine Butler Polymer Research Laboratory, and §Center for Macromolecular Science and Engineering, University of Florida, Gainesville, Florida 32611, United States.|⊥Department of Physiological Sciences, College of Veterinary Medicine and ¶Department of Orthodontics, College of Dentistry, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: C Adrian
authors.initials: CA
authors.lastname: Figg
authors.affiliation: †Department of Chemistry, ‡George and Josephine Butler Polymer Research Laboratory, and §Center for Macromolecular Science and Engineering, University of Florida, Gainesville, Florida 32611, United States.|⊥Department of Physiological Sciences, College of Veterinary Medicine and ¶Department of Orthodontics, College of Dentistry, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Messer
authors.affiliation: †Department of Chemistry, ‡George and Josephine Butler Polymer Research Laboratory, and §Center for Macromolecular Science and Engineering, University of Florida, Gainesville, Florida 32611, United States.|⊥Department of Physiological Sciences, College of Veterinary Medicine and ¶Department of Orthodontics, College of Dentistry, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Brent S
authors.initials: BS
authors.lastname: Sumerlin
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010024:Osteoporosis / Q000188:drug therapy* / Q000473:pathology; D053244:Osteoprotegerin / Q000008:administration & dosage / Q000737:chemistry*; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry; D051381:Rats
chemical_list: D053244:Osteoprotegerin; D011108:Polymers