Date of Award

Summer 8-13-2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Jenny Yang

Abstract

Liver metastases are often observed with primary cancers, including uveal melanoma (UM), breast, ovarian, and colon cancer. Chemokine receptor 4 (CXCR4) is one of the major chemokine receptors that overexpressed by cancers due to its role in tumor growth, migration, and progression. Organs such as the liver, bone, and brain have an intrinsically high concentration of CXCR4 ligand, C-X-C motif chemokine ligand 12 (CXCL12). As a result, CXCR4 is also often expressed at metastases in these organs. There is an unmet medical need for noninvasively early detecting, staging, and monitoring the prognosis of liver cancers and metastases as well as probing tumor microenvironment for target therapy and drug. In this dissertation, we first report the elevated expression of CXCR4 in the UM patients’ liver metastases and metastatic UM mouse models and validate its role as an imaging biomarker for liver metastases. We then report our achievement in the development of a CXCR4-targeted MRI contrast agent, ProCA32.CXCR4, for sensitive detection of UM liver metastases using MRI. ProCA32.CXCR4 exhibits high relaxivities (r1 = 30.9 mM-1 s-1, r2 = 43.2 mM-1 s-1, 1.5 T; r1 = 23.5 mM-1 s-1, r2 = 98.6 mM-1 s-1, 7.0 T), strong CXCR4 binding affinity (Kd = 1.1 ± 0.2 µM), and the capability of CXCR4 molecular imaging in both metastatic and intrahepatic xenotransplantation UM mouse models. ProCA32.CXCR4 enables robust detection of UM metastases as small as 0.1 mm2 in the liver. CXCR4 receptor blockage experiment proved the specific binding of ProCA32.CXCR4 to CXCR4. In addition, the application of ProCA32.CXCR4 in primary liver cancer detection and treatment effect monitoring are tested in hepatocellular carcinoma (HCC) mouse model. Except for gadolinium, we explored the possibility of manganese-based protein contrast agent and proved manganese-based ProCA exhibits high relaxivity and strong gadolinium binding affinity. We further designed and characterized ProCA32.RGD for integrin avb3 molecular imaging to reveal the tumor microenvironment. ProCA32.RGD targeted imaging was achieved in a 4T1 breast cancer mouse model. Further development of the biomarker targeted imaging agents is expected to have strong translation potential for early detection, surveillance, and treatment stratification of cancer and related diseases.

DOI

https://doi.org/10.57709/15010111

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