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

ABSTRACT

The response rates of relapsed osteosarcoma and melanoma pulmonary metastases to traditional i.v. chemotherapeutic regimens have been disappointing. Direct drug delivery of chemotherapy to the lungs could increase the drug concentration in the tumor area and may offer a new therapeutic approach for these patients. Previous studies demonstrated that drugs delivered to the respiratory tract in liposomal formulation resulted in high pulmonary drug concentration, reduced systemic toxicity, and reduced dosage requirements compared with parenteral and oral administration. To determine whether this approach has utility against pulmonary metastases, the efficacy of aerosol therapy with liposome-encapsulated 9-nitrocamptothecin (L-9NC) was determined using two different experimental lung metastasis models. C57BL/6 mice were treated the day after the i.v. injection of B16 melanoma cells with aerosol L-9NC for 1 h (153 microg 9-nitrocamptothecin/kg) for 5 days per week for up to 3 weeks. Aerosol L-9NC treatment resulted in a reduction in lung weights (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 untreated control mice (P < 0.001). Using a newly developed human osteosarcoma experimental metastasis model in nude mice, we demonstrated that aerosol L-9NC was also effective against established lung metastases. Aerosol therapy 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 animals 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 tumor nodules (P < 0.02). These data suggest that L-9NC aerosol therapy may offer significant advantage over existing methods in the treatment of melanoma and osteosarcoma pulmonary metastases.