A heparin-mimicking polymer conjugate stabilizes basic fibroblast growth factor

• Published in: Nature chemistry Vol. 5; no. 3; pp. 221 - 227
• Main Authors: Nguyen, Thi H., Kim, Sung-Hye, Decker, Caitlin G., Wong, Darice Y., Loo, Joseph A., Maynard, Heather D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-03-2013; Nature Publishing Group
• Subjects: 639/638/298/54/1754; 639/638/455/952; Analytical Chemistry; Anticoagulants; Biochemistry; Biological activity; Biomimetic Materials - chemical synthesis; Biomimetic Materials - chemistry; Biomimetic Materials - pharmacology; Cells, Cultured; Chemistry; Chemistry/Food Science; Cytotoxicity; Fibroblast Growth Factor 2 - analogs & derivatives; Fibroblast Growth Factor 2 - chemistry; Fibroblast Growth Factor 2 - pharmacology; Fibroblasts - drug effects; Growth factors; Heparin - chemistry; Heparin - pharmacology; Humans; Inorganic Chemistry; Methacrylates - chemical synthesis; Methacrylates - chemistry; Methacrylates - pharmacology; Models, Molecular; Organic Chemistry; Physical Chemistry; Polyethylene Glycols - chemical synthesis; Polyethylene Glycols - chemistry; Polyethylene Glycols - pharmacology; Polymers; Polystyrenes - chemical synthesis; Polystyrenes - chemistry; Polystyrenes - pharmacology; Protein Stability; Proteins; Receptor, Fibroblast Growth Factor, Type 1 - antagonists & inhibitors; Styrene; Sulfonates; Los Angeles California; United States > US; California
• ISSN: 1755-4330; 1755-4349
• DOI: 10.1038/nchem.1573

Basic fibroblast growth factor (bFGF) is a protein that plays a crucial role in diverse cellular functions, from wound healing to bone regeneration. However, a major obstacle to the widespread application of bFGF is its inherent instability during storage and delivery. Here, we describe the stabilization of bFGF by covalent conjugation with a heparin-mimicking polymer, a copolymer consisting of styrene sulfonate units and methyl methacrylate units bearing poly(ethylene glycol) side chains. The bFGF conjugate of this polymer retained bioactivity after synthesis and was stable to a variety of environmentally and therapeutically relevant stressors—such as heat, mild and harsh acidic conditions, storage and proteolytic degradation—unlike native bFGF. Following the application of stress, the conjugate was also significantly more active than the control conjugate system in which the styrene sulfonate units were omitted from the polymer structure. This research has important implications for the clinical use of bFGF and for the stabilization of heparin-binding growth factors in general.
Basic fibroblast growth factor (bFGF) is crucial for a range of diverse cellular processes, from wound healing to bone regeneration, yet is inherently unstable. This important biologic has now been covalently linked to a polymer that mimics the polysaccharide heparin to produce a conjugate that shows remarkable stability to a wide range of therapeutically and environmentally relevant stressors.