title: Cellular uptake and in vitro antitumor efficacy of composite liposomes for neutron capture therapy.
abstract: BACKGROUND
  Neutron capture therapy for glioblastoma has focused mainly on the use of (10)B as neutron capture isotope. However, (157)Gd offers several advantages over boron, such as higher cross section for thermal neutrons and the possibility to perform magnetic resonance imaging during neutron irradiation, thereby combining therapy and diagnostics. We have developed different liposomal formulations of gadolinium-DTPA (Magnevist®) for application in neutron capture therapy of glioblastoma. The formulations were characterized physicochemically and tested in vitro in a glioma cell model for their effectiveness.
  
  
  METHODS
  Liposomes entrapping gadolinium-DTPA as neutron capture agent were manufactured via lipid/film-extrusion method and characterized with regard to size, entrapment efficiency and in vitro release. For neutron irradiation, F98 and LN229 glioma cells were incubated with the newly developed liposomes and subsequently irradiated at the thermal column of the TRIGA reactor in Mainz. The dose rate derived from neutron irradiation with (157)Gd as neutron capturing agent was calculated via Monte Carlo simulations and set in relation to the respective cell survival.
  
  
  RESULTS
  The liposomal Gd-DTPA reduced cell survival of F98 and LN229 cells significantly. Differences in liposomal composition of the formulations led to distinctly different outcome in cell survival. The amount of cellular Gd was not at all times proportional to cell survival, indicating that intracellular deposition of formulated Gd has a major influence on cell survival. The majority of the dose contribution arises from photon cross irradiation compared to a very small Gd-related dose.
  
  
  CONCLUSIONS
  Liposomal gadolinium formulations represent a promising approach for neutron capture therapy of glioblastoma cells. The liposome composition determines the uptake and the survival of cells following radiation, presumably due to different uptake pathways of liposomes and intracellular deposition of gadolinium-DTPA. Due to the small range of the Auger and conversion electrons produced in (157)Gd capture, the proximity of Gd-atoms to cellular DNA is a crucial factor for infliction of lethal damage. Furthermore, Gd-containing liposomes may be used as MRI contrast agents for diagnostic purposes and surveillance of tumor targeting, thus enabling a theranostic approach for tumor therapy.
authors.affiliation: Institute of Pharmacy and Biochemistry, Department of Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, Staudingerweg 5, D-55128, Mainz, Germany. petersta@uni-mainz.de.
authors.forename: Tanja
authors.initials: T
authors.lastname: Peters
authors.affiliation: Institute of Nuclear Chemistry, Johannes Gutenberg University Mainz, Fritz-Strassmann Weg 6, D-55128, Mainz, Germany. grunewal@uni-mainz.de.
authors.forename: Catrin
authors.initials: C
authors.lastname: Grunewald
authors.affiliation: AIT Austrian Institute of Technology, Health & Environment Department, Biomedical Systems, Donau-City-Strasse 1/2, A-1220, Vienna, Austria. matthias.blaickner@ait.ac.at.
authors.forename: Matthias
authors.initials: M
authors.lastname: Blaickner
authors.affiliation: AIT Austrian Institute of Technology, Health & Environment Department, Biomedical Systems, Donau-City-Strasse 1/2, A-1220, Vienna, Austria. markus.ziegner.fl@ait.ac.at.
authors.forename: Markus
authors.initials: M
authors.lastname: Ziegner
authors.affiliation: Institute of Nuclear Chemistry, Johannes Gutenberg University Mainz, Fritz-Strassmann Weg 6, D-55128, Mainz, Germany. schuetc@uni-mainz.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Schütz
authors.affiliation: Institute of Nuclear Chemistry, Johannes Gutenberg University Mainz, Fritz-Strassmann Weg 6, D-55128, Mainz, Germany. iffland@uni-mainz.de.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Iffland
authors.affiliation: Institute of Nuclear Chemistry, Johannes Gutenberg University Mainz, Fritz-Strassmann Weg 6, D-55128, Mainz, Germany. gabriele.hampel@uni-mainz.de.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Hampel
authors.affiliation: Institute of Pharmacy and Biochemistry, Department of Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, Staudingerweg 5, D-55128, Mainz, Germany. nawroth@uni-mainz.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nawroth
authors.affiliation: Institute of Pharmacy and Biochemistry, Department of Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, Staudingerweg 5, D-55128, Mainz, Germany. langguth@uni-mainz.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Langguth
mesh_terms: D001932:Brain Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D049109:Cell Proliferation / Q000528:radiation effects*; D003287:Contrast Media / Q000493:pharmacokinetics; D019786:Gadolinium DTPA / Q000493:pharmacokinetics; D005910:Glioma / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D066298:In Vitro Techniques; D008081:Liposomes; D008279:Magnetic Resonance Imaging / Q000379:methods; D009010:Monte Carlo Method; D017247:Neutron Capture Therapy; D009502:Neutrons; D014407:Tumor Cells, Cultured
chemical_list: D003287:Contrast Media; D008081:Liposomes; D019786:Gadolinium DTPA