Abstract

The epidermal growth factor receptor (EGFR) is over-expressed in a variety of human cancers, including in hormone-refractory prostate carcinomas, in which the EGFR has been associated with advanced disease stage, resistance to standard treatment and poor prognosis. Therefore, the EGFR is considered to be a promising molecular target for molecular imaging and therapy for hormone-refractory prostate cancer. This work describes the synthesis and initial tumor affinity testing of the EGFR antagonist 123I-mAb425 and the EGF receptor tyrosine kinase (EGFR-TK) inhibitor 123I-PD153035 as potential imaging probes for studying EGFR-expressing prostate cancer using single photon emission tomography. Methods 123I-mAb425 and 123I-PD153035 were prepared, starting from the IgG2a antibody and EGFR antagonist mAb425, that binds to the external domain of the EGF receptors, and from the EGFR-TK inhibitor PD153035, targeting the intra-endothelial tyrosine kinase domain of the EGFR, respectively. The potential of 123I-mAb425 and 123I-PD153035 to target EGFR-positive prostate carcinoma was tested on androgen-insensitive PC-3 and DU-145 prostate carcinoma cell lines, and on the androgen-sensitive LNCaP prostate cancer cell line for comparison. In vivo, the capability of 123I-mAb425 and 123I-PD153035 to target hormone-refractory prostate cancer was assessed in RNU rats or nu/nu mice bearing human PC3 prostate cancer xenografts. Results 123I-mAb425 was obtained in >90% radiochemical yield using the IODO-GEN ® method. 123I-PD153035 was synthesized by a non-isotopic [ 123I]iodo-debromination of PD153035 in 50–60% radiochemical yield in a total synthesis time including HPLC separation of 70 min. In vitro 123I-mAb425 and 123I-PD153035 accumulated highly in human PC-3 and DU-145 prostate cancer cells. Radioactivity incorporation into PC-3 and DU-145 tumor cells following 15-min incubation at 37 °C varied from 25% to 48% of the total loaded activity per 10 6 tumor cells (560–1230 cpm/1000 cells). In comparison, the uptake of the EGFR-affine probes into LNCaP prostate carcinoma cells was significantly low (105 ± 25 cpm/1000 cells). Inhibition experiments revealed that 123I-mAb425 is taken up into tumor cells via the same pathway as the naturally occurring epidermal growth factor (EGF), while 123I-PD153035 accumulation in prostate cancer cells occurs presumably via the same pathway as the selective EGFR-Tyrosine kinase antagonist AG1418. In vivo, the human prostate cancer xenografts in mouse war accurately visualized after i.v. administration of 123I-mAb425 by a gamma camera. Conclusion These data suggest that 123I-mAb425 and 123I-PD153035 are promising candidates as imaging probes for EGFR-positive prostate cancer and warrant further in vivo validations to ascertain their potential as imaging agents for clinical used.

Full Text
Paper version not known

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call