Synthesis and Biodistribution Studies of ³H- and ⁶⁴Cu-labeled Dendritic Polyglycerol and Dendritic Polyglycerol Sulfate

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 ca. 10 kDa was radiolabeled with ³H and ⁶⁴Cu, and evaluated by performing biodistribution studies and small animal positron emission tomography (PET). ³H-labeling was accomplished by an oxidation-reduction process with sodium periodate and [³H]-borohydride. ⁶⁴Cu-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 ⁶⁴CuCl₂. 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 analogs 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, underlines the potential of dPG as a multifunctional scaffold for various nanomedical applications.