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Heparin-Mimicking Polymers for Improving Stability and Bioactivity of Basic Fibroblast Growth Factor


Proteins are an important class of therapeutics. The have many advantages over small-molecule drugs including high target specificity, low cytotoxicity and low immunogenicity. However, due to their inherent instability during storage, transport and delivery in vitro and in vivo, their therapeutic usefulness has not been maximized. One approach is to conjugate poly(ethylene glycol) to proteins to enhance pharmacokinetics in vivo, and there are eleven FDA approved therapeutic PEG conjugates. However, efforts to stabilize proteins against environmental stressors are still limited. In this dissertation, the development of biomimetic polymers, specifically heparin-mimicking polymers, to stabilize an important unstable therapeutic protein, basic fibroblast growth factor (bFGF), is described.

Chapter 1 reviews the biomedical applications of heparin-based hydrogels and heparin-mimicking polymers. Heparin is a naturally occurring polysaccharide that was first exploited for its antithrombotic activity. It was later realized that heparin-mediated biological functions were wide-ranging and included cell differentiation, angiogenesis, inflammation, host defense and viral infection mechanisms, lipid transport and clearance, and cell adhesion and interaction. Thus, researchers have shifted to investigate other properties of heparin-mimicking polymers besides its use as an anticoagulant. This chapter focuses on the development of heparin-based hydrogels and heparin-mimicking polymers for treatments of skin wounds specifically.

Chapter 2 describes the stabilization of bFGF by covalent conjugation of a heparin-mimicking polymer, a copolymer consisting of styrene sulfonate units and methyl methacrylate units bearing poly(ethylene glycol) side chains. bFGF plays a crucial role in diverse cellular functions from wound healing to bone regeneration. However, a major obstacle in the widespread application of bFGF is its inherent instability during storage and delivery. The bFGF conjugate of this polymer, bFGF-p(SS-co-PEGMA), 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, compared to native bFGF. After applied stress, the conjugate was also significantly more active than the control conjugate system where the styrene sulfonate units were omitted from the polymer structure. This research has important implications for the clinical use of bFGF and for stabilization of heparin-binding growth factors in general.

Chapter 3 describes a study of the preclinical value of the bFGF-p(SS-co-PEGMA) conjugate as a potential therapy for active wound healing. The cellular uptake and trafficking of the bFGF-heparin-mimcking polymer conjugate, bFGF-p(SS-co-PEGMA), was studied to better understand the cellular fate of the conjugate. The long-term storage stability of the conjugate was examined at 4 �C and 23 �C to evaluate the usefulness of the conjugate as a widely available therapeutic to patients, including at-home patients and patients in the remote areas. In addition, we report for the first time the superagonist characteristic of the heparin-mimicking polymer conjugate when used in the presence of exogenous heparin.

Chapter 4 describes the development of a 2nd-generation and a 3rd-generation heparin-mimicking polymer. Since the 1st-generation heparin-mimicking polymer described in Chapters 2 and 3, p(SS-co-PEGMA), stabilizes bFGF but is unable to activate FGF receptors (FGFRs) as is heparin, we looked for other heparin-mimicking polymers that could do both. Activation of FGFRs by two bFGF molecules and a heparin molecule leads to the dimerization and phosphorylation of the receptors, and subsequently results in cell responses such as proliferation or migration. Thus, 2nd and 3rd-generation sulfonated polymers were prepared. The 2nd-generation polymer was found to be a strong activator of FGFRs but its conjugate to bFGF had reduced bioactivity. The 3rd-generation polymer was a block copolymer of the 1st- and the 2nd-generation polymers. Although it was not as strong an activator as the 2nd-generation polymer, its conjugate to bFGF exhibited enhanced mitogenic activity compared to other conjugates and native bFGF in heparan sulfate-deficient cells and in human umbilical vein endothelial cells (HUVECs). The 3rd-generation conjugate also stimulated HUVEC migration better than the native protein. Taken together, the 3rd-genration conjugate is promising for applications where promoting angiogenesis is desired, such as in tissue engineering.

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