title: In vivo evaluation of PEGylated ⁶⁴Cu-liposomes with theranostic and radiotherapeutic potential using micro PET/CT.
abstract: OBJECTIVE
  The objective of this study was to evaluate the potential of PEGylated (64)Cu-liposomes in clinical diagnostic positron emission tomography (PET) imaging and PEGylated (177)Lu-liposomes in internal tumor radiotherapy through in vivo characterization and dosimetric analysis in a human xenograft mouse model.
  
  
  METHODS
  Liposomes with 5 and 10 mol% PEG were characterized with respect to size, charge, and (64)Cu- and (177)Lu-loading efficiency. The tumor imaging potential of (64)Cu-loaded liposomes was evaluated in terms of in vivo biodistribution, tumor accumulation and tumor-to-muscle (T/M) ratios, using PET imaging. The potential of PEGylated liposomes for diagnostic and therapeutic applications was further evaluated through dosimetry analysis using OLINDA/EXM software. The (64)Cu-liposomes were used as biological surrogates to estimate the organ and tumor kinetics of (177)Lu-liposomes.
  
  
  RESULTS
  High remote loading efficiency (>95 %) was obtained for both (64)Cu and (177)Lu radionuclides with PEGylated liposomes, and essentially no leakage of the encapsulated radionuclide was observed upon storage and after serum incubation for 24 h at 37 °C. The 10 mol% PEG liposomes showed higher tumor accumulation (6.2 ± 0.2 %ID/g) than the 5 mol% PEG liposomes, as evaluated by PET imaging. The dosimetry analysis of the (64)Cu-liposomes estimated an acceptable total effective dose of 3.3·10(-2) mSv/MBq for diagnostic imaging in patients. A high absorbed tumor dose (114 mGy/MBq) was estimated for the potential radiotherapeutic (177)Lu-liposomes.
  
  
  CONCLUSIONS
  The overall preclinical profile of PEGylated (64)Cu-liposomes showed high potential as a new PET theranostic tracer for imaging in humans. Dosimetry results predicted that initial administered activity of 200 MBq of (64)Cu-liposomes should be acceptable in patients. Work is in progress to validate the utility of PEGylated (64)Cu-liposomes in a clinical research programme. The high absorbed tumor dose (114 mGy/MBq) estimated for (177)Lu-liposomes and the preliminary dosimetric studies justify further therapeutic and dosimetry investigation of (177)Lu-liposomes in animals before potential testing in man.
authors.affiliation: Department of Micro- and Nanotechnology, Technical University of Denmark, Building 345, 2800, Lyngby, Denmark.|Center for Nanomedicine and Theranostics, Technical University of Denmark, 2800, Lyngby, Denmark.
authors.forename: Anncatrine Luisa
authors.initials: AL
authors.lastname: Petersen
authors.affiliation: Center for Nanomedicine and Theranostics, Technical University of Denmark, 2800, Lyngby, Denmark.|Department of Chemistry, Technical University of Denmark, Building 206, 2800, Lyngby, Denmark.
authors.forename: Jonas Rosager
authors.initials: JR
authors.lastname: Henriksen
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet & Cluster for Molecular Imaging, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark.
authors.forename: Tina
authors.initials: T
authors.lastname: Binderup
authors.affiliation: Center for Nanomedicine and Theranostics, Technical University of Denmark, 2800, Lyngby, Denmark.|Center for Nuclear Technologies, Hevesy Laboratory, Technical University of Denmark, Frederiksborgvej 399, 4000, Roskilde, Denmark.
authors.forename: Dennis Ringkjøbing
authors.initials: DR
authors.lastname: Elema
authors.affiliation: Center for Nuclear Technologies, Hevesy Laboratory, Technical University of Denmark, Frederiksborgvej 399, 4000, Roskilde, Denmark.
authors.forename: Palle Hedengran
authors.initials: PH
authors.lastname: Rasmussen
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet & Cluster for Molecular Imaging, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark.
authors.forename: Anne Mette
authors.initials: AM
authors.lastname: Hag
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet & Cluster for Molecular Imaging, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kjær
authors.affiliation: Department of Micro- and Nanotechnology, Technical University of Denmark, Building 345, 2800, Lyngby, Denmark. thomas.andresen@nanotech.dtu.dk.|Center for Nanomedicine and Theranostics, Technical University of Denmark, 2800, Lyngby, Denmark. thomas.andresen@nanotech.dtu.dk.
authors.forename: Thomas Lars
authors.initials: TL
authors.lastname: Andresen
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003301:Copper Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D008081:Liposomes / Q000737:chemistry / Q000493:pharmacokinetics*; D008187:Lutetium / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D018358:Neuroendocrine Tumors / Q000000981:diagnostic imaging* / Q000532:radiotherapy; D011092:Polyethylene Glycols / Q000737:chemistry; D000072078:Positron Emission Tomography Computed Tomography; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014018:Tissue Distribution
chemical_list: D003301:Copper Radioisotopes; D008081:Liposomes; D019275:Radiopharmaceuticals; D011092:Polyethylene Glycols; D008187:Lutetium
keywords: Cancer imaging; Diagnostic; Nanoparticle; PET; Radiotherapy; Theranostic