030 - Aerosoltherapy in lung cancer - 05/12/08

Introduction: Although airways route is an attractive alternative route to systemic administration, increasing concentration of the drug in the lungs while reducing whole-body toxicity, it is not often exploited in lung cancer treatment. After checking that cetuximab, an anti-cancer antibody binding to EGFR, resists the physical constraints of nebulization, we established an animal model of lung tumour sensitive to the antibody. Then, we used the animal model to evaluate cetuximab antitumor efficiency, biodistribution and pharmacokinetic following delivery through airways.

Methods: Cetuximab was nebulized with the IA-1C MicroSprayer™ (PennCentury Inc., USA) connected to a FMJ-250 high pressure syringe, a device used to administrate, directly inside the trachea, aerosol in mice. The effect of nebulization on cetuximab was assessed in terms of its affinity for membrane EGFR (using flow cytometry), inhibition of cell growth and inhibition of EGFR phosphorylation. To ensure that airways delivery of cetuximab did not lead to additional toxicity, we compared tolerance to cetuximab delivered through systemic and pulmonary routes in mice without tumors. An animal model of lung cancer sensitive to cetuximab was established and consists in the instillation of human epidermoid carcinoma cells endotracheally in nude mice. The model was exploited to study cetuximab biodistribution and pharmacokinetic following delivery through systemic and pulmonary routes. Therapeutic efficiency of nebulized cetuximab was determined in tumor- bearing animals.

Results: Firstly, our results showed that MicroSprayer™ did not alter cetuximab integrity, immunological and pharmacological properties. Secondly, airways administration of cetuximab in mice seemed to be well-tolerated and did not induced additional toxicity in lungs, kidney, colon, skin, liver or spleen. Finally, higher, more rapid and prolonged lung uptake was observed in animals receiving cetuximab through the pulmonary route. Antitumor efficiency of nebulized cetuximab is currently under investigation.

Conclusion: These results highlight the potential of the pulmonary route for delivery of anticancer antibody in lung cancer.