Quantitative imaging of the receptor for advanced glycation end-products in prostate cancer
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ORIGINAL ARTICLE
Quantitative imaging of the receptor for advanced glycation end-products in prostate cancer Christian J. Konopka 1,2 & Marcin Woźniak 2,3 & Jamila Hedhli 1,2 & Anna Siekierzycka 3 & Jarosław Skokowski 3,4,5 & Rafał Pęksa 6 & Marcin Matuszewski 7 & Gnanasekar Munirathinam 8 & Andre Kajdacsy-Balla 9 & Iwona T. Dobrucki 2 & Leszek Kalinowski 3,4 & Lawrence W. Dobrucki 1,2,3,4,10,11 Received: 21 October 2019 / Accepted: 10 February 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Purpose Current screening and monitoring of prostate cancer (PCa) is insufficient, producing inaccurate diagnoses. Presence of the receptor for advanced glycation end-products (RAGE) is associated with signature characteristics of PCa development such as cell proliferation, anchorage-independent growth, angiogenesis, migration, invasion, and poor patient survival. Therefore, we developed a preclinical multimodal imaging strategy targeted at RAGE to diagnose and monitor PCa. Methods In this work, RAGE-targeted multimodal nanoparticles (64Cu-Cy5-G4-CML) were synthesized and rendered functional for nuclear and optical imaging using previously established methods. The probe’s binding affinity and targeting specificity was assessed in androgen-dependent (LNCaP) and androgen-independent (DU145) prostate cancer cells using flow cytometry and confocal microscopy. In vivo PET-CT imaging was used to evaluate RAGE levels in DU145 and LNCaP xenograft models in mice. Then, tumors were excised post-imaging for histological staining and autoradiography to further assess RAGE levels and targeting efficiency of the tracer. Finally, RAGE levels from human PCa samples of varying Gleason Scores were evaluated using Western blot and immunohistochemical staining. Results PCa cell culture studies confirmed adequate RAGE-targeting with 64Cu-Cy5-G4-CML with KD between 360 and 540 nM as measured by flow cytometry. In vivo PET-CT images of PCa xenografts revealed favorable kinetics, rapid blood clearance, and a non-homogenous, enhanced uptake in tumors, which varied based on cell type and tumor size with mean uptake between 0.5 and 1.4%ID/g. RAGE quantification of human samples confirmed increased RAGE uptake corresponding to increased Gleason scoring. Conclusions Our study has shown that RAGE-targeted cancer imaging is feasible and could significantly impact PCa management. Keywords Molecular imaging . Receptorfor advancedglycation end-products . RAGE . PET-CT . Cancer . Multimodal imaging . Inflammation This article is part of the Topical Collection on Preclinical Imaging * Lawrence W. Dobrucki [email protected]
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Department of Pathology, Medical University of Gdansk, Gdansk, Poland
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Department of Urology, Medical University of Gdansk, Gdansk, Poland
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Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA
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Beckman Institute for Advanced Science and Technology, Urbana, IL, USA
Department of Biomedical Sciences, University of Illinois College of Medicine, Rockford, IL, USA
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