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Quantitative imaging of the receptor for advanced glycation end-products in prostate cancer

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

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.

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Abbreviations

PCa:

Prostate cancer

LPCa:

Localized prostate cancer

AS:

Active surveillance

DRE:

Digital rectal exam

PSA:

Prostate-specific antigen

RAGE:

Receptor for advanced glycation end-product

AGE:

Advanced glycation end-products

PET:

Positron emission tomography

CT:

Computed tomography

PAMAM:

Polyamidoamine

DU145:

Human prostate cancer cell line

LNCaP:

Lymph node carcinoma of the prostate

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Funding

This work was funded in part by the Cancer Center at Illinois (CCIL) pilot grant, Ministry of Science and Higher Education Poland ((DIR/WK/2017/01), and Foundation for Polish Science (TEAM/2011-7/5).

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Correspondence to Lawrence W. Dobrucki.

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The authors declare that they have no conflict of interest.

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All applicable international, national, and institutional guidelines for the care and use of animals were followed. Samples from prostate cancer patients were obtained from the Medical University of Gdansk, Poland, and Biobanking and Biomolecular Resources Research Infrastructure in Poland following the approval by the local Ethics Review Committee of the Medical University of Gdansk, Gdansk, Poland (no. NKBBN/217/2016).

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Konopka, C.J., Woźniak, M., Hedhli, J. et al. Quantitative imaging of the receptor for advanced glycation end-products in prostate cancer. Eur J Nucl Med Mol Imaging 47, 2562–2576 (2020). https://doi.org/10.1007/s00259-020-04721-1

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