title: Synthesis and biodistribution studies of (3)H- and (64)Cu-labeled dendritic polyglycerol and dendritic polyglycerol sulfate.
abstract: Dendritic polyglycerol sulfate (dPGS) is a biocompatible, bioactive polymer which exhibits anti-inflammatory activity in vivo and thus represents a promising candidate for therapeutic and diagnostic applications. To investigate the in vivo pharmacokinetics in detail, dPGS with a molecular weight of approx. 10 kDa was radiolabeled with (3)H and (64)Cu, and evaluated by performing biodistribution studies and small animal positron emission tomography (PET). (3)H-labeling was accomplished by an oxidation-reduction process with sodium periodate and [(3)H]-borohydride. (64)Cu-labeling was achieved by conjugation of isothiocyanate- or maleimide-functionalized copper(II)-chelating ligands based on 1,4-bis(2-pyridinylmethyl)-1,4,7-triazacyclononane (DMPTACN) to an amino functionalized dPGS scaffold, followed by reaction with an aqueous solution containing (64)CuCl2. Independent biodistribution by radioimaging and PET imaging studies with healthy mice and rats showed that the neutral dPG was quantitatively renally eliminated, whereas the polysulfated analogues accumulated mainly in the liver and spleen. Small amounts of the dPGS derivatives were slowly excreted via the kidneys. The degree of uptake by the reticuloendothelial system (RES) was similar for dPGS with 40% or 85% sulfation, and surface modification of the scaffold with the DMPTACN chelator did not appear to significantly affect the biodistribution profile. On the basis of our data, the applicability of bioactive dPGS as a therapeutic agent might be limited due to organ accumulation even after 3 weeks. The inert characteristics and clearance of the neutral polymer, however, emphasizes the potential of dPG as a multifunctional scaffold for various nanomedical applications.
authors.affiliation: †Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, D-01328 Dresden, Germany.
authors.forename: Kritee
authors.initials: K
authors.lastname: Pant
authors.affiliation: ‡Organische Chemie, Institut für Chemie und Biochemie, Freie Universität Berlin, Takustrasse 3, D-14195, Berlin, Germany.
authors.forename: Dominic
authors.initials: D
authors.lastname: Gröger
authors.affiliation: †Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, D-01328 Dresden, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bergmann
authors.affiliation: †Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, D-01328 Dresden, Germany.|§Technische Universität Dresden, Department of Chemistry and Food Chemistry, D-01062 Dresden, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Pietzsch
authors.affiliation: †Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, D-01328 Dresden, Germany.|§Technische Universität Dresden, Department of Chemistry and Food Chemistry, D-01062 Dresden, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.affiliation: ∥Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
authors.forename: Bim
authors.initials: B
authors.lastname: Graham
authors.affiliation: ⊥School of Chemistry, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Leone
authors.initials: L
authors.lastname: Spiccia
authors.affiliation: #CEA-Saclay, Service d'Ingénierie Moléculaire de Protéines (SIMOPRO), Labex LERMIT, CEA-DSV-iBiTecS, 91191 Gif/Yvette Cedex, France.
authors.forename: Fannely
authors.initials: F
authors.lastname: Berthon
authors.affiliation: #CEA-Saclay, Service d'Ingénierie Moléculaire de Protéines (SIMOPRO), Labex LERMIT, CEA-DSV-iBiTecS, 91191 Gif/Yvette Cedex, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Czarny
authors.affiliation: #CEA-Saclay, Service d'Ingénierie Moléculaire de Protéines (SIMOPRO), Labex LERMIT, CEA-DSV-iBiTecS, 91191 Gif/Yvette Cedex, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Devel
authors.affiliation: #CEA-Saclay, Service d'Ingénierie Moléculaire de Protéines (SIMOPRO), Labex LERMIT, CEA-DSV-iBiTecS, 91191 Gif/Yvette Cedex, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Dive
authors.affiliation: †Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, D-01328 Dresden, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Stephan
authors.affiliation: ‡Organische Chemie, Institut für Chemie und Biochemie, Freie Universität Berlin, Takustrasse 3, D-14195, Berlin, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Haag
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000737:chemistry; D002614:Chelating Agents / Q000737:chemistry; D060326:Chemistry Techniques, Synthetic; D003301:Copper Radioisotopes / Q000737:chemistry*; D050091:Dendrimers / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D004355:Drug Stability; D005260:Female; D005990:Glycerol / Q000737:chemistry*; D007553:Isotope Labeling; D051379:Mice; D010880:Piperidines / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D049268:Positron-Emission Tomography; D011854:Radiochemistry; D051381:Rats; D013431:Sulfates / Q000737:chemistry*; D014018:Tissue Distribution; D014316:Tritium / Q000737:chemistry*
chemical_list: D001372:Aza Compounds; D002614:Chelating Agents; D003301:Copper Radioisotopes; D050091:Dendrimers; D010880:Piperidines; D011108:Polymers; D013431:Sulfates; C482777:triazacyclononane; D014316:Tritium; C043941:polyglycerol; D005990:Glycerol