Sirolimus Delivery from Esophageal Stents to Prevent Scarring after Mucosectomy

抽象概括 在过去的50年里，美国的食管癌诊断已经从 鳞状细胞癌到主要是腺癌，影响食管上部。早期 治疗是获得更好结果的关键， 这些技术能够去除较大的损伤。然而，鞋面的直径 食管较小，这些大的病变-通常长度>30 mm或> 75%的 周长-容易结疤，导致狭窄。发生狭窄的患者 通常用类似于血管成形术的内窥镜扩张治疗 扩张我们的长期目标是通过结合抗增殖药物输送来预防狭窄 在临床上已经使用的食管支架用于切除癌性的 或癌前组织。中心假设是缓慢、稳定地递送抗增殖药物， 药物西罗莫司将抑制成纤维细胞增殖和瘢痕形成，这是狭窄背后的罪魁祸首， 但是没有我们在我们的猪模型中从丝裂霉素C的类似递送中观察到的细胞毒性， 并且在与细胞重塑相关的治疗时间范围内（4-6周）。这个证明-- 下一个工作的原则将在两个目标中完成：1。制定和 使用我们的基于亲和力的递送平台表征西罗莫司负载的支架涂层; 和2.）使用猪骨髓基质细胞体外验证递送的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，它代表了第一个能够持续的局部药物治疗。 用于预防食管狭窄的递送。我们使用一种新颖的方法来实现高负载 和长期的，持续释放的治疗远远超过其他的，扩散的能力， 只有系统研究。预期结果包括开发能够 释放药物4-6周，抑制细胞增殖和迁移， 细胞毒这些结果将对内窥镜手术领域产生积极影响， 切除大的癌性或癌前病变引起的痛苦和昂贵的并发症 食管病变未来的工作将把这些R 03原理验证研究转化为我们的 猪体内模型，以验证食管狭窄的长期预防。另外我们 继续与我们的内窥镜手术合作者合作， 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.