Resection of tumor lesions using targeted dual-modality probes combining preoperative imaging with intraoperative guidance is of high clinical relevance and might considerably impact the outcome of prostate cancer therapy. This work aims at the development of dual-labeled prostate specific membrane antigen (PSMA)-inhibitors derived from the established positron emission tomography (PET)- and N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC) based tracer 68Ga-Glu-urea-Lys(Ahx)-HBED-CC (68Ga-PSMA-11) to allow accurate intraoperative detection of PSMA-positive tumor lesions. Methods: A series of novel PSMA-targeting fluorescent dye conjugates of Glu-urea-Lys-HBED-CC were synthesized and their biological properties determined in cell based assays and confocal microscopy. As a preclinical proof-of-concept, specific tumor uptake, pharmacokinetics and feasibility for intraoperative fluorescence-guidance were investigated in tumor-bearing mice and healthy pigs. Results: The designed dual-labeled PSMA-inhibitors exhibit high binding affinity and PSMA-specific effective internalization. Conjugation of Fluoresceinisothiocyanate (FITC) (10.86±0.94 %ID/g), IRDye800CW (13.66±3.73 %ID/g) and DyLight800 (15.62±5.52 %ID/g) resulted in a significantly increased specific tumor uptake, while 68Ga-Glu-urea-Lys-HBED-CC-AlexaFluor488 (9.12±5.47 %ID/g) revealed a similar tumor uptake as compared to 68Ga-PSMA-11 (4.89±1.34 %ID/g). First proof-of-concept studies with the clinically relevant candidate 68Ga-Glu-urea-Lys-HBED-CC-IRDye800CW reinforce a fast specific enrichment in PSMA-positive tumors with rapid background clearance. With regard to intraoperative navigation a specific fluorescence signal was detected in PSMA-expressing tissue. Conclusion: This study demonstrates that PSMA-11 derived dual-labeled dye-conjugates are feasible to provide PSMA-specific pre-, intra- and postoperative detection of prostate cancer lesions and have high potential for future clinical translation.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2017 Nov 30 [Epub ahead of print]
Ann-Christin Baranski, Martin Schäfer, Ulrike Bauder-Wüst, Mareike Roscher, Jana Schmidt, Esther Stenau, Tobias Simpfendörfer, Dogu Teber, Lena Maier-Hein, Boris Hadaschik, Uwe Haberkorn, Matthias Eder, Klaus Kopka
German Cancer Research Center, Germany., Heidelberg University Hospital, Germany., University Hospital Essen, Germany., German Cancer Consortium, Germany.