In Vivo Evaluation of a Chemopreventive Agent, Ciclesonide, in Mouse Lung Tumor Model by Inhalation

A Corticosteroid (CS) is the most potent anti-inflammatory agent used in clinic for treating many inflammatory diseases. In addition to possessing a strong anti-inflammatory activity, CSs exert anti-proliferative effects in a number of different tissues and cell types. Preliminary data also suggest that inhalation of CS prevents lung adenoma in preclinical models and a small clinical study. However, CS has a narrow therapeutic index due to the systemic exposure, which has limited the chronic administration of this class of medicine. Therefore, molecule(s) with distinctive pharmacokinetic properties to decrease systemic exposure is coveted to enhance margin-of-safety. In order to address the significant side effects associated with the long-term use of CS, several delivery systems, such as inhalation and topical administration, have been developed in the past decades to improve therapeutic index of the CS. The principal advantage of the inhaled corticosteroids (ICSs) is their preferential lung deposition that contributes to the desired therapeutic effect and low systemic activity. The FDA approved Ciclesonide in 2008 for the treatment of asthma; it is a prodrug and formulates in hydrofluoroalkane (HFA) solution as an inhaler. More than 50% of the inhaled dose is deposited in the lungs as demonstrated by scintigraphical methods after inhalation of Ciclesonide. Ciclesonide is not active until metabolized to des-ciclesonide through cytosolic esterase in the lung airway; therefore, it has a superior pulmonary targeting with minimal systemic adverse effects. Additionally, the swallowed Ciclesonide does not contribute to the systemic circulation because of the low oral systemic bioavailability, which is below 1% for Ciclesonide. Hitherto, clinical experience of using inhaled Ciclesonide for the treatment of asthma demonstrated a similar effectiveness in patients with an improved therapeutic index compared to that of traditionally inhaled CSs. The main goal of this contract is to evaluate Ciclesonide for its anti-tumor activity in our established A/J mice lung tumor model by delivering the agent directly to the lung tissues thereby minimizing the systemic exposure. Furthermore, the induction of GILZ by ciclesonide will be used as a biomarker for target-specific biomarker.