Growth inhibition of established
tumor metastases in the lungs poses a difficult challenge for most clinical settings in spite of extensive multi-modality approaches.
Aerosol delivery of drugs and genes holds promise for the treatment of disseminated lung
metastases, since
aerosol delivery can target the lungs specifically and uniformly. We previously demonstrated that
aerosol delivery of
dilauroylphosphatidylcholine liposome formulation of
9-nitrocamptothecin (9NC-DLPC) inhibits B16-F10
melanoma lung
metastases.
Aerosol delivery of polyethleneimine-p53
DNA (PEI-p53) complexes results in a similar anti-
tumor effect in the B16-F10 model. In both these previous studies, the protocols were designed to inhibit development of lung
metastases. In this study we demonstrate, using the B16-F10
melanoma lung
metastasis model, that sequential
aerosol delivery of PEI-p53 and 9NC-DLPC acts additively to inhibit growth of established B16-F10
tumor metastases in the lungs. Mice injected with B16-F10 cells and treated with a combination of 9NC-DLPC (twice weekly) and PEI-p53 (once weekly)
aerosol complexes starting on day 11 after
tumor inoculation, exhibited a highly significant (P < 0.01) reduction in the number of visible
tumor foci as compared with untreated mice or mice treated with either single agent alone, or with a combination of 9NC and a control plasmid. There was a highly significant reduction in the
tumor burden, as well as the lung weights for the 9NC and p53 combination group (P < 0.001 as compared with other groups). Moreover, the doses of p53 gene and 9NC in the combination group were reduced at least two-fold as compared with our previous single agent studies, but still achieved significant
tumor inhibition. Furthermore, the sequential
aerosol delivery of p53 and 9NC lead to a 30-40% increase in the mean survival time of these mice, as compared with animals in different control groups. The data suggest that the combination of 9NC and p53 gene delivered by
aerosol is an attractive strategy for growth inhibition of established
tumor metastases in the lungs.