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Noninvasive Molecular Imaging of the Enhanced Permeability and Retention Effect by 64Cu-Liposomes: In vivo Correlations with 68Ga-RGD, Fluid Pressure, Diffusivity and 18F-FDG

Authors Børresen B, Hansen AE, Fliedner FP, Henriksen JR, Elema DR, Brandt-Larsen M, Kristensen LK, Kristensen AT, Andresen TL, Kjær A

Received 19 November 2019

Accepted for publication 29 March 2020

Published 2 November 2020 Volume 2020:15 Pages 8571—8581


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Prof. Dr. Anderson Oliveira Lobo

Betina Børresen,1 Anders Elias Hansen,2,3 Frederikke Petrine Fliedner,2 Jonas Rosager Henriksen,3 Dennis Ringkjøbing Elema,3,4 Malene Brandt-Larsen,5 Lotte Kellemann Kristensen,2– 6 Annemarie Thuri Kristensen,1– 6 Thomas Lars Andresen,3 Andreas Kjær2,5

1Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C 1870, Denmark; 2Cluster for Molecular Imaging, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N 2200, Denmark; 3DTU Health Technology, Center for Nanomedicine and Theranostics, Technical University of Denmark, Lyngby, Kgs 2800, Denmark; 4DTU Health Technology, The Hevesy Laboratory, Center for Nuclear Technologies, Technical University of Denmark, Roskilde, 4000, Denmark; 5Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Copenhagen Ø 2100, Denmark; 6Minerva Imaging, Copenhagen N 2200, Denmark

Correspondence: Andreas Kjær
Cluster for Molecular Imaging, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen N 2200, Denmark
Tel +45 35 32 75 04
Fax +45 35 32 75 46

Background: The accumulation of liposome encapsulated chemotherapy in solid cancers is dependent on the presence of the enhanced permeability and retention (EPR) effect. Positron emission tomography (PET) imaging with a liposome encapsulated radioisotope, such as liposome encapsulated Cu-64 (64Cu-liposome) may help to identify tumors with high liposome accumulation, and thereby stratify patients based on expected benefit from liposomal chemotherapy. However, intravenous administration of liposomes without a cytotoxic content is complicated by the accelerated blood clearance (ABC) phenomenon for succeeding therapeutic liposome dosing. Alternative markers for assessing the tumor’s EPR level are therefore warranted.
Materials and Methods: To increase our understanding of EPR variations and to ultimately identify an alternative marker for the EPR effect, we investigated the correlation between 64Cu-liposome PET/CT (EPR effect) and 68Ga-RGD PET/CT (neoangiogenesis), 18F-FDG PET/CT (glycolysis), diffusion-weighted MRI (diffusivity) and interstitial fluid pressure in two experimental cancer models (CT26 and COLO 205).
Results: 64Cu-liposome and 68Ga-RGD SUVmax displayed a significant moderate correlation, however, none of the other parameters evaluated displayed significant correlations. These results indicate that differences in neoangiogenesis may explain some EPR variability, however, as correlations were only moderate and not observed for SUVmean, 68Ga-RGD is probably insufficient to serve as a stand-alone surrogate marker for quantifying the EPR effect and stratifying patients.

Keywords: EPR effect, liposome, positron emission tomography, neoangiogenesis

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