Pulmonary Effects of Chronic Exposure to Liposome Aerosols in Mice

Abstract

Administering liposome-encapsulated drugs by aerosols could be a feasible way of targeting drugs to the lung, specifically to pulmonary alveolar macrophages (AM). In the mouse model, we characterized uptake of carboxyfluorescein- (CF-) labeled liposomes by AM in vivo after acute inhalation of liposome aerosols, and the effects of chronic exposure to liposome aerosols on lung histology and AM function. Mice were placed in a nose-only exposure module and exposed to liposome or saline aerosols for 1 h per day, 5 days per week, for 4 weeks. Five mice of both the experimental and control groups were removed weekly and their lungs examined. Liposomes were made from hydrogenated soy phosphatidylcholine (HSPC) at 50 mg/mL. In vivo uptake of liposomes by AM was documented by fluorescence microscopy and flow cytometry of bronchoalveolar lavage (BAL). A consistent amount of 1-3 micrograms of lipid inhaled per dosing per mouse was estimated from fluorescence measurements. Addition of Triton X-100 to BAL caused a significant increase in fluorescence intensity, indicating that liposomes remained intact in the lung for a period of time. The chronic inhalation study showed no histologic changes of the lung or untoward effects on the general health or survival of animals. AM phagocytic function, intracellular killing, and fatty acid composition were not affected. Transmission electron microscopy and morphometry (computerized image analysis) of AM likewise showed no alterations as a result of the treatment. It was concluded that AM uptake of liposomes delivered by aerosol was operant in vivo. This finding validates the concept of alveolar macrophage-directed delivery of liposome-encapsulated agents to the lung via inhalation. It was also concluded that chronic liposome aerosol inhalation in mice produced no untoward effects on survival, histopathology, and macrophage function. These data confirm and extend prior findings regarding the functional and morphologic interactions of liposomes with AM in vitro (Gonzalez-Rothi et al., Exp. Lung Res. 17:687-705, 1991).

Drug-Loaded Nanocarriers: Passive Targeting and Crossing of Biological Barriers

“…Liposomal aerosols have proven to be non-toxic in acute human and animal studies [340][341][342][343][344]. These results suggest that drug-liposome aerosols should be more effective for the delivery, deposition, and retention of waterinsoluble, hydrophobic, lipophilic compounds in contrast to watersoluble compounds [345][346][347].…”

A Gamma Scintigraphy Study to Investigate Lung Deposition and Clearance of Inhaled Amikacin-Loaded Liposomes in Healthy Male Volunteers

“…DPPC and cholesterol are the principal phospholipid and neutral lipid components of endogenous lung surfactant, and have a demonstrated history of safety within the lung. (13)(14)(15) The amikacin content in the final drug product was approximately 20 mg/mL. DPPC and cholesterol were obtained from Avanti Polar Lipids (Alabaster, AL).…”

Formulation and Characterization of Lipid-Coated Tobramycin Particles for Dry Powder Inhalation

“…Indeed, phospholipids and cholesterol, two physiologically well tolerated components, may present interesting characteristics for the delivery of drugs by the pulmonary route. Like liposomes, they may reduce local irritation, offering a good tolerance in the pulmonary tract as they are mainly constituted of biocompatible and biodegradable material; for example, phosphatidylcholine comprises an estimated 70Y80% of the naturally occurring pulmonary surfactant pool (24). A novel approach of delivering liposomes in dry powder form was developed and was advantageous to avoid the detrimental effects of lyophilization and jet milling on leakage of the encapsulated drug (25).…”