9-nitrocamptothecin liposome aerosol treatment of melanoma and osteosarcoma lung metastases in mice

The response rates of relapsed osteosarcoma and melanoma pulmonary metastas es to traditional i.v. chemotherapeutic regimens have been disappointing. D irect drug delivery of chemotherapy to the lungs could increase the drug co ncentration in the tumor area and may offer a new therapeutic approach for these patients. Previous studies demonstrated that drugs delivered to the r espiratory tract in liposomal formulation resulted in high pulmonary drug c oncentration, reduced systemic toxicity, and reduced dosage requirements co mpared with parenteral and oral administration, To determine whether this a pproach has utility against pulmonary metastases, the efficacy of aerosol t herapy with liposome-encapsulated 9-nitrocamptothecin (L-9NC) was determine d using two different experimental lung metastasis models. C57BL/6 mice wer e treated the day after the i.v. injection of B16 melanoma cells with aeros ol L-9NC for 1 h (153 mu g 9-nitrocamptothecin/kg) for 5 days per week for up to 3 weeks, Aerosol L-9NC treatment resulted in a reduction in lung weig hts (P = 0.005) and number of tumor foci (P < 0.001), Visible tumor nodules were fewer and smaller in the 9-nitrocamptothecin-treated group than in un treated control mice (P < 0.001), Using a newly developed human osteosarcom a experimental metastasis model in nude mice, we demonstrated that aerosol L-9NC was also effective against established lung metastases, Aerosol thera py initiated on the ninth week after i.v. tumor injection and continued for 8 or 10 weeks produced highly significant reductions in the number of anim als with both visible and microscopic disease (P < 0.02), the total number of tumor foci in the lungs (P < 0.005), and the size of the individual tumo r nodules (P < 0.02), These data suggest that L-9NC aerosol therapy may off er significant advantage over existing methods in the treatment of melanoma and osteosarcoma pulmonary metastases.