title: Tumor targeting and imaging with dual-peptide conjugated multifunctional liposomal nanoparticles.
abstract: BACKGROUND
  The significant progress in nanotechnology provides a wide spectrum of nanosized material for various applications, including tumor targeting and molecular imaging. The aim of this study was to evaluate multifunctional liposomal nanoparticles for targeting approaches and detection of tumors using different imaging modalities. The concept of dual-targeting was tested in vitro and in vivo using liposomes derivatized with an arginine-glycine-aspartic acid (RGD) peptide binding to αvβ3 integrin receptors and a substance P peptide binding to neurokinin-1 receptors.
  
  
  METHODS
  For liposome preparation, lipids, polyethylene glycol building blocks, DTPA-derivatized lipids for radiolabeling, lipid-based RGD and substance P building blocks and imaging labels were combined in defined molar ratios. Liposomes were characterized by photon correlation spectroscopy and zeta potential measurements, and in vitro binding properties were tested using fluorescence microscopy. Standardized protocols for radiolabeling were developed to perform biodistribution and micro-single photon emission computed tomography/computed tomography (SPECT/CT) studies in nude mice bearing glioblastoma and/or melanoma tumor xenografts. Additionally, an initial magnetic resonance imaging study was performed.
  
  
  RESULTS
  Liposomes were radiolabeled with high radiochemical yields. Fluorescence microscopy showed specific cellular interactions with RGD-liposomes and substance P-liposomes. Biodistribution and micro-SPECT/CT imaging of (111)In-labeled liposomal nanoparticles revealed low tumor uptake, but in a preliminary magnetic resonance imaging study with a single-targeted RGD-liposome, uptake in the tumor xenografts could be visualized.
  
  
  CONCLUSIONS
  The present study shows the potential of liposomes as multifunctional targeted vehicles for imaging of tumors combining radioactive, fluorescent, and magnetic resonance signaling. Specific in vitro tumor targeting by fluorescence microscopy and radioactivity was achieved. However, biodistribution studies in an animal tumor model revealed only moderate tumor uptake and no additive effect using a dual-targeting approach.
authors.affiliation: Department of Nuclear Medicine, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Rangger
authors.affiliation: Department of Nuclear Medicine, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Anna
authors.initials: A
authors.lastname: Helbok
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Sosabowski
authors.affiliation: Department of Radiology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Kremser
authors.affiliation: Department of Computational and Structural Biology, Max Perutz Laboratories, University of Vienna, Wien, Austria.
authors.forename: Gottfried
authors.initials: G
authors.lastname: Koehler
authors.affiliation: Institute of Biophysics, Medical University of Graz, Graz, Austria ; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
authors.forename: Ruth
authors.initials: R
authors.lastname: Prassl
authors.affiliation: piCHEM Research and Development, Graz, Austria.
authors.forename: Fritz
authors.initials: F
authors.lastname: Andreae
authors.affiliation: Department of Nuclear Medicine, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Irene J
authors.initials: IJ
authors.lastname: Virgolini
authors.affiliation: Department of Nuclear Medicine, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: von Guggenberg
authors.affiliation: Department of Nuclear Medicine, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Clemens
authors.initials: C
authors.lastname: Decristoforo
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D008081:Liposomes / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D057054:Molecular Imaging / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry*; D009374:Neoplasms, Experimental / Q000473:pathology / Q000532:radiotherapy; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*; D014057:Tomography, X-Ray Computed / Q000379:methods; D023041:Xenograft Model Antitumor Assays
chemical_list: D008081:Liposomes; D010455:Peptides; D019275:Radiopharmaceuticals; D011092:Polyethylene Glycols
keywords: dual-targeting; liposomal nanoparticles; multifunctionality; radiolabeling; tumor imaging