Bronchio-adventitial Drug Delivery: Paclitaxel for Bronchial Carcinoma

支气管外膜药物输送：紫杉醇治疗支气管癌

• 批准号: 7746592
• 负责人: Kirk Seward
• 金额: $ 21.81万
• 依托单位: MERCATOR MEDSYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-16 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7746592
• 关键词: Adventitious Tissue; Albumins; Argon; Asthma; Benign; Binding; Blood Vessels; Breathing; Bronchi; Bronchogenic Carcinoma; Bronchoscopes; Bronchoscopy; Caliber; Carcinoma in Situ; Cartilage; Catheters; Chronic; Clinical; Clinical Research; Coagulation Process; Cold Therapy; Data; Deposition; Development; Devices; Diagnosis; Diagnostic; Diffusion; Disease; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Dyes; Electrocoagulation; Epithelial; Epithelium; Failure; Family; Family suidae; Forcep; Granulation Tissue; Human; Inflammation; Infusion procedures; Injectable; Intervention; Kinetics; Lasers; Learning; Liquid substance; Lung; Marketing; Measures; Methylene blue; Microscopic; Modeling; Morbidity - disease rate; National Cancer Institute; Necrosis; Needles; Operative Surgical Procedures; Paclitaxel; Patients; Pattern; Pharmaceutical Preparations; Phase II Clinical Trials; Pilot Projects; Plasma; Prevention; Procedures; Process; Pulmonology; Radiofrequency Interstitial Ablation; Research; SEER Program; Safety; Saline; Shunt Device; Site; Smooth Muscle; Solutions; Stents; Structure of parenchyma of lung; System; Systemic Therapy; Technology; Testing; Therapeutic; Time; Tissues; Toxic effect; Tracheal Stenosis; Translating; Translations; Tunica Adventitia; Work; base; chemotherapy; clinically relevant; commercialization; design; effective therapy; improved; innovation; local drug delivery; lung volume; meetings; mortality; nanoparticle; novel; public health relevance; research study; response; restenosis; success; tool; trend; tumor

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.

描述(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)计划，2008年美国将有超过215,000人被诊断为肺癌。目前，美国有2290万人患有哮喘，300万人患有气管软化。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)注入药物来治疗。事实上，数据表明，支气管病发生在上皮下的支气管壁，因此有必要进行上皮以外的局部治疗。尽管这些问题很严重，而且有可能找到简单的解决方案，但目前还没有有效的设备可以安全可靠地将药物输送到支气管壁。墨卡托医疗系统公司已经开发出一种血管外膜输液导管，该导管具有FDA 510(K)许可，可用于人体。这是一种血管内球囊导管，当球囊充气时，它会将一根针穿过血管壁，从而允许直接进入血管外膜。已经发现，血管外膜递送导致药物在血管周围圆柱状沉积，形成一个天然的药物洗脱储存库。在这项建议中，我们假设通过为支气管使用定制墨卡托微量输液导管，我们可以证明局部输注到支气管壁是安全的，并可以产生适当的药代动力学曲线。我们打算验证该设备可以从目前的8 mm直径扩大到16 mm直径用于支气管镜使用，同时保持与2.8 mm支气管镜工作通道的兼容性(具体目标1)。在此之后，我们将测试简单的生理盐水注入猪的支气管外膜，并分析不同体积的生理盐水在0.05~1.0ml(特定目标2)的输注对组织的损伤。最后，我们将建立紫杉醇的药代动力学和毒性曲线，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，剂量范围从1到100&lt；M(特定目标3)。我们认为这一建议的意义在于：(A)我们计划针对顽固性临床问题测试一种新型的创新的局部给药装置，(B)了解一种常见的化疗和抗再狭窄药物如紫杉醇的药代动力学和毒性概况可产生广泛的临床影响，(C)支气管外周疗法在预防和治疗支气管疾病方面可能比吸入或全身疗法更有效，(D)紫杉醇用于治疗肺癌的治疗成功可迅速推广到其他以支气管狭窄为特点的临床环境。事实上，如果这些初步的初步研究取得成功，上述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：由于缺乏对这一重要临床问题的有效治疗，这项建议的相关性在于它有可能降低与支气管闭塞性疾病相关的发病率和死亡率。

项目成果

Learning from the Cardiologists and Developing Eluting Stents Targeting the Mtor Pathway for Pulmonary Application; A Future Concept for Tracheal Stenosis.

• DOI: 10.4172/1747-0862.1000065
• 发表时间: 2013-08-26
• 期刊: Journal of molecular and genetic medicine : an international journal of biomedical research
• 作者: Zarogoulidis P;Darwiche K;Tsakiridis K;Teschler H;Yarmus L;Zarogoulidis K;Freitag L
• 通讯作者: Freitag L

Experimental Pilot Study of a Novel Endobronchial Drug Delivery Catheter.

新型支气管内药物输送导管的实验性试点研究。

• DOI: 10.1097/lbr.0000000000000209
• 发表时间: 2015
• 期刊: Journal of bronchology & interventional pulmonology
• 影响因子: 3.3
• 作者: Tsukada,Hisashi;Seward,KirkP;Rafeq,Samaan;Kocher,Olivier;Ernst,Armin
• 通讯作者: Ernst,Armin