Bronchio-adventitial Drug Delivery: Paclitaxel for Bronchial Carcinoma

DESCRIPTION (provided by applicant): Over 215,000 people will be diagnosed in 2008 with bronchial carcinoma in the U.S. according to the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. Currently, asthma afflicts 22.9 million people in the U.S., and tracheomalacia is believed to afflict 3 million people in the U.S. In addition to these chronic or deadly conditions, intervention into the bronchial passageways with bronchoscopic procedures can cause bronchial granulation tissue that obstructs airflow. These diseases of the bronchi each may potentially be treated with local, direct infusion of medications into the bronchial wall and adventitia (the tissue between smooth muscle layers and cartilage). In fact, data suggests that diseases of the bronchi arise in the sub-epithelial bronchial wall, and thus local treatment beyond the epithelium is warranted. Despite the magnitude of these problems, and the potential for a simple solution, there exists no device useful to deliver safely and reliably into the bronchial wall. Mercator MedSystems has developed a vascular adventitial infusion catheter that has FDA 510(k) clearance to market for use in humans. This is an endovascular balloon catheter which extrudes a single needle through the vessel wall when the balloon is inflated, thus allowing direct therapeutic access to the adventitia. It has been discovered that vascular adventitial delivery leads to cylindrical deposition of drugs around the vessel, creating a natural drug-eluting reservoir. In this proposal, we hypothesize that by tailoring the Mercator Micro-Infusion Catheter for bronchial use, we can show that local infusion into the bronchial wall is safe and can result in an appropriate pharmacokinetic profile. We intend to verify that the device can be sized up from its current 8 mm diameter to 16 mm diameter for bronchial use while remaining compatible with the 2.8 mm working channel of bronchoscopes (Specific Aim 1). After this, we will test simple saline infusion into pig bronchial adventitia and analyze the tissue for damage at different volume infusions from 0.05 ml to 1.0 ml (Specific Aim 2). Finally, we will establish the pharmacokinetic and toxicity profile of paclitaxel, a drug that may be used for local chemotherapy or to reduce the buildup of granulation tissue, at doses ranging from 1 to 100 ltM (Specific Aim 3). We believe that the significance of this proposal lies in the fact that (a) we plan to test out a novel and innovative local drug delivery device for a recalcitrant clinical problem, (b) learning the pharmacokinetic and toxicity profile of a common chemotherapeutic and antirestenotic drug like paclitaxel can have broad-ranging clinical impact, (c) bronchial adventitial therapy may be more effective in the prevention and treatment of bronchial maladies than inhalation or systemic therapies, and (d) therapeutic success in the delivery of paclitaxel for the treatment of bronchial carcinoma could be rapidly translated to other clinical settings characterized by bronchial narrowing. Indeed, all of the above suggest a huge commercial potential for the Mercator MedSystems device, if these initial pilot studies are successful. PUBLIC HEALTH RELEVANCE: The relevance of this proposal lies in its potential to reduce morbidity and mortality associated with occlusive diseases of the bronchi, due to a lack of effective therapies for this important clinical problem.