Peptide-functionalized Biomaterials for Hemostasis and Cancer Imaging

Abstract

Molecular recognition drives all biological processes and can be leveraged to engineer a broad range of biomaterials for detection and treatment of altered states in the body. Part I of this dissertation focuses on the use of peptide-fluorophore conjugates to bind and label cell surface targets that are upregulated in dysplastic (pre-cancerous) esophageal tissue for endoscopic imaging. Initially, fluorescent nanoparticles functionalized with anti-epidermal growth factor receptor (EGFR) antibodies were synthesized and evaluated for their ability to label dysplasia in human biopsies. However, EGFR was found to be a non-ideal molecular target due to high expression in non-dysplastic tissues. Subsequently, phage display was used to identify peptides that would bind to molecular targets specific to dysplastic cells. A family of peptides was found and is believed to bind with low affinity to glycan targets on dysplastic cells. Part II focuses on development of peptide-functionalized polymers for intravenous administration to fortify blood clots and resolve bleeding after traumatic injury. Polymer hemostats (PolySTATs) with multivalent display of fibrin-binding peptides were engineered to strengthen blood clots by cross-linking fibrin. PolySTAT integration in fibrin networks in vitro resulted in stiffer clots that were more resistant to enzymatic breakdown. These results translated in vivo, where PolySTAT injection into animal injury models reduced blood loss and improved survival rate. Further characterization of PolySTAT demonstrates similar functional outputs to current clinical hemostatic agents (e.g. recombinant factor VIIa and tranexamic acid) and its potential use in resolving bleeding in congenital bleeding disorders such as hemophilia A.