Abstract
Gastrin-releasing peptide receptor (GRPR) is differentially expressed on the surfaces of various diseased cells, including prostate and lung cancer. However, monitoring temporal and spatial expression of GRPR in vivo by clinical MRI is severely hampered by the lack of contrast agents with high relaxivity, targeting capability and tumor penetration. Here, we report the development of a GRPR-targeted MRI contrast agent by grafting the GRPR targeting moiety into a scaffold protein with a designed Gd3+ binding site (ProCA1.GRPR). In addition to its strong binding affinity for GRPR (Kd = 2.7 nM), ProCA1.GRPR has high relaxivity (r1 = 42.0 mM−1s−1 at 1.5 T and 25 °C) and strong Gd3+ selectivity over physiological metal ions. ProCA1.GRPR enables in vivo detection of GRPR expression and spatial distribution in both PC3 and H441 tumors in mice using MRI. ProCA1.GRPR is expected to have important preclinical and clinical implications for the early detection of cancer and for monitoring treatment effects.
Highlights
Prostate cancer is the leading cause of tumor-related death in men in the Western world
We have previously shown that the relaxivity of ProCA1 is significantly greater than that of clinically approved contrast agent, Gd-DTPA21
We hypothesize that grafting a full length sequence (14 residues) of bombesin rather than 10 residue fragment from the C-terminal of gastrin-releasing peptide (GRP) or Bombesin in ProCA1 would bestow greater Gastrin-releasing peptide receptor (GRPR) binding affinity
Summary
Prostate cancer is the leading cause of tumor-related death in men in the Western world. There is an urgent need to develop sensitive and accurate non-invasive imaging methods to assess cancer states in vivo using biomarkers, and subsequently monitor tumor progression, metastasis, and treatment effectiveness with high specificity. Biomarkers, such as gastrin-releasing peptide (GRP) receptor (GRPR), were suggested to be attractive early cancer indicators[1,2]. MRI is more accurate than CT, ultrasound and digital rectal examination in the assessment of unilateral or bilateral diseases (stage T2), extracapsular extension and invasion of seminal vesicles (stage T3), as well as invasion of adjacent structures (stage T4)[18] It remains as a challenge for MRI to follow the recurrence and metastasis of prostate cancer upon PSA levels increasing after drug treatment. There is an urgent need to develop MRI contrast agents with significantly improved relaxivities and targeting capabilities to monitor changes of disease biomarkers with sufficient temporal and spatial resolution
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