Preclinical evaluation of aerosol administration systems using Positron Emission Tomography

Abstract

Pulmonary administration of drugs has recently gained attention because it exhibits numerous advantages compared to oral or intravenous administration. The administration of aerosols for inhalation to animals, however, remains a critical challenge and only a few methods of administration have been developed. Herein, we compare the regional distribution of aerosols in the lungs of wild type rats after pulmonary administration using three different methods: (a) The Penn-Century MicroSprayer® Aerosolizer; (b) an in-house designed aerosol generation system; and (c) the Aeroneb® Lab Micropump Nebulizer. Both the regional distribution and the fraction of aerosol deposited in the lungs were determined by means of radiolabelling of the aerosol followed by in vivo and ex vivo Positron Emission Tomography (PET) imaging and dissection and gamma counting. Endotracheal insufflation using the PennCentury MicroSprayer resulted in >85% of the administered dose accumulated in the lungs, with a non-uniform distribution of the radioactivity in different lobes and a low animal-to-animal reproducibility. Administration using the in-house designed and the Aeroneb nebulizers resulted in a uniform distribution over the lungs, but only a small fraction of the nebulized activity (ca. 0.1%) was deposited in the lungs.

Therapeutic Efficacy of Novel Antimicrobial Peptide AA139-Nanomedicines in a Multidrug-Resistant Klebsiella pneumoniae Pneumonia-Septicemia Model in Rats

“…ϳ2% of delivered dose) was low. These findings matched our in vivo imaging results, as well as the findings from an earlier study in which the deposition of 2-deoxy-2-[ 18 F]fluoro-Dglucose (a clinically used radiotracer) after the same administration method was studied (33).…”

COSAN-stabilised omega-3 oil-in-water nanoemulsions to prolong lung residence time for poorly water soluble drugs

“…20 µm droplet size. 37 The free drug ([ 18 F]FES) was also investigated as control and administered using the same system, to ensure that water droplet sizes were equivalent in both scenarios, thus guaranteeing an equivalent initial distribution. Intra-tracheal administration of [ 18 F]FES resulted in fast lung clearance, with 50%, 10% and 5% of the labelled compound remaining in the lungs at t=2, t=10 and t=40 minutes after administration, respectively (Fig.…”

Adapting the Aerogen Mesh Nebulizer for Dried Aerosol Exposures Using the PreciseInhale Platform

“…The latter phenomenon has been described as condensation or rain out when running the nebulizer at high output into a confined exposure container. (23) The rain out process is also likely enhanced by the coalescence of primary droplets into more rapidly impacting/sedimenting larger droplets in the very concentrated and turbulent aerosol plume generated. It is worth to note, however, that at the full wet aerosol output, the humidity in the carrier air of such aerosols should attain equilibrium with the droplets undergoing only minor changes in droplet sizes, irrespective of the carrier being supplied dry or humidified.…”

“…It is most likely the secondary air entrainment flow patterns established around the nebulizer head when operated at full output that causes the large substance losses when connected for single rodent exposures in confined spaces. This phenomenon is sometimes labeled condensation, (23) but is more likely caused by aerosol coalescence, impaction, and sedimentation of larger aerosol droplets generated in the local flow patterns of highly concentrated aerosol established around the nebulizer head. At a substantially reduced output the generated aerosol can instead be easily contained within a carrier airstream optimally matched for either exposing single rodents without rebreathing problems or for not bypassing the animal with too much aerosol.…”

“…This is between one and two orders of magnitude better than when using the Aeroneb in a single rodent setting at full aerosol output. (23) One particularly attractive opportunity this provides is to test water-soluble compounds in early development, including macromolcules, using inhalation exposures with respirable aerosols and under good dosing control when test materials are available only in the tens of milligram range.…”