Amerigo Pagoto1, Francesca Garello1, Giada Maria Marini1, Martina Tripepi1, Francesca Arena1, Paola Bardini1, Rachele Stefania1, Stefania Lanzardo1, Giovanni Valbusa2, Francesco Porpiglia3, Matteo Manfredi3, Silvio Aime1,4, Enzo Terreno5. 1. Molecular & Preclinical Imaging Centers, Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy. 2. EPHORAN-Multi Imaging Solutions, Colleretto Giacosa, Torino, Italy. 3. Division of Urology, San Luigi Gonzaga Hospital, University of Torino, Orbassano, Torino, Italy. 4. IBB-CNR, Sede Secondaria c/o MBC, Via Nizza 52, Torino, Italy. 5. Molecular & Preclinical Imaging Centers, Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy. enzo.terreno@unito.it.
Abstract
PURPOSE: Prostate cancer (PCa), the most widespread male cancer in western countries, is generally eradicated by surgery, especially if localized. However, during surgical procedures, it is not always possible to identify malignant tissues by visual inspection. Among the possible consequences, there is the formation of positive surgical margins, often associated with recurrence. In this work, the gastrin-releasing peptide receptor (GRPR), overexpressed in the prostatic carcinoma and not in healthy tissues or in benign hyperplasia (BPH), is proposed as target molecule to design a novel near-infrared fluorescent (NIRF) probe for image-guided prostatectomy. PROCEDURES: The NIRF dye Sulfo-Cy5.5 was conjugated to a Bombesin-like peptide (BBN), targeting GRPR. The final product, called BBN-Cy5.5, was characterized and tested in vitro on PC-3, DU145, and LnCAP cell lines, using unconjugated Sulfo-Cy5.5 as control. In vivo biodistribution studies were performed by optical imaging in PC-3 tumor-bearing and healthy mice. Finally, simulation of the surgical protocol was carried out. RESULTS: BBN-Cy5.5 showed high water solubility and a good relative quantum yield. The ability of the probe to recognize the GRPR, highly expressed in PC-3 cells, was tested both in vitro and in vivo, where a significant tumor accumulation was achieved 24 h post-injection. Furthermore, a distinguishable fluorescent signal was visible in mice bearing PCa, when the surgery was simulated. By contrast, low signal was found in healthy or BPH-affected mice. CONCLUSIONS: This work proposes a new NIRF probe ideal to target GRPR, biomarker of PCa. The promising data obtained suggest that the dye could allow the real-time intraoperative visualization of prostate cancer.
PURPOSE:Prostate cancer (PCa), the most widespread male cancer in western countries, is generally eradicated by surgery, especially if localized. However, during surgical procedures, it is not always possible to identify malignant tissues by visual inspection. Among the possible consequences, there is the formation of positive surgical margins, often associated with recurrence. In this work, the gastrin-releasing peptide receptor (GRPR), overexpressed in the prostatic carcinoma and not in healthy tissues or in benign hyperplasia (BPH), is proposed as target molecule to design a novel near-infrared fluorescent (NIRF) probe for image-guided prostatectomy. PROCEDURES: The NIRF dye Sulfo-Cy5.5 was conjugated to a Bombesin-like peptide (BBN), targeting GRPR. The final product, called BBN-Cy5.5, was characterized and tested in vitro on PC-3, DU145, and LnCAP cell lines, using unconjugated Sulfo-Cy5.5 as control. In vivo biodistribution studies were performed by optical imaging in PC-3tumor-bearing and healthy mice. Finally, simulation of the surgical protocol was carried out. RESULTS:BBN-Cy5.5 showed high water solubility and a good relative quantum yield. The ability of the probe to recognize the GRPR, highly expressed in PC-3 cells, was tested both in vitro and in vivo, where a significant tumor accumulation was achieved 24 h post-injection. Furthermore, a distinguishable fluorescent signal was visible in mice bearing PCa, when the surgery was simulated. By contrast, low signal was found in healthy or BPH-affected mice. CONCLUSIONS: This work proposes a new NIRF probe ideal to target GRPR, biomarker of PCa. The promising data obtained suggest that the dye could allow the real-time intraoperative visualization of prostate cancer.
Authors: Alexander L Vahrmeijer; Merlijn Hutteman; Joost R van der Vorst; Cornelis J H van de Velde; John V Frangioni Journal: Nat Rev Clin Oncol Date: 2013-07-23 Impact factor: 66.675
Authors: James A Eastham; Kentaro Kuroiwa; Makoto Ohori; Angel M Serio; Alex Gorbonos; Norio Maru; Andrew J Vickers; Kevin M Slawin; Thomas M Wheeler; Victor E Reuter; Peter T Scardino Journal: Urology Date: 2007-11 Impact factor: 2.649
Authors: Ofer Yossepowitch; Anders Bjartell; James A Eastham; Markus Graefen; Bertrand D Guillonneau; Pierre I Karakiewicz; Rodolfo Montironi; Franceso Montorsi Journal: Eur Urol Date: 2008-10-01 Impact factor: 20.096
Authors: Dae Chul Jung; Hak Jong Lee; Jin Won Seo; So Yeon Park; Sang Jin Lee; Joo Hyuk Lee; In Hoo Kim Journal: Korean J Radiol Date: 2011-12-23 Impact factor: 3.500
Authors: Steve S Cho; Saad Sheikh; Clare W Teng; Joseph Georges; Andrew I Yang; Emma De Ravin; Love Buch; Carrie Li; Yash Singh; Denah Appelt; Edward J Delikatny; E James Petersson; Andrew Tsourkas; Jay Dorsey; Sunil Singhal; John Y K Lee Journal: Mol Imaging Biol Date: 2020-10 Impact factor: 3.488