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2-ω-carboxyethylpyrrole (CEP) is a product of docosahexaenoic acid (DHA) oxidation, which forms covalent adducts with different proteins. CEP-modified proteins can interact with macrophage receptor, integrin αDβ2. This study aims to compare αDβ2 binding to its physiological ligand, fibrinogen, and CEP-modified fibrinogen, which is formed during inflammation. We hypothesize that modification of fibrinogen changes its ligand-binding properties to integrin αDβ2 which can affect macrophage migration and retention. Recombinant αD I-domain and αDβ2-transfected HEK293 cells were used for the experiments. Using biolayer interferometry, we found that the affinity of αD I-domain binding to fibrinogen-CEP was higher than fibrinogen and inhibited by the anti-CEP antibody. In agreement, αDβ2-transfected cells demonstrated stronger adhesion to fibrinogen-CEP and this adhesion was significantly inhibited by polyglutamic acid that mimics CEP-mediated binding. These findings suggest that αDβ2's interaction with DHA-modified extracellular matrix (ECM) proteins significantly increases macrophage adhesion and may serve for macrophage retention during chronic inflammation.

Combining linear polymers and dendrimers provides numerous advantages such as increased solubility, biodegradability and a large number of functionalizable peripheral moieties. In this work, novel carborane-containing dendronized polymers were designed as potential candidates for Boron Neutron Capture Therapy (BNCT). These polymers were successfully synthesized using two different approaches. The resulting carborane-functionalized polymers were dendronized using a divergent approach to introduce aliphatic polyester dendrons of generation 1-4 grafted from the polymer backbone. Both approaches produced water-soluble dendronized polymers with high molecular weights. The synthetic approach developed in the first part of this work was also applied in the functionalization of poly(ethylene glycol) (PEG)-grafted gold surfaces with hydrophilic dendrons. In this project, the effect of surface dendronization on protein adsorption was investigated. Contrary to our expectation, protein resistance was found to decrease when the surfaces were covalently functionalized with the hydrophilic dendrons despite their improved hydrophilicity. It was postulated that several factors could be responsible for the increased protein adsorption to the dendronized surfaces, including increased surface area, the introduction of hydrogen-bond donor groups, and a decrease in the mobility of the surface-grafted polymers as a result of inter- and intra-molecular hydrogen bonding between the dendrons. To circumvent these confounding phenomena, while maintaining surface hydrophilicity, we have chosen to covalently attach PEG mono-methyl ether (PEG-OMe) chains of various molecular weight to the peripheral hydroxyl groups of first to fourth generation dendronized surfaces. Results showed that protein adsorption was reduced when dendronized surfaces were grafted with PEG-OMe chains. The hydroxyl-terminated G l-G4 dendronized surfaces and PEG-grafted dendronized surfaces were also investigated for cell adhesion and proliferation. These studies showed that little or no cell adhesion occurred on PEG-grafted gold surfaces. However, greater cell affinity for the dendronized surfaces was observed. When dendronized surfaces were coupled with PEG-OMe chains, cell adhesion was significantly diminished. / Thesis / Doctor of Philosophy (PhD)

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