Sirolimus Delivery from Esophageal Stents to Prevent Scarring after Mucosectomy

摘要摘要 在过去的50年里，美国的食道癌诊断已经从 影响上段食道的鳞状细胞癌到以腺癌为主。早些时候 治疗是微创内窥镜取得更好结果和最新进展的关键 技术使更大的病变得以切除。然而，鞋面的直径 食道较小，这些大的病变--通常长30毫米或75% 周长--容易形成疤痕，导致狭窄。出现狭窄的患者有 通常采用与血管成形术类似的内窥镜扩张治疗，可能需要多次 扩张。我们的长期目标是通过结合抗增殖药物的输送来预防狭窄 在癌症切除手术后已经临床使用的食道支架 或癌前组织。中心假设是缓慢、稳定的抗增殖剂的输送 药物西罗莫司将抑制成纤维细胞的增殖和瘢痕形成，这是狭窄背后的主要罪魁祸首， 但在我们的猪模型中，没有我们观察到的类似丝裂霉素C的细胞毒性， 以及与细胞重塑相关的治疗时间范围(4-6周)。这份证明- 这项下一步工作的原则将通过两个目标完成：1)配方和 使用我们的亲和力递送平台对西罗莫司支架涂层进行表征； 和2.)西罗莫司对猪体内抗增殖作用的体外验证 平滑肌和食道上皮细胞。 我们提出的工作是创新的；它代表了第一种能够持续、局部药物治疗的疗法 预防食道狭窄的分娩。我们使用一种新的方法来实现高负载 以及长期、持续的治疗药物释放，远远超过其他能够扩散的- 只有研究过的系统。预期的结果包括开发能够 释放药物4-6周，在没有公开的情况下抑制细胞增殖和迁移 细胞毒性。这些结果将对内窥镜手术领域产生积极影响， 切除大癌或癌前病变引起的疼痛和昂贵的并发症 食道损伤。未来的工作将把这些R03原则验证研究转化为我们的 猪在体模型，以验证长期预防食道狭窄。此外，我们 继续与我们的内窥镜手术合作者合作，将这种狭窄预防 治疗更接近临床现实。

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.