Molecular imaging of EGFR/HER2 cancer biomarkers by protein MRI contrast agents

Abstract

Epidermal growth factor receptor (EGFR) and HER2 are major prognosis biomarkers and drug targets overexpressed in various types of cancer cells. There is a pressing need to develop MRI contrast agents capable of enhancing the contrast between normal tissues and tumors with high relaxivity, capable of targeting tumors, and with high intratumoral distribution and minimal toxicity. In this review, we first discuss EGFR signaling and its role in tumor progression as a major drug target. We then report our progress in the development of protein contrast agents with significant improvement of both r1 and r2 relaxivities, pharmacokinetics, in vivo retention time, and in vivo dose efficiency. Finally, we report our effort in the development of EGFR-targeted protein contrast agents with the capability to cross the endothelial boundary and with good tissue distribution across the entire tumor mass. The noninvasive capability of MRI to visualize spatially and temporally the intratumoral distribution as well as quantify the levels of EGFR and HER2 would greatly improve our ability to track changes of the biomarkers during tumor progression, monitor treatment efficacy, aid in patient selection, and further develop novel targeted therapies for clinical application.

Contrast agents for MRI: 30+ years and where are we going?

“…As for every in vivo application, biological barriers like the blood-brain-barrier and toxicity of the contrast agent also need to be considered. Three different approaches for targeted delivery are highlighted in this issue: Yang proposes protein-based biomarkers targeting liver tumors [49]; Sherry and Mason report a small gadolinium complex that naturally accumulates in hypoxic tumors [50]; and Tóth and coworkers use targeting moieties for imaging β-amyloid plaques [51]. …”

Prostate-specific membrane antigen targeted protein contrast agents for molecular imaging of prostate cancer by MRI

“…19,26,33,61,62 Our current studies illuminate several additional advances in molecular imaging especially for prostate cancer. First, GRPR and HER-2 are expressed in multiple tumors, therefore, these GRPR and HER-2 targeted contrast agents can be applied for the imaging of tumor originating from different tissues.…”

“…These studies along with our previous studies further demonstrate the strategy of extending the protein contrast agent to biomarker targeting by the addition of peptide, glycans, or synthesized small ligands without sacrificing metal binding affinity and relaxivity. 19–21,30 …”

Targeted Contrast Agents for Molecular MRI

“…Yang et al have reported on the development of novel type of Gd 3+ -binding protein MRI probes, ProCA [3,44,45]. The scaffold of these CAs is based on the domain 1 of CD2.…”