Date of Award

8-7-2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Jenny J. Yang

Second Advisor

Markus Germann

Third Advisor

Ming Luo

Fourth Advisor

Zhi-Ren Liu

Fifth Advisor

Shella Keilholz

Sixth Advisor

Phillip Zhe Sun

Abstract

Chronic diseases and conditions such as liver and heart diseases are among the most common, costly, and preventable of all health problems. As of 2012 in the U.S., about half of all adults—117 million people—had one or more chronic health conditions. Aortic aneurysm and liver fibrosis are among the most common chronic diseases which are generated by the formation and deposition of excess extracellular matrix proteins (largely type I collagen) as a result of a reparative process, represents one of the most major global health problems. Collagen type I is one of the major diagnostic biomarkers and therapeutic targets for many chronic diseases including heart and liver diseases. Early diagnosis, noninvasive detection and staging of these diseases, remain as one of the major clinical barriers which can lead to effective treatment and stop further progression toward major clinical consequences. MRI as one the popular imaging modalities has several unique advantages for monitoring slow progression and detection of disease with high resolution without using radiation, however, there is an unmet medical need to develop MRI contrast agents with desired sensitivity and collagen specificity. In this dissertation, the successful design of a protein-based contrast agent with collagen type I targeting capability (ProCA32.collagen1) is reported to diagnose and stage liver and heart diseases in many mouse models of caner, fibrosis and aortic aneurysm. ProCA32.collagen1 exhibits the highest relaxivity values for r1 (34 ± 0.12 mM-1.s-1) and r2 (50 ± 0.16 mM-1.s-1) per Gd3+ at 1.4 T and r1 (21.3 ± 0.5 mM-1.s-1) and r2 (108.5 ± 1.2 mM-1.s-1) at 7.0 T. ProCA32.collagen1 can detect both early (Ishak 3 of 6) and late stage mouse liver fibrosis as well as early stage nonalcoholic steatohepatitis (Ishak 1 of 6) in different models with strong metal binding affinity and selectivity. The targeted contrast agent is also capable of detecting disease heterogeneity with high collagen type I binding affinity with dissociation constant of Kd=1.42 ± 0.2 mM. ProCA32.collagen1 has largely reduced dose and strong resistance against transmetallation (104-1012-fold higher metal selectivity for Gd3+ over Ca2+ and Zn2+) compared to existing contrast agents. ProCA32.collagen1 is expected to have strong translational potential to improve detection of different diseases at early stages with high confidence, and subsequently monitor disease progression and patient response to treatment.

DOI

https://doi.org/10.57709/12568868

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