Synthesis, characterization and in vivo evaluation of radiolabeled anti-inflammatory dendritic polyglycerol: A structure – pharmacokinetics relationship

Dendritic polyglycerols (dPGs) represent highly biocompatible scaffolds with narrow polydispersity, multivalency and ease of synthesis. The sulfate derivatives (dPGS) in particular, are potent candidates for, e.g., in the development of anti-inflammatory drugs due to their ability to inhibit the L & P selectins. In order to understand the physiological fate of these nano-objects, it is crucial to understand their behavior especially with respect to their absorption, distribution, metabolism and excretion (ADME). Herein, we present the in vivo distribution pattern of the neutral (dPG) as well as the therapeutically active polymer scaffolds using radiolabeling strategies. A novel ³H radiolabeling strategy has been established for these nano-objects which enable to study longer biochemical processes via radio imaging. In parallel, isothiocyanate and/or maleimide-functionalized TACN based Cu^II-chelating ligands were attached to dPGS derivatives with terminal amine or mercapto groups to allow for performing positron emission tomography (PET) studies using ⁶⁴Cu (t_1/2 = 12.5 h). ¹H NMR, DLS and zeta potential measurements have been performed in order to achieve information about the number of chelators, size and charge of the dPGS derivatives. A new titration assay was established to determine the copper loading capacity and to obtain exact numbers of CuII chelators for the dPG derivatives. The ⁶⁴Cu - conjugates are resistant to transchelation in vitro as well as in vivo. Independent studies in rats & mice show different routes of excretion for neutral dPGs in contrast to their polysulfated analogs. Furthermore, to derive an insight on the pharmacokinetics, effect of size, charge and surface groups have been studied in a range of scaffolds. Uptake mechanism in the cells, protein adsorption profile and cytotoxicity will be discussed. The results from these studies show that these polyglycerols are highly promising candidates for theranostic applications and drug targeting.