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.
This proposal is critically concerned with the issue of public health in that its long-term goal is to prevent esophageal stricture following endoscopic submucosal dissection. The short-term goal of this work is to generate a sirolimus-loaded drug delivery coating for a graft that is currently introduced surgically immediately following dissection surgery, with the goal of preventing the excessive scarring that results in esophageal stricture. We will assess the efficacy of delivery esophageal cell culture models developed at Case Western Reserve University.
