LUNG-DIRECTED DELIVERY OF THERAPEUTICS FOR THE TREATMENT OF PULMONARY FRANCISELLA INFECTION

This study investigates the efficacy of a novel nanoaerosol generation technique—electrospray-neutralization (ESN)—for the treatment of respiratory infections. Pulmonary delivery is a promising route for therapeutics because it targets the alveoli directly, bypassing digestive destruction and first-pass hepatic metabolism. The researcher specifically tested the ESN-generated nanoaerosol delivery of the antibiotic levofloxacin against a lethal pulmonary Francisella tularensis (subsp. novicida) infection in BALB/c mice. Furthermore, the study evaluates the potential of pulmonary passive immunization by delivering monoclonal antibodies (FB11) directly to the lungs.

The study utilized a custom-built conductive whole-body exposure chamber to deliver nanoaerosols (particles < 200 nm). The ESN generator produces charged nano-clusters that are neutralized in the gas phase, an approach designed to be gentler on fragile biomolecules than conventional jet nebulizers. The research team compared the survival of mice treated with nanoaerosolized levofloxacin against traditional delivery methods, including intraperitoneal (i.p.) injection, oral administration, and standard aerosol (1–5 μm particles). Additionally, the team assessed passive immunization by administering the anti-Francisella LPS IgG2a antibody, FB11, via the intranasal route.

Results showed that nanoaerosolized levofloxacin achieved an 8-fold reduction in effective dose compared to i.p. injection and a 94-fold reduction compared to oral administration. The ESN method proved superior to conventional nebulization, as it required 40 times less material and preserved the integrity of liposome-encapsulated therapeutics. Pathological examination confirmed that this nanoaerosol delivery caused no detectable damage to lung tissue. Regarding passive immunization, intranasal delivery of the FB11 antibody effectively rescued mice from high-dose pulmonary Francisella challenge, with evidence suggesting that early administration (3 hours post-infection) is critical for survival. These results demonstrate that direct delivery to the alveolar space can significantly enhance therapeutic potency while reducing systemic exposure and required doses.