An efficient MRI agent targeting extracellular markers in prostate adenocarcinoma

Purpose: Prostate cancer (PCa) is the most widespread tumor affecting males in Western countries. We propose a novel MRI molecular tetrameric probe based on the heptadentate gadolinium (Gd)-AAZTA (6-amino-6-methylperhydro-1,4-diazepine-tetraacetic acid) that is able to in vivo detect PCa through the recognition of the fibrin-fibronectin (FB-FN) complex. Methods: The peptide CREKA (Cys-Arg-Glu-Lys-Ala), targeting the FB-FN complex in the reactive stroma of the tumor, was synthesized by solid phase peptide synthesis (SPPS) and conjugated to the tetramer dL-(Gd-AAZTA)(4). The resulting probe was characterized by H-1 relaxometry, tested in vitro on FB clots and in vivo on an orthotopic mouse model of PCa. Results: CREKA-dL-(Gd-AAZTA)(4) showed a remarkable relaxivity of 18.2 mM(Gd)(-1s-1) (0.47 T, 25 degrees C) because of the presence of 2 water molecules (q = 2) in the inner coordination sphere of each Gd3+ ion, whose rotational motion (tau(R)) is lengthened as the result of the relatively high molecular weight. The probe displayed a detectable affinity for plasma-derived FB clots. On intravenous injection of the probe in an orthotopic mouse model of PCa, a significant increase in the prostate T-1 contrast (similar to 40%) was observed. The MRI signal appears statistically higher either with respect to the one observed for the control probes and to the one detected when CREKA-dL-(Gd-AAZTA)(4) was administered to healthy animals. Conclusions: This study demonstrated the ability of the CREKA-dL-(Gd-AAZTA)(4) probe to specifically localize in prostate tumor after injection. The high relaxivity of the probe allows the reduction of the injected dose to 20 mu mol(Gd)/kg, yielding a good in vivo contrast enhancement in the region of prostate tumor.