Bronchio-adventitial Drug Delivery: Paclitaxel for Bronchial Carcinoma

描述（由申请人提供）：根据美国国家癌症研究所的监测、流行病学和最终结果（SEER）项目，2008年美国将有超过215,000人被诊断为支气管癌。目前，美国有2290万人患有哮喘，据信美国有300万人患有气管软化症。除了这些慢性或致命的疾病外，通过支气管镜手术干预支气管通道可能会导致支气管肉芽组织阻塞气流。这些支气管疾病都有可能通过局部直接向支气管壁和外膜（平滑肌层和软骨之间的组织）输注药物来治疗。事实上，数据表明支气管疾病起源于支气管亚上皮壁，因此需要对上皮外的局部治疗。尽管这些问题很严重，而且有可能找到简单的解决方案，但目前还没有一种有效的设备可以安全可靠地进入支气管壁。Mercator MedSystems开发了一种血管外输液导管，该导管已获得FDA 510(k)批准，可用于人类市场。这是一种血管内球囊导管，当球囊膨胀时，通过血管壁挤出一根针，从而允许直接治疗外膜。人们已经发现，血管外输送导致药物在血管周围的圆柱形沉积，形成一个天然的药物洗脱库。在这个建议中，我们假设通过为支气管使用量身定制墨卡托微输注导管，我们可以证明局部输注支气管壁是安全的，并且可以产生适当的药代动力学特征。我们打算验证该设备可以从目前的8毫米直径扩大到16毫米直径，用于支气管使用，同时与2.8毫米的支气管镜工作通道保持兼容（具体目标1）。在此之后，我们将进行猪支气管外膜简单生理盐水输注试验，并分析0.05 ml至1.0 ml不同输注量下的组织损伤情况（Specific Aim 2）。最后，我们将建立紫杉醇的药代动力学和毒性谱，紫杉醇是一种可用于局部化疗或减少肉芽组织积聚的药物，剂量范围为1至100 <M （Specific Aim 3）。我们认为，这项提议的意义在于：(a)我们计划测试一种新的和创新的局部药物输送装置，以解决顽抗的临床问题；(b)了解一种常见的化疗和抗再狭窄药物（如紫杉醇）的药动学和毒性特征，可以产生广泛的临床影响；(c)支气管外动脉治疗在预防和治疗支气管疾病方面可能比吸入或全身治疗更有效。(d)紫杉醇治疗支气管癌的治疗成功可以迅速转化为其他以支气管狭窄为特征的临床环境。事实上，如果这些初步的试验研究成功的话，所有这些都表明墨卡托医疗系统公司的设备具有巨大的商业潜力。公共卫生相关性：由于缺乏针对这一重要临床问题的有效治疗方法，该建议的相关性在于其降低与支气管闭塞性疾病相关的发病率和死亡率的潜力。

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 <M (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.