p53 aerosol formulation with low toxicity and high efficiency for early lung cancer treatment.

Abstract

PURPOSE:

To develop an optimal nonviral aerosol formulation for locoregional treatment of early lung cancer.

EXPERIMENTAL DESIGN:

The formulation was made of polylysine/protamine combination (AND) as the carrier and p53 gene (p53sm) as therapeutic agent. To estimate the aerosol deposition, the aerodynamic size of the AND-p53sm was measured with extrusion-precipitation method. To accurately determine the dose, the aerosol efficiency in mice was measured with a fluorescent dye. The transfection efficiency and DNA protection function of the aerosolized formulation in cultured cells and mouse lungs were detected with reporter gene assays and/or reverse transcription-PCR. The preclinical safety and efficacy of AND-p53sm were studied in healthy mice and mice bearing orthotopic human non-small-cell lung cancer (NSCLC) xenograft.

RESULTS:

After aerosolization, AND is 3- to 17-fold more effective than commonly used PEI or cationic lipid formulations in transfecting the NSCLC cells (relative light units, 1,494 versus 534 and 86; P < 0.003). Aerodynamic size of AND-p53sm ranged 0.2 to 3 mum is the optimal aerosol droplets for deposition in the entire human respiratory tract. Significant gene expression was detected in the lungs of mice given aerosolized AND-p53sm and AND-luciferase. Aerosolized AND-p53sm significantly prolonged the life of mice bearing orthotopic human NSCLC xenografts, and it was more effective than an optimal i.v. cisplatin chemotherapy (increased life span, 93% versus 25%; P = 0.014). Inhalation of AND produced low and reversible pulmonary toxicity and no systemic toxicity.

CONCLUSIONS:

This optimal formulation is suitable for delivering biological materials to human lung with aerosol administration. This therapeutic strategy is an option for patients with early lung cancer and bronchoalveolar carcinoma.

• Authors: Yiyu Zou, Carmen Tornos, Xuan Qiu, Marie Lia, Roman Perez-Soler
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 13 Issue 16 Pg. 4900-8 (Aug 15 2007) ISSN: 1078-0432 [Print] United States
• PMID: 17699870 (Publication Type: Journal Article)

Chemical References

• Aerosols
• Protamines
• Polylysine

Topics

• Aerosols
• Animals
• Carcinoma, Non-Small-Cell Lung (therapy)
• Chemistry, Pharmaceutical
• Female
• Gene Transfer Techniques
• Genes, p53
• Genetic Therapy (adverse effects)
• Humans
• Lung Neoplasms (therapy)
• Male
• Mice
• Mice, Inbred ICR
• Plasmids
• Polylysine (administration & dosage)
• Protamines (administration & dosage)