title: Positron Emission Tomography Based Elucidation of the Enhanced Permeability and Retention Effect in Dogs with Cancer Using Copper-64 Liposomes.
abstract: Since the first report of the enhanced permeability and retention (EPR) effect, the research in nanocarrier based antitumor drugs has been intense. The field has been devoted to treatment of cancer by exploiting EPR-based accumulation of nanocarriers in solid tumors, which for many years was considered to be a ubiquitous phenomenon. However, the understanding of differences in the EPR-effect between tumor types, heterogeneities within each patient group, and dependency on tumor development stage in humans is sparse. It is therefore important to enhance our understanding of the EPR-effect in large animals and humans with spontaneously developed cancer. In the present paper, we describe a novel loading method of copper-64 into PEGylated liposomes and use these liposomes to evaluate the EPR-effect in 11 canine cancer patients with spontaneous solid tumors by PET/CT imaging. We thereby provide the first high-resolution analysis of EPR-based tumor accumulation in large animals. We find that the EPR-effect is strong in some tumor types but cannot be considered a general feature of solid malignant tumors since we observed a high degree of accumulation heterogeneity between tumors. Six of seven included carcinomas displayed high uptake levels of liposomes, whereas one of four sarcomas displayed signs of liposome retention. We conclude that nanocarrier-radiotracers could be important in identifying cancer patients that will benefit from nanocarrier-based therapeutics in clinical practice.
authors.affiliation: †Center for Nanomedicine and Theranostics, DTU Nanotech, Technical University of Denmark, Building 423, DK-2800 Lyngby, Denmark.
authors.forename: Anders E
authors.initials: AE
authors.lastname: Hansen
authors.affiliation: †Center for Nanomedicine and Theranostics, DTU Nanotech, Technical University of Denmark, Building 423, DK-2800 Lyngby, Denmark.
authors.forename: Anncatrine L
authors.initials: AL
authors.lastname: Petersen
authors.affiliation: †Center for Nanomedicine and Theranostics, DTU Nanotech, Technical University of Denmark, Building 423, DK-2800 Lyngby, Denmark.|§DTU Chemistry, Technical University of Denmark, Building 206, DK-2800 Lyngby, Denmark.
authors.forename: Jonas R
authors.initials: JR
authors.lastname: Henriksen
authors.affiliation: ∥Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Dyrlaegevej 16, DK-1870 Frederiksberg, Denmark.
authors.forename: Betina
authors.initials: B
authors.lastname: Boerresen
authors.affiliation: †Center for Nanomedicine and Theranostics, DTU Nanotech, Technical University of Denmark, Building 423, DK-2800 Lyngby, Denmark.|⊥DTU Nutech, Hevesy Laboratory, Technical University of Denmark, Frederiksborgvej 399, DK-4000 Roskilde, Denmark.
authors.forename: Palle
authors.initials: P
authors.lastname: Rasmussen
authors.affiliation: †Center for Nanomedicine and Theranostics, DTU Nanotech, Technical University of Denmark, Building 423, DK-2800 Lyngby, Denmark.|⊥DTU Nutech, Hevesy Laboratory, Technical University of Denmark, Frederiksborgvej 399, DK-4000 Roskilde, Denmark.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Elema
authors.affiliation: #Radiation Medicine Research Center, Department of Radiation Oncology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
authors.forename: Per Munck
authors.initials: PM
authors.lastname: af Rosenschöld
authors.affiliation: ∥Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Dyrlaegevej 16, DK-1870 Frederiksberg, Denmark.
authors.forename: Annemarie T
authors.initials: AT
authors.lastname: Kristensen
authors.forename: Andreas
authors.initials: A
authors.lastname: Kjær
authors.affiliation: †Center for Nanomedicine and Theranostics, DTU Nanotech, Technical University of Denmark, Building 423, DK-2800 Lyngby, Denmark.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Andresen
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000000981:diagnostic imaging* / Q000662:veterinary; D003301:Copper Radioisotopes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004285:Dogs; D005260:Female; D008081:Liposomes / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D064847:Multimodal Imaging; D011092:Polyethylene Glycols / Q000737:chemistry; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014057:Tomography, X-Ray Computed
chemical_list: D003301:Copper Radioisotopes; D008081:Liposomes; D019275:Radiopharmaceuticals; D011092:Polyethylene Glycols
keywords: EPR-effect; cancer; drug delivery; imaging; liposomes; nanomedicine; nanoparticles