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Inhibition of experimental lung metastasis by aerosol delivery of PEI-p53 complexes
A Gautam1, C L Densmore, J C Waldrep
1Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
Abstract:
Mutations in the p53 tumor suppressor gene and the pathways mediated by the p53 protein are common in many human cancers. Replacement of functional p53 by gene therapy is a potential way of combating these cancers and the associated drug resistance and tumor growth. Aerosol delivery of genes is a noninvasive way of targeting genes to the lung for gene therapy. Here we demonstrate, using a murine melanoma lung metastasis model, that aerosol delivery of polyethyleneimine-p53 (PEI-p53) complexes inhibits the growth of lung metastasis. A significantly reduced number of visible foci were observed in C57BL/6 mice injected with B16-F10 melanoma and treated with PEI-p53 complexes by aerosol for 3 weeks at twice a week. Fifty percent of the mice in the PEI-p53-treated group exhibited no visible tumor foci. There was a significant reduction in the lung weights of p53-treated mice (P < 0.01) compared to control groups. The tumor burden was also significantly lower (P < 0.001) in mice treated with PEI-p53 complexes. No extrapulmonary metastasis was observed in the groups treated with PEI-p53 complexes compared to 50% of the mice in control groups, which showed metastasis to lymph nodes in the neck or abdomen. Treatment with PEI-p53 aerosol also led to about a 50% increase in the mean length of survival of the mice injected with B16-F10 cells. These data suggest that delivery of the p53 gene by aerosol using PEI as the gene delivery vector can inhibit the growth of lung metastasis.
Insights
Gene therapy using aerosolized p53-polyethyleneimine (PEI-p53) complexes effectively inhibited lung metastasis growth in a mouse model. This noninvasive approach significantly reduced tumor burden and increased survival, offering a promising strategy for treating metastatic cancers.
Area of Science:
- Oncology
- Gene Therapy
- Nanomedicine
Background:
- Mutations in the p53 tumor suppressor gene are prevalent in human cancers, driving tumor growth and drug resistance.
- Gene therapy aims to restore functional p53, offering a therapeutic strategy against cancer.
- Aerosol delivery presents a noninvasive method for lung-targeted gene therapy.
Purpose of the Study:
- To evaluate the efficacy of aerosolized polyethyleneimine-p53 (PEI-p53) complexes in inhibiting lung metastasis growth.
- To assess the impact of PEI-p53 aerosol delivery on tumor burden, metastasis, and survival in a murine melanoma model.
Main Methods:
- Utilized a murine model of B16-F10 melanoma lung metastasis in C57BL/6 mice.
- Administered PEI-p53 complexes via aerosol twice weekly for 3 weeks.
- Monitored visible lung foci, lung weights, tumor burden, extrapulmonary metastasis, and survival rates.
Main Results:
- PEI-p53 aerosol treatment significantly reduced the number of visible lung tumor foci, with 50% of mice showing no visible foci.
- Significant reductions in lung weight and tumor burden were observed in the PEI-p53 treated group (P < 0.01 and P < 0.001, respectively).
- No extrapulmonary metastasis was detected in treated mice, and mean survival increased by approximately 50%.
Conclusions:
- Aerosol delivery of p53 gene using PEI as a vector is an effective noninvasive strategy to inhibit lung metastasis growth.
- This approach demonstrates potential for treating metastatic cancers by restoring p53 function.
- PEI-p53 aerosol therapy offers a promising therapeutic avenue, reducing tumor burden and improving survival in preclinical models.
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