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

Abstract

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 3 H-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 3 H 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 3 H-phosphatidylcholine suggested higher liposome bioavailability and more prolonged absorption from inflamed lungs. Concentrations of the pro-inflammatory cytokine IL-1β 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.

Efficacy of Levofloxacin Loaded Nonionic Surfactant Vesicles (Niosomes) in a Model of Pseudomonas aeruginosa Infected Sprague Dawley Rats

“…The niosomal formulation appears to concentrate at these organs and was able to reduce viable bacterial counts more efficiently than the conventional unentrapped drug. These results are similar to various studies done with a liposomal drug delivery system [ 28 – 30 ].…”

Pulmonary Delivery of Anticancer Drugs via Lipid-Based Nanocarriers for the Treatment of Lung Cancer: An Update

“…The plasma pharmacokinetics of 3 H-phosphatidylcholine revealed higher liposomal bioavailability and more prolonged absorption from inflamed lungs. Concentrations of the pro-inflammatory cytokine IL-1β were increased in bronchoalveolar lavage fluid after a single pulmonary dose of liposomes to rats with inflamed lungs, but no other significant changes in inflammatory lung markers were identified in healthy or bleomycin-challenged rats [ 24 ]. Moreover, inhaled drugs are also drained by the lymphatic system; they were commonly detected in the lungs’ lymph nodes ( Figure 1 ).…”

In Vitro and In Vivo Assessment of PEGylated PEI for Anti-IL-8/CxCL-1 siRNA Delivery to the Lungs

“…This was likely due to the very short time between LPS challenge and euthanasia of the animals (3 h). Previous work has demonstrated that it can take between 24–72 h for cytokine levels to peak in pulmonary instilled animals [ 39 , 61 ]. This was the case for CXCL-1 expression in all animals, with the exception of the PEI-LPEG NT siRNA-treated animals.…”