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dc.contributor.advisorGaponenko, Vadimen_US
dc.contributor.authorLee, Youngshimen_US
dc.date.accessioned2012-12-10T16:58:36Z
dc.date.available2012-12-10T16:58:36Z
dc.date.created2012-05en_US
dc.date.issued2012-12-10
dc.date.submitted2012-05en_US
dc.identifier.urihttp://hdl.handle.net/10027/9211
dc.description.abstractCXCR4 is a chemokine receptor that induces cell migration upon binding its ligand CXCL12 that is also known as the stromal derived factor 1 (SDF1α). Recent studies show that CXCR4 is highly expressed in many kinds of cancer including breast cancer, prostate cancer, and lung cancer. Also, cancer cells expressing CXCR4 exhibit highly invasive and migratory behavior at the sites containing high concentration of SDF-1α. Interaction between CXCR4 and SDF-1α is crucial during metastasis. Therefore, it is possible that inhibition of this interaction may reduce metastasis. We developed a peptide antagonist X4-2-6 against CXCR4 function. The peptide antagonist is able to bind specifically to its target CXCR4 and to prolong survival in a mouse breast cancer dissipation model. This suggests that the peptide does not only have an anti-cancer therapeutic effect but also possesses low toxicity. The X4-2-6 peptide antagonist requires SDF-1α to inhibit CXCR4 downstream signal transduction. This requirement is expected to reduce toxicity further because the peptide interacts only with CXCR4 that is activated by SDF-1α. Moreover X4-2-6 peptide is able to form spherical nanoparticles that have high proteolytic stability due to strong intermolecular interactions within nanoparticles. Thus, X4-2-6 nanoparticles can be targeted to and accumulated in the tumor tissue passively mainly due to the long half-life time of the peptide antagonist and the enhanced permeability and retention effect (EPR) of solid tumors. We observed that nude mice developed metastatic cancer by injection of MDA-MB-231 breast cancer cells and died rapidly. However, the animals that were treated with X4-2-6 nanoparticles survived much longer. In vivo mice experiments proved that X4-2-6 nanoparticles have potential to be used as therapeutics for the cancer treatment. We also found an interesting mechanism of peptide self-assembly by studying the monomer structure of X4-2-6 peptide derivatives. The X4-2-9 peptide has identical primary structure to that of X4-2-6 except the first two leucine residues. However, the X4-2-9 peptide is assembled into fibrils. In order to understand mechanism, we determined monomer structure of both peptides by NMR techniques and found that the initial intermolecular contacts between monomers of different topology are important for self-assembly. We found that monomer structure of X4-2-1, nonPEGylated form of X4-2-6 adopts a conical shape of hairpin-like structure while X4-2-9 is cylindrical hairpin-like structure. The difference in overall shape of monomers may be the reason for the preference in the final morphology. We suggest that the conical shape of monomeric subunits defines the preference for assembly of spherical nanoparticles and cylindrical monomers assemble into fibers. Furthermore, I used the reductive methylation technique to study the extremely large size of protein complex, which consists of actin, tropomyosin, and the inhibitory peptide derived from the inhibitory subunit of cardiac troponin. The reductively methylated lysines on actin filaments are detectable by NMR due reduced order parameters of lysine side chains and make it possible to observe conformational changes upon addition of tropomyosin and/or the inhibitory peptide. The reductive methylation followed by NMR is a good tool to study protein-protein interactions regardless of molecular weight of proteins.en_US
dc.language.isoenen_US
dc.rightsen_US
dc.rightsCopyright 2012 Youngshim Leeen_US
dc.subjectPeptide structureen_US
dc.titlePeptide Nanoparticles As CXCR4 Chemokine Receptor Antagonistsen_US
thesis.degree.departmentBiochemistry and molecular geneticsen_US
thesis.degree.disciplineBiochemistry and Molecular Geneticsen_US
thesis.degree.grantorUniversity of Illinois at Chicagoen_US
thesis.degree.levelDoctoralen_US
thesis.degree.namePhD, Doctor of Philosophyen_US
dc.type.genrethesisen_US
dc.contributor.committeeMemberCaffrey, Michaelen_US
dc.contributor.committeeMemberLiao, Xiubeien_US
dc.contributor.committeeMemberShikano, Sojinen_US
dc.contributor.committeeMemberJohnson, Michael E.en_US
dc.type.materialtexten_US


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