Designing Magnetic Resonance Protein-based Contrast Agents with High Relaxivity

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DESCRIPTION (provided by applicant): Biomarkers such as the epidermal growth factor receptors EGFR and HER2/Neu and gastrin-releasing peptide (GRP) receptors (GRPRs) are highly expressed in various diseases such as breast and prostate cancers and play important roles in disease progression and survival. They are also major drug targets for targeted therapy. There is an urgent need to develop non-invasive and accurate methods for diagnosis and selection of patients and to monitor biomarker levels/distribution and their changes upon treatment by targeted drugs. Molecular imaging of cancer biomarkers using MRI potentially improves our understanding of the disease and drug activity during preclinical and clinical drug treatment. However, lack of desired MRI contrast agents capable of enhancing the contrast between normal tissues and tumors with high relaxivity, tumor targeting, high intratumoral distribution and no toxicity is one of the major barriers for the application of MRI to assess specific biomarkers for diagnosis and monitor drug effect. The goals of this research are to develop protein-based MRI contrast agents for future clinical application with further improved relaxivity, targeting capability and reduced toxicity to enable accurate monitoring of the expression level and distribution of two biomarkers (HER2/Neu and EGFR) in different types of cancers, and to monitor tumor response to treatment using targeted therapeutics with significantly reduced metal toxicity. Aim 1 is to further increase relaxivity by varying structural arrangements in inner coordination shell and optimizing relaxation properties in outer sphere coordination. Aim 2 is to develop targeted contrast agents to monitor the expression and distribution of HER2 and EGFR during cancer progression and treatment. Aim 3 is to study the safety profiles for biostability and toxicity in preclinical models. In addition to improving our understanding of the relaxation theory, our proposed study to improve the relaxivity, targeting capability, and good tumor tissue distribution of the designed contrast agents has potential to overcome the major barriers in the clinical application of molecular imaging by MRI to assess specific disease markers. Detecting the temporal and spatial changes of a set of related disease biomarkers such as HER2 and EGFR sharing the same signaling pathway will allow for earlier disease diagnosis, monitoring disease progression and the synergistic treatment by targeted therapy, aiding in patient selection, and development of novel targeted therapies for clinical applications.