Author ORCID Identifier

0000-0003-2393-2647

Date of Award

Fall 12-8-2023

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Jenny. J. Yang

Abstract

Magnetic resonance imaging (MRI) is a powerful technique for disease diagnosis, but extending this technology to applications in molecular imaging has been challenging due to lack of safe and effective contrast agents with required sensitivity and specificity. To address this need, we have developed a new generation of protein-based contrast agents (ProCA32) that exhibit high relaxivity, high metal selectivity, and low toxicity.

Here we report development and application of biomarker targeted contrast agents such as ProCA32.Collagen, ProCA32.CXCR4, and ProCA32.CXCL12 to image Collagen I, CXCR4, and CXCL12, which are molecular biomarkers overexpressed with chronic diseases. The collagen-targeted agent, ProCA32.Collagen, exhibits strong collagen I affinity and high relaxivities, enabling early-stage detection of liver fibrosis with a 7-fold increase in contrast-to-noise ratio (CNR) in mouse models. In addition, ProCA32.Collagen detects primary liver and pancreatic tumors and liver metastasis from uveal melanoma (UM), colon cancer, and pancreatic cancer. We further demonstrate that ProCA32.Collagen detects small liver cancer (sHCC) and premalignant nodules in several mouse models with different liver backgrounds, including steatosis and fibrosis. In addition, ProCA32.Collagen can detect fibrotic regions in the hearts of Ischemia-Reperfusion and Myocardial Infarction mouse models, and can monitor the treatment by PKM1/PKM2 during cardiovascular MRI imaging. We also report the development of Gd3+/Mn2+-ProCA32.CXCL12 and Gd3+-ProCA32.CXCR4 to detect liver fibrosis and cancer with multi-color imaging.

Overall, the development of ProCA32.Collagen, ProCA32.CXCR4, and ProCA32.CXCL12, and their successful preclinical applications using7T MRI scanner, represent a promising approach to early detection and accurate diagnosis of primary/metastatic liver cancers, and other cancers such as pancreas cancer, as well as heart fibrosis, with high sensitivity and specificity. These agents have broad applications in both early detection and probing heterogeneous changes in the microenvironment upon disease progression, which may help to determine the most effective treatment for patients.

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