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

开发用于不能手术的食管恶性肿瘤的多功能可生物降解载药聚合物支架

• 批准号: 9023017
• 负责人: Yunqing Kang
• 金额: $ 7.1万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-13 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9023017
• 关键词: 3D Print; Affect; Animal Model; Antineoplastic Agents; Chest Pain; Clinical; Complication; Deglutition Disorders; Detection; Development; Disease; Elasticity; Esophageal; Esophageal Neoplasms; Esophagus; Esters; Excision; Family suidae; Foundations; Future; Goals; Graph; Growth; Hemorrhage; In Vitro; Local Therapy; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of esophagus; Measures; Mechanics; Medical; Metals; Modeling; Natural regeneration; Neoplasm Metastasis; Obstruction; Operative Surgical Procedures; Outcome Study; Paclitaxel; Palliative Care; Patients; Perforation; Performance; Pharmaceutical Preparations; Phase; Polymers; Property; Refractory; Research; Risk; Stents; Stomach; Structure; Survival Rate; Techniques; Testing; Therapeutic; Time; Tissue Engineering; Translational Research; Tubular formation; Tumor Tissue; Unresectable; Urethane; biodegradable polymer; biomaterial compatibility; cancer cell; cancer therapy; cell growth; design; elastomeric; grasp; improved; in vitro testing; in vivo; migration; mortality; neoplastic cell; novel; palliation; poly(lactic acid); prevent; public health relevance; research study; treatment choice; tumor

 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.

 描述（由申请人提供）：食道癌是世界范围内第六种最常见的癌症。食管癌的治疗仍然是一个重大的医学挑战。这些患者的5年生存率仍然很低，低于15%。尽管手术技术有所改进，但仍有 50% 至 60% 的患者由于肿瘤检测较晚或转移灶不可切除，在就诊时不适合手术。对于这些患者，只能采取姑息治疗。治疗选择是缓解吞咽困难。目前，自膨式金属支架（SEMS）已用于恶性食管梗阻患者的姑息治疗。然而，这些支架的应用却出现了并发症，例如食道出血和穿孔、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，无法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，临床上尚无能够预防或减少迁移并发症并同时提供癌症治疗药物输送能力的支架。为了克服上述问题，在本研究中，我们建议开发新型可生物降解的弹性聚合物负载抗癌药物支架，用于治疗无法手术的食管恶性肿瘤患者。我们将使用可生物降解的弹性聚合物聚（酯-聚氨酯）（PEU）和结晶聚（乳酸）（PLA）作为基质来生产弹性但足够坚硬的可调节食道支架，以减少并发症。我们将在支架外部设计一种称为向上螺旋凹槽结构的几何特征，以抵抗迁移。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）具有向上螺旋槽的可生物降解弹性PEU/PLA支架将显着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，在体外持续抑制食道癌细胞的生长。为了检验这些假设，我们提出以下具体目标： 目标 1) 制造具有向上螺旋槽的 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)制备具有向上螺旋槽的PTX-PEU/PLA支架，并表征其体外抑制食管癌细胞生长的能力。对于 PTX-PEU/PLA 支架，我们将表征体外药物释放曲线以及支架对食管肿瘤细胞生长的抑制能力。具有向上螺旋槽的新型 PTX-PEU/PLA 载药支架在治疗无法手术的食管恶性肿瘤患者方面具有广阔的前景。这项研究的成功结果可能会对食管癌的治疗以及手术切除后食管再生所需的组织工程支架产生更广泛的影响。