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

Prostate-specific membrane antigen (PSMA) is one of the most specific cell surface markers for prostate cancer diagnosis and targeted treatment. However, achieving molecular imaging using non-invasive MRI with high resolution has yet to be achieved due to the lack of contrast agents with significantly improved relaxivity for sensitivity, targeting capabilities and metal selectivity. We have previously reported our creation of a novel class of protein Gd3+ contrast agents, ProCA32, which displayed significantly improved relaxivity while exhibiting strong Gd3+ binding selectivity over physiological metal ions. In this study, we report our effort in further developing biomarker-targeted protein MRI contrast agents for molecular imaging of PSMA. Among three PSMA targeted contrast agents engineered with addition of different molecular recognition sequences, ProCA32. PSMA exhibits a binding affinity of 1.1 +/- 0.1 mu M for PSMA while the metal binding affinity is maintained at 0.9 +/- 0.1 x 10-22 M. In addition, ProCA32. PSMA exhibits r(1) of 27.6 mM(-1) s(-1) and r(2) of 37.9 mM(-1) s(-1) per Gd (55.2 and 75.8 mM(-1) s(-1) per molecule r(1) and r(2), respectively) at 1.4 T. At 7 T, ProCA32. PSMA also has r(2) of 94.0 mM(-1) s(-1) per Gd (188.0 mM(-1) s(-1) per molecule) and r(1) of 18.6 mM(-1) s(-1) per Gd (37.2 mM(-1) s(-1) per molecule). This contrast capability enables the first MRI enhancement dependent on PSMA expression levels in tumor bearing mice using both T-1 and T-2-weighted MRI at 7 T. Further development of these PSMA-targeted contrast agents are expected to be used for the precision imaging of prostate cancer at an early stage and to monitor disease progression and staging, as well as determine the effect of therapeutic treatment by non-invasive evaluation of the PSMA level using MRI.