Lisa M. Kaminskas

Dendrimers show increasing promise as drug-delivery vectors and can be generated with a wide range of scaffold structures, sizes and surface functionalities. To this point, the majority of studies of dendrimer-based drug-delivery systems have detailed pharmacodynamic outcomes, or have followed the pharmacokinetics of a solubilized or conjugated drug. By contrast, detailed commentary on the in vivo fate of the dendrimer carrier is less evident, even though the pharmacokinetics of the carrier will likely dictate both pharmacodynamic and toxicokinetic outcomes. In the current article, the influence of size, structure and surface functionality on the absorption, distribution, metabolism and elimination (ADME) properties of dendrimers have been examined and the implications of these findings for delivery system design are discussed.

The impact of PEGylation on the pharmacokinetics and biodistribution of (3)H-labeled poly l-lysine dendrimers has been investigated after intravenous administration to rats. The volumes of distribution, clearance and consequently the plasma half-lives of the PEGylated dendrimers were markedly dependent on the total molecular weight of the PEGylated dendrimer, but were not specifically affected by the PEG chain length alone. In general, the larger dendrimer constructs (i.e. >30 kDa) had reduced volumes of distribution, were poorly renally cleared and exhibited extended elimination half-lives ( t 1/2 1-3 days) when compared to the smaller dendrimers (i.e. <20 kDa) which were rapidly cleared from the plasma principally into the urine ( t 1/2 1-10 h). At later time points the larger dendrimers concentrated in the organs of the reticuloendothelial system (liver and spleen); however, the absolute extent of accumulation was low. Size exclusion chromatography of plasma and urine samples revealed that the PEGylated dendrimers were considerably more resistant to biodegradation in vivo than the underivatized poly l-lysine dendrimer cores. The results suggest that the size of PEGylated poly l-lysine dendrimer complexes can be manipulated to optimally dictate their pharmacokinetics, biodegradation and bioresorption behavior.