Hyperbranched polyglycerols: Biodistribution and structure-compatibility relationships

Dendritic polyglycerols (PG’s) are promising biocompatible scaffolds for drug delivery, targeting and other therapeutic applications due to their low polydispersity, multivalency and convenient large scale one-pot synthesis. In particular, the sulphated polyglycerol derivatives are potent candidates for, e.g., anti-inflammatory drugs due to their ability to inhibit the L & P Selectins [1]. It is therefore crucial to know the physiological fate of these scaffolds in order to establish their suitability for potential biomedical applications. The present work deals with the biodistribution studies of the dendritic polyglycerol sulphate derivatives (dPGS, 10 kDa) using ⁶⁴Cu (t_1/2 = 12.5 h) for tracking them with positron emission tomography (PET). Since PG’s do not have any metal binding sites, coupling of bifunctional chelators (BFCs) capable of binding ⁶⁴Cu to PG’s is required. A prerequisite for achieving reliable biodistribution data is that the BFCs form stable complexes with ⁶⁴Cu. For this reason, BFCs based on macrocyclic triazacyclononane containing two pendant pyridyl rings (DMPTACN) [2] (Log_Cu-L > 25) have been synthesized with maleimide and isothiocyanate coupling groups to enable conjugation to mercapto and amine groups of the polyglycerol derivatives. These conjugates form highly stable radiocopper complexes at room temperature within 5 minutes. The conjugates are resistant to transchelation and are stable in the presence of superoxide dismutase. The biodistribution of the dPGS has been studied in healthy Wistar rats for 72 h. Furthermore, in order to exploit the properties PG’s for further applications, the effect of size, charge and surface groups have been investigated. Cytotoxicity has been studied using a selection of cell lines. The results from these studies show that these polyglycerols are highly biocompatible and potential candidates for theranostics that combine multimodal imaging and drug targeting.

References:

[1] H. Türk et al, Bioconjug. Chem. 2004, 15, 162-167.
[2] G. Gasser et al, Bioconjug. Chem 2008, 19, 719-730