Effect of increased surface hydrophobicity via drug conjugation on the clearance of inhaled PEGylated polylysine dendrimers.

PEGylated polylysine dendrimers are attractive and well tolerated inhalable drug delivery platforms that have the potential to control the release, absorption kinetics and lung retention time of conjugated drugs. The clinical application of these systems though, would likely require partial substitution of surface PEG groups with drug molecules that are anticipated to alter their lung clearance kinetics and clearance pathways. In the current study, we therefore evaluated the impact of increased surface hydrophobicity via substitution of 50% surface PEG groups with a model hydrophobic drug (α-carboxyl OtButylated methotrexate) on the lung clearance of a Generation 5 PEGylated polylysine dendrimer in rats. PEG substitution with OtBu-methotrexate accelerated lung clearance of the dendrimer by increasing polylysine scaffold catabolism, improving systemic absorption of the intact dendrimer and low molecular weight products of scaffold catabolism, and enhancing mucociliary clearance. These results suggest that the conjugation of hydrophobic drug on the surface of a PEGylated dendrimer is likely to accelerate lung clearance when compared to a fully PEGylated dendrimer.

Using ambiguous plaid stimuli to investigate the influence of immediate prior experience on perception.

In a series of three experiments, we used an ambiguous plaid motion stimulus to explore the behavioral and electrophysiological effects of prior stimulus exposures and perceptual states on current awareness. The results showed that prior exposure to a stimulus biased toward one percept led to subsequent suppression of that percept. In contrast, in the absence of stimulus bias, prior perceptual experience can have a facilitative influence. The suppressive effects caused by the prior stimulus were found to transfer to an ambiguous plaid test stimulus rotated 180º relative to the adaptation stimulus, but were abolished if (1) the ambiguous test stimulus was only rotated 90º relative to the adaptation stimulus or (2) the adaptation stimulus was heavily biased toward the component grating percept. Event-related potential recordings were consistent with the involvement of visual cortical areas and suggested that the influence of recent stimulus exposure may involve recruitment of additional brain processes beyond those responsible for initial stimulus encoding. In contrast, the effects of prior and current perceptual experience appeared to depend on similar brain processes. Although the data presented here focus on vision, the work is discussed within the context of data from a parallel series of experiments in audition.