Development of multifunctional biodegradable drug-loaded polymer stents for inoperable esophageal malignancies

 描述（由申请人提供）：食管癌是全球第六大常见癌症。食管癌的治疗仍然是一个重大的医学挑战。5-这些患者的年生存率仍然很低，不到15%。尽管手术技术有所改进，但50%至60%的患者由于肿瘤检测较晚或无法切除的转移，在就诊时不适合手术。对于这些患者，只能进行姑息治疗。治疗选择是缓解吞咽困难。目前，自膨式金属支架（SEMS）已被用于缓解恶性食管梗阻患者的症状。然而，这些支架的应用已经暴露出并发症，例如食管出血和穿孔、胸痛以及支架迁移到胃中。在这些并发症中，迁移是最常见的一种。此外，这些支架由金属丝组成，不能携带和输送抗癌药物来治疗食管肿瘤和防止肿瘤组织向内生长。目前，在临床环境中没有支架可用，其具有预防或减少迁移并发症的能力，同时提供递送癌症治疗药物的能力。为了克服上述问题，在本研究中，我们建议开发新的可生物降解的弹性聚合物支架装载抗癌药物治疗患者不能手术的食管恶性肿瘤。我们将使用可生物降解的弹性聚合物聚（酯-氨基甲酸酯）（PEU）和结晶聚（乳酸）（PLA）作为基质，生产弹性但足够刚性的可调节食管支架，以减少并发症。我们将在支架外部设计一种称为向上螺旋槽结构的几何特征，以阻止迁移。为了提供抗癌效力，我们将在支架上装载抗癌药物紫杉醇（PTX）。我们建议使用3D打印技术来制造PTX-PEU/PLA支架。我们假设1）具有向上螺旋凹槽的可生物降解弹性PEU/PLA支架将显著增加抗迁移力并防止支架滑移; 2）可生物降解的PTX-PEU/PLA将具有释放PTX的能力，从而在体外持续抑制食管癌细胞的生长。为了验证这些假设，我们提出了以下具体目标：目的1）制备具有向上螺旋槽的PEU/PLA管状支架，并表征其理化性能、抗迁移性能和生物相容性。目的2）制备具有螺旋槽的PTX-PEU/PLA支架，并研究其对食管癌细胞生长的抑制作用。对于PTX-PEU/PLA支架，我们将表征体外药物释放特性和支架对食管肿瘤细胞生长的抑制能力。具有向上螺旋凹槽的新型PTX-PEU/PLA载药支架对于治疗不可手术的食管恶性肿瘤患者具有很好的潜力。这项研究的成功结果可能对食管癌的治疗产生更广泛的影响，并需要组织工程支架用于手术切除后的食管再生。

 DESCRIPTION (provided by applicant): Esophageal cancer is the sixth most common form of cancer worldwide. The treatment for esophageal cancer remains a major medical challenge. 5-year survival rate of these patients remain very low, less than 15%. Despite improvements in surgical techniques, 50% to 60% of patients are not suitable for surgery at the time of presentation due to late tumor detection or unresectable metastases. For these patients, only palliative therapy is possible. The treatment option is to relieve dysphagia. Currently, self-expanding metal stents (SEMS) have been used in the palliation of patients with malignant esophageal obstruction. However, application of these stents has revealed complications, such as bleeding and perforation of esophagus, chest pain, and stent's migration into the stomach. Among these complications, migration is the most common one. Additionally, these stents are composed of metallic wires and are unable to carry and deliver anti-cancer drugs to treat esophageal tumors and prevent tumor tissue ingrowth. Currently, there are no stents available in a clinical setting, which have the ability of preventing or decreasing the complication of migration and at the same time provide the capability of delivering cancer therapy drugs. To overcome the above problems, in this study we propose to develop new biodegradable elastic polymer stents loaded with anti-cancer drugs for treating patients with inoperable esophageal malignancies. We will use biodegradable elastomeric polymer poly(ester- urethane) (PEU) and crystalline poly(lactic acid) (PLA) as a matrix to produce elastic, yet sufficiently stiff adjustabe esophagus stents for decreasing complications. We will design a geometrical feature called an upward spiral groove structure on the outside of the stent that resists migration. To provide anti-cancer potency, we will load the stents with anti-cancer drug paclitaxel (PTX). We propose to use a 3D printing technique to fabricate the PTX-PEU/PLA stents. We hypothesize that 1) the biodegradable elastic PEU/PLA stent with upward spiral grooves will significantly increase the anti-migration force and prevent the stent's slippage; 2) the biodegradable PTX-PEU/PLA will have the ability to release PTX for sustained inhibition on the growth of esophagus cancer cells in vitro. To test these hypotheses, we propose the following specific aims: Aim 1) Fabricate PEU/PLA tubular stents with upward spiral grooves and characterize the physicochemical properties, anti-migration property, and biocompatibility. Aim 2) Fabricate PTX-PEU/PLA stents with upward spiral grooves and characterize their inhibition ability on the growth of esophageal cancer cells in vitro. For PTX-PEU/PLA stents, we will characterize drug release profile in vitro and inhibition ability of the stents on esophageal tumor cell growth. The novel PTX-PEU/PLA drug-loaded stents with upward spiral grooves hold a promising potential for the treatment of patients with inoperable esophageal malignancies. A successful outcome for this study could have a wider impact on the treatment of esophageal cancer and the need for tissue-engineered stents for esophagus regeneration after surgical removal.