The impact of size and charge on the pulmonary pharmacokinetics and immunological response of the lungs to PLGA nanoparticles after intratracheal administration to rats.

Polylactide-co-glycolide (PLGA) nanoparticles are one of the most commonly explored biodegradable polymeric drug carriers for inhaled delivery. Despite their advantages as inhalable nanomedicine scaffolds, we still lack a complete understanding of the kinetics and major pathways by which these materials are cleared from the lungs. This information is important to evaluate their safety over prolonged use and enable successful clinical translation. This study aimed to determine how the size and charge of 3H-labeled PLGA nanoparticles affect the kinetics and mechanisms by which they are cleared from the lungs and their safety in the lungs. The results showed that lung clearance kinetics and retention patterns were more significantly defined by particle size, whereas lung clearance pathways were largely influenced by particle charge. Each of the nanoparticles caused transient inflammatory changes in the lungs after a single dose that reflected lung retention times.

Hydrogenated Soy Phosphatidylcholine Liposomes Stimulate Differential Expression of Chemokines And Cytokines by Rat Alveolar Macrophages In Vitro.

Liposomes are being developed as inhalable drug delivery systems, but concerns remain about their impact on the lungs. To better understand the impact of liposomes and their physicochemical properties on alveolar macrophages, the cytokine and chemokine expression profile of rat alveolar Nr8383 macrophages exposed to 0.1 and 1 mg/ml hydrogenated soy phosphatidylcholine (HSPC) liposomes was examined. Expression patterns varied considerably between liposomes in a concentration-dependent manner, with both anti- and pro-inflammatory chemokines/cytokines produced. Uncharged liposomes induce the greatest production of cytokines and chemokines, followed by PEGylated liposomes. The most significant increase in cytokine/chemokine expression was seen for IL-2 (up to 24-fold), IL-4 (up to 5-fold), IL-18 and VEGF (up to 10-fold), while liposome exposure significantly reduced MIP1 expression (5-fold). In summary, we demonstrate that liposome surface properties promote variable patterns of cytokine and chemokine secretion by alveolar macrophages. This suggests that the type of liposome employed may influence the type of immune response generated in the lung and by extension, dictate how inhaled liposomal nanomedicines affect the lungs response to inhaled toxicants and local infections.

Lipidated brush-PEG polymers as low molecular weight pulmonary drug delivery platforms.

OBJECTIVES: Nanomedicines are being actively developed as inhalable drug delivery systems. However, there is a distinct utility in developing smaller polymeric systems that can bind albumin in the lungs. We therefore examined the pulmonary pharmacokinetic behavior of a series of lipidated brush-PEG (5 kDa) polymers conjugated to 1C2, 1C12 lipid or 2C12 lipids. METHODS: The pulmonary pharmacokinetics, patterns of lung clearance and safety of polymers were examined in rats. Permeability through monolayers of primary human alveolar epithelia, small airway epithelia and lung microvascular endothelium were also investigated, along with lung mucus penetration and cell uptake. RESULTS: Polymers showed similar pulmonary pharmacokinetic behavior and patterns of lung clearance, irrespective of lipid molecular weight and albumin binding capacity, with up to 30% of the dose absorbed from the lungs over 24 h. 1C12-PEG showed the greatest safety in the lungs. Based on its larger size, 2C12-PEG also showed the lowest mucus and cell membrane permeability of the three polymers. While albumin had no significant effect on membrane transport, the cell uptake of C12-conjugated PEGs were increased in alveolar epithelial cells. CONCLUSION: Lipidated brush-PEG polymers composed of 1C12 lipid may provide a useful and novel alternative to large nanomaterials as inhalable drug delivery systems.

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

The development of inhalable 'nanomedicines' based on biocompatible lipids and polymers is attracting increasing interest worldwide. Our understanding of how pulmonary inflammation impacts on lung distribution and clearance kinetics however, is limited. Similarly, there is limited information on how the inhaled delivery of biocompatible nanomaterials affects existing respiratory disease. We have addressed these knowledge gaps by describing and comparing the pulmonary pharmacokinetic behaviour of a 3H-labelled PEGylated liposome loaded with a model drug (ciprofloxacin) after intratracheal administration to healthy rats and rats with bleomycin-induced lung inflammation by following both 3H label and drug. Cell- and cytokine-based markers of lung inflammation were used to evaluate the response of healthy and inflamed lungs to the liposome. Liposomes were initially cleared more rapidly from inflamed lungs than from healthy lungs, but exhibited similar rates of lung clearance after 3 days. This was interesting given that mucociliary clearance was more efficient from healthy lungs, despite evidence of higher mucus retention in inflamed lungs and reduced association of the liposome with lung tissue. Although the plasma pharmacokinetics of ciprofloxacin did not differ between rats with healthy or inflamed lungs after pulmonary administration, the plasma pharmacokinetics of 3H-phosphatidylcholine suggested higher liposome bioavailability and more prolonged absorption from inflamed lungs. Concentrations of the pro-inflammatory cytokine IL-1ß were increased in bronchoalveolar lavage fluid after a single pulmonary dose of liposomes to rats with inflamed lungs, but no other significant changes in lung inflammatory markers were identified in healthy or bleomycin-challenged rats.

A comparison of the lung clearance kinetics of solid lipid nanoparticles and liposomes by following the 3H-labelled structural lipids after pulmonary delivery in rats.

The utility of biodegradable nanosized drug carriers for the local and controlled delivery of therapeutics to the lungs has prompted significant interest in the development of inhalable nanomedicines. Still, little is known about how these systems are cleared from the lungs, including the kinetics of the structural lipids. Most preclinical and clinical studies to date have evaluated the lung clearance of loaded drugs, which in many cases poorly reflects the kinetics of the nanocarrier, or the bulk-labelled particles. This study therefore aimed to describe and compare the pulmonary pharmacokinetic behaviour and patterns of lung clearance of two commonly explored inhalable nanocarriers (anionic ∼150 nm liposomes and solid lipid nanoparticles [SLNs]) in rats by following the 3H-labelled structural lipids (phosphatidylcholine and tristearin respectively). The data showed that SLNs and liposomes were cleared from the lungs at similar rates, despite SLNs being deposited after intratracheal instillation in the upper respiratory track, and primarily via the mucociliary escalator, but this process was more pronounced for SLNs. Structural lipids were mainly associated with plasma proteins rather than nanocarrier in plasma. The lipids also exhibit prolonged lung exposure and are associated with the lung tissue (rather than BALF) over 2 weeks.

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.