Chemoprevention of lung carcinogenesis: Aerosol administration and deposition in the mouse lung

INTRODUCTION The efficacy of a given drug via aerosol administration depends on many factors such as particle size distribution, total particle mass concentration, and the physiochemical properties of drug particles. Genetically-engineered mice play an important role in drug screening and preclinical studies. However, because mice have much smaller lungs than those of human beings, the lung deposition data attained for humans cannot be applied to the mouse. Hence few studies have focused on particle deposition in the mouse lung. It is thus necessary to measure the mass deposition of particles in the mouse lung.;METHOD A spray-drying process was used to study the inhibitory effects of potential chemopreventive agents on carcinogen-induced tumors in the A/J mouse. The carcinogen in the studies was benzo[a]pyrene, unless otherwise specified. In addition to the bioassays, drug deposition in the mouse lung was evaluated for both polydispersed and monodispersed drug particles for a better understanding of the delivery process and for future applications.;RESULTS Aerosolized erlotinib (5 mg/ml) did not inhibit tumor multiplicity but reduced tumor load by 63.8% (P < 0.05). Aerosolized gefitinib in three separate doses (5, 10, and 15 mg/ml) inhibited tumor multiplicity by ~30% for all three doses when the tumors were induced by one dose of benzo[a]pyrene (100 mg/kg body weight), but the results were not statistically significant. Aerosolized gefitinib showed consistent inhibitory effects on tumor load, and the inhibition rate increased as the dose increased. The tumor load was reduced by 39.0%, 46.2%, and 56.4% (P < 0.05) for 5, 10, and 15 mg/ml gefitinib solutions, respectively. The highest dose (15 mg/ml) of gefitinib was repeated in mice whose tumors were induced by two doses of benzo[a]pyerene (100 mg/kg body weight, one week apart) and it inhibited both tumor multiplicity (by 49.8%, P < 0.001) and tumor load (by 57.0%, P < 0.001). No visible skin alteration was observed in mice treated with aerosolized gefitinib or erlotinib. Both aerosolized lapatinib (50 mg/ml) and orally-administered lapatinib (100 mg/kg body weight) showed inhibitory effects. Aerosolized lapatinib reduced tumor multiplicity by 39.6% (P < 0.05) and tumor load by 41.7% (P < 0.05). Orally-dosed lapatinib reduced tumor multiplicity by 37.6% (not significant) and tumor load by 42.4% (P < 0.05). At the current doses of lapatinib, no adverse side effect was observed in either the aerosol group or the orally-dosed group. Wortmannin showed striking inhibitory effects via aerosol inhalation and per os. Oral wortmannin (1.0 mg/kg body weight) inhibited tumor multiplicity by 85.5% (P < 0.001) and tumor load by 77.9% (P < 0.05). In the same model, aerosolized wortmannin (2.0 mg/ml) inhibited tumor multiplicity by 50.8% (P < 0.05) and tumor load by 79.7% (P < 0.05). Despite the efficacy of oral wortmannin, the accompanying systemic adverse effects were not negligible.;The particle deposition in the mouse lung was estimated using gefitinib as the model compound. For the Collison atomizer, the aerosol mass concentration in the exposure chamber increased linearly from 12.3 to 179.8 &mgr;g/L as the solution concentration increased from 1 to 50 mg/ml. The lung and plasma levels of gefitinib increased monotonically with increased solution concentration and exposure time, and the concentration in the lung was much higher than that in the plasma. The deposition efficiency is defined as the ratio of the mass deposited in the lung to the dose, and it is a function of particle size. In general, monodispersed particles have a higher delivery efficiency than polydispersed particles.;CONCLUSIONS Aerosol delivery is a promising approach for the chemoprevention of lung cancer. Many natural and synthetic compounds showed inhibitory effects on benzo[a]pyrene-induced lung tumorigenesis in A/J when they are delivered via aerosol inhalation. In contrast to oral administration, aerosol delivery of the agents mitigated systemic toxicities with comparable inhibitory effects and improved the efficacy of some agents by increasing their bioavailability in the lung. The current aerosol delivery system was characterized and the mass deposition in the mouse lung was positively correlated with both the solution concentration and the exposure time. Aerosols with an MMAD around 100 nm may have the highest delivery efficiency, for both polydispersed and monodispersed distributions. (Abstract shortened by UMI.).