Systemic Availability and in vivo Stability of PEGylated Poly-Lysine Dendrimers Following Pulmonary Delivery is Highly Size Dependent

Pulmonary drug delivery is a viable noninvasive route of systemic access for therapeutics which cannot be delivered orally. However, several barriers to absorption as well as the presence of alveolar macrophages and enzymes in the lungs present obstacles to controlling the rate of systemic absorption and stability of biogenic and macromolecular therapeutics once delivered to the lungs. PEGylation, however, may usefully be utilized to control the absorption and biodegradation properties of biogenic therapeutics and drug delivery systems in the lungs. We therefore sought to evaluate the pharmacokinetics and stability of generation 4 polylysine dendrimers capped with various sized PEG groups following pulmonary administration in rats. The rate and extent of dendrimer absorption into systemic circulation, biodistribution, clearance from lungs and scaffold stability were all found to be highly dependent on PEG molecular weight (MW), where increasing PEG chain length led to more prolonged lung retention and reduced dendrimer degradation in the lungs. The results suggest that PEGylated polylysine dendrimers may represent useful inhalable drug delivery systems which can be developed to display either prolonged retention in the lungs, absorption of the intact species or biodegradation and liberation of surface conjugated moieties in the lungs.