Development of Targeted Near-Infrared Imaging Agents for Prostate Cancer

Abstract

Prostate cancer is the most common noncutaneous malignancy affecting men in North America. Radical prostatectomy remains a definitive treatment for prostate cancer. However, prostate surgeries are still performed “blindly” with the extent of tumor infiltration past the margins of the surgery only being determined postoperatively. An imaging modality that can be used during surgery is needed to help define the tumor margins. With its abundant expression in prostate cancer, prostate-specific membrane antigen (PSMA) is an ideal target for detection of prostate cancer. The purpose of this study was to develop PSMA-targeted near-infrared (NIR) optical imaging probes for intraoperative visualization of prostate cancer. We synthesized a high-affinity PSMA ligand (PSMA-1) with low molecular weight and further labeled it with commercially available NIR dyes IRDy800 and Cy5.5. PSMA-1 and PSMA-1–NIR conjugates had binding affinities better than the parent ligand Cys-CO-Glu. Selective binding was measured for each of the probes in both in vitro and in vivo studies using competitive binding and uptake studies. Interestingly, the results indicated that the pharmacokinetics of the probes was dependent of the fluorophore conjugated to the PSMA-1 ligand and varied widely. These data suggest that PSMA-targeted probes have the potential to be further developed as contrast agents for clinical intraoperative fluorescence-guided surgery.

Theranostic Agents for Photodynamic Therapy of Prostate Cancer by Targeting Prostate-Specific Membrane Antigen

“…When an excess amount of Cys-CO-Glu was included in the incubation, no fluorescence signal was observed, confirming that cellular uptake of fluorescence was attributed to the specific binding of PSMA-1-PDT conjugates to PSMA. Once internalized into PC3pip cells, the PSMA-1-PDT conjugates were located in the perinuclear position, concurring with our previous results with PSMA-NIR conjugates (38).…”

“…Competition binding assay showed that both PSMA-1-Pc413 (IC 50 Table 1) and an affinity similar to that measured in previous studies using PSMA-1-Cy5.5 or PSMA-1-IR800 (38).…”

“…PSMA targeting peptide Glu-CO-Glu'-Amc-Ahx-Glu-Glu-GluLys-NH 2 (PSMA-1) was synthesized by Fmoc chemistry as reported previously (38). (S)-2-(3-((S)-5-amino-1-carboxypentyl)ureido)pentanedioic acid (Cys-CO-Glu; Supplementary Fig.…”

“…The assay was carried out as reported previously (38) by incubation PC3pip cells with different concentrations of Fig. S1; GE Healthcare Life Sciences).…”

“…Previously, we have developed a peptide-based, highly negatively charged PSMA ligand (PSMA-1; Supplementary Fig. S1) for PSMA-targeted imaging of prostate cancer (37,38). In this study, we have designed two PSMA-1-based PDT conjugates (PSMA-1-PDT), PSMA-1-Pc413 (Fig.…”