Lung cancer is the leading single cause of cancer-related death in the US, and chemoprevention strategies have become increasingly appealing as a means to decrease this toll. Broadly, chemoprevention refers to inhibiting, blocking, or reversing cancer development at any point in the multistep carcinogenesis process. Suitable agents must be efficacious, mechanistically appropriate, and safe for chronic administration. We suggest that pulmonary delivery of alpha-tocopheryl succinate (aTS) as an inhaled aerosol is an attractive possibility for lung cancer chemoprevention. aTS is nontoxic to cultured normal cells, but is cytotoxic to many kinds of cultured cancer cells, including lung cancer cells. Because aTS is hydrolyzed in the gut to vitamin E, which is not toxic to cancer cells, we propose to administer it directly to the lungs as an inhaled aerosol.
Our specific aims are 1) to generate and characterize aTS aerosols and administer them to mice by inhalation, and 2) to determine the chemopreventive effects of aTS in a model of carcinogen-induced lung cancer. We hypothesize that aerosol delivery will allow administration of aTS in a dose and form that will inhibit the development of lung tumors. We have developed a method to aerosolize and administer lipophilic compounds such as aTS to the lungs using supercritical carbon dioxide. We propose to measure aTS solubility in carbon dioxide, determine aTS aerosol particle size distribution, evaluate lung deposition characteristics in mice, and determine the chemopreventive effects of aTS when administered as an inhaled aerosol, by oral gavage, or by intraperitoneal injection in a relevant mouse model of lung cancer in which A/J mice are exposed to the carcinogens NNK or BaP. The overall goal of this work is that it may contribute to an eventual reduction in the incidence or severity of human lung cancers.
| Hybertson, Brooks M (2007) Solubility of the sesquiterpene alcohol patchoulol in supercritical carbon dioxide. J Chem Eng Data 52:235-238 |
| Hybertson, Brooks M (2007) Solubility of [unreadable]-Tocopheryl Succinate in Supercritical Carbon Dioxide Using Offline HPLC-MS/MS Analysis. J Chem Eng Data 52:1123-1127 |
