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

[Display omitted] 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 requir...

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Published in:	European journal of pharmaceutics and biopharmaceutics 2017-10, Vol.119, p.408-418
Main Authors:	Haque, Shadabul, McLeod, Victoria M., Jones, Seth, Fung, Sandy, Whittaker, Michael, McIntosh, Michelle, Pouton, Colin, Owen, David J., Porter, Christopher J.H., Kaminskas, Lisa M.
Format:	Article
Language:	eng
Subjects:	Animals Clearance Dendrimer Dendrimers - chemistry Drug delivery Drug Delivery Systems - methods Hydrophobic and Hydrophilic Interactions Inhalation Kinetics Lung - metabolism Male Metabolic Clearance Rate - drug effects Methotrexate - chemistry Polyethylene Glycols - chemistry Polylysine - chemistry Pulmonary Rats Rats, Sprague-Dawley
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Summary:	[Display omitted] 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.
ISSN:	0939-6411 1873-3441