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

Abstract

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.

Local inflammation alters the lung disposition of a drug loaded pegylated liposome after pulmonary dosing to rats

“…While the authors revealed no significant changes in lung clearance as a result of acute lung inflammation, this study was limited to only 2 days. Our group has previously shown however, that nanomaterials are cleared from the lungs of rodents and sheep over a matter of weeks, not days [17][18][19]. The true impact of lung inflammation on the clearance kinetics of nanomaterials may therefore not be evident over short time periods.…”

“…Rats were allowed to recover overnight from surgery prior to dosing the following day. Bleomycin was administered to rats (group 2) the day after rat, total faeces were collected over the entire sampling period and pooled to quantify the proportion of the 3 H dose excreted via the faeces using a previously described liquid scintillation assay [11,19].…”

“…All rats used in this study were euthanized after collection of the last blood sample under isoflurane anaesthesia via exsanguination through the carotid artery cannula. For pulmonary dosed rats, bronchoalveolar lavage fluid (BALF) was collected as previously described [11,19]. Briefly, the trachea was surgically exposed after euthanasia and a 5 cm length of polyethylene tubing (1.70 mm × 1.20 mm) was inserted into the trachea.…”

“…A 500 μl aliquot of each BALF supernatant fraction was added to a 6 ml scintillation vial containing 2 ml Ultima Gold™ to quantify the proportion of the 3 H dose remaining in the BALF. Aliquots of BALF supernatant were also frozen as previously described for quantification of cytokines via ELISA and ciprofloxacin via HPLC [11,19]. Cells obtained from BALF via centrifugation were counted on a Tali cell counter before being analysed via FACS for the total number of alveolar macrophages, T-lymphocytes and neutrophils as previously described [11,19].…”

Overcoming Hurdles in Nanoparticle Clinical Translation: The Influence of Experimental Design and Surface Modification

“…Furthermore, dendrimers have excellent water solubility, as well as areas of increased hydrophobicity, allowing them to be very effective at carrying a drug payload [70]. Despite these advantages, dendrimer drug delivery is not a magic bullet, as it has a long production time and contradictory results [71,72,73]. While the unique chemical synthesis of dendrimers allows for more autonomy in design, few dendrimer designs vary from standards [70].…”