Sirolimus Delivery from Esophageal Stents to Prevent Scarring after Mucosectomy

从食管支架输送西罗莫司以防止粘膜切除术后留下疤痕

• 批准号: 9232682
• 负责人: Horst A. von Recum
• 金额: $ 7.02万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9232682
• 关键词: Address; Adenocarcinoma; Affect; Affinity; Aliquot; Angioplasty; Barrett Esophagus; Caliber; Cancerous; Cardiovascular system; Cell Culture Techniques; Cell Proliferation; Cicatrix; Clinical; Comb animal structure; Data; Development; Devices; Diffusion; Dissection; Dose; Drug Controls; Drug Delivery Systems; Early treatment; Endothelial Cells; Epithelial Cells; Esophageal; Esophageal Stenosis; Esophagus; Evaluation; Excision; Family suidae; Fibroblasts; Fibrosis; Formulation; Future; Gastrointestinal tract structure; Goals; Grant; Hour; In Vitro; Incubated; Infection; Injection of therapeutic agent; Laboratories; Length; Lesion; Malignant neoplasm of esophagus; Measures; Mitomycin A; Mitomycins; Modeling; Mucous Membrane; Muscle; Operative Surgical Procedures; Outcome; Pain; Patients; Pharmaceutical Preparations; Polymers; Premalignant; Prevention; Procedures; Public Health; Series; Sirolimus; Smooth Muscle; Smooth Muscle Myocytes; Squamous Cell; Stents; Structure; System; Techniques; Testing; Therapeutic; Time; Tissues; Traction; Translating; United States; Universities; University Hospitals; Validation; Work; antiproliferative drugs; base; cancer diagnosis; cell motility; cytotoxicity; experience; in vivo; in vivo Model; innovation; local drug delivery; migration; minimally invasive; novel strategies; prevent; standard of care; success

Abstract Summary Over the last 50 years esophageal cancer diagnosis in the United States has switched from squamous cell to predominantly adenocarcinomas affecting the upper esophagus. Early treatment is key to better outcomes and recent advances in minimally invasive endoscopic techniques have enabled removal of larger lesions. However, the diameter of the upper esophagus is smaller and these large lesions – typically >30 mm in length or >75 % of circumference – are prone to scarring that leads to stricture. Patients who develop stricture are typically treated with endoscopic dilation similar to angioplasty and may require multiple dilations. Our long-term goal is to prevent stricture by combing antiproliferative drug delivery with an esophageal stent already used clinically after procedures for the removal of cancerous or precancerous tissue. The central hypothesis is that slow, steady delivery of antiproliferative drug sirolimus will inhibit fibroblast proliferation and scarring, the main culprit behind stricture, but without the cytotoxicity we observed from similar delivery of mitomycin C in our pig model, and over a therapeutic timeframe relevant to cellular remodeling (4-6 weeks). This Proof-of- Principle for this next work will be accomplished in two aims: 1.) Formulation and characterization of sirolimus-loaded stent coatings using our affinity-based delivery platform; and 2.) In vitro validation of the anti-proliferative effect of delivered sirolimus using porcine smooth muscle and esophageal epithelial cells. Our proposed work is innovative; it represents the first therapy capable of sustained, local drug delivery for preventing esophageal stricture. We use a novel approach to achieve high loading and long-term, sustained release of therapeutics well beyond that capable of other, diffusion- only systems studied. The expected outcomes include development of coated stent capable of releasing drug for 4-6 weeks that inhibits cell proliferation and migration without overt cytotoxicity. These results will positively impact the field of endoscopic surgery by decreasing painful and expensive complications resulting from removal of large cancerous or precancerous esophageal lesions. Future work will translate these R03 proof-of-principle studies to our porcine in vivo model to validate long-term prevention of esophageal stricture. In addition, we continue to work with our endoscopic surgical collaborators to bring this stricture-preventing therapy closer to a clinical reality.

摘要摘要 过去 50 年来，美国的食管癌诊断已从 鳞状细胞癌到主要影响早期食管的腺癌。 治疗是获得更好结果的关键，也是微创内窥镜的最新进展 技术已经能够切除较大的病变，但是，上部的直径。 食管较小，这些大病变 – 通常长度 >30 毫米或 >75% 周长——容易形成疤痕，导致狭窄。 通常采用类似于血管成形术的内窥镜扩张治疗，并且可能需要多次 我们的长期目标是通过结合抗增殖药物输送来严格预防。 食管支架在切除癌组织后已在临床上使用 或癌前组织的中心假设是抗增殖剂的缓慢、稳定的输送。 西罗莫司药物会抑制成纤维细胞增殖和疤痕形成，这是狭窄背后的罪魁祸首， 但没有我们在猪模型中通过类似的丝裂霉素 C 递送观察到的细胞毒性， 以及与细胞重塑相关的治疗时间范围（4-6 周）。 下一步工作的原则将实现两个目标：1.）制定和 使用我们基于亲和力的输送平台表征西罗莫司支架涂层； 2.) 使用猪体外验证西罗莫司的抗增殖作用 平滑肌和食管上皮细胞。 我们提出的工作是创新的；它代表了第一种能够持续局部药物的疗法。 我们使用一种新颖的方法来实现高负荷分娩。 以及长期、持续释放的治疗药物远远超出其他扩散药物的能力 预期的结果包括开发能够进行涂层支架的系统。 释放药物 4-6 周，抑制细胞增殖和迁移而不明显 这些结果将通过减少细胞毒性对内窥镜手术领域产生积极影响。 切除大的癌变或癌前病变引起的痛苦且昂贵的并发症 未来的工作将把这些 R03 原理验证研究转化为我们的研究成果。 猪体内模型验证食管狭窄的长期预防。 继续与我们的内窥镜外科合作者合作，以实现这种预防狭窄的目标 治疗更接近临床实际。