SUPERHYDROPHOBIC DRUG LOADED BUTTRESSES FOR PREVENTION OF LUNG TUMOR RECURRENCE

用于预防肺肿瘤复发的超疏水载药支撑

• 批准号: 10083724
• 负责人: Yolonda L Colson
• 金额: $ 43.77万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10083724
• 关键词: 3-Dimensional; Address; Adverse effects; Adverse event; Air; Antineoplastic Agents; Biocompatible Materials; Biodistribution; Brachytherapy; Caliber; Cancer Etiology; Cancer cell line; Cessation of life; Chemotherapy and/or radiation; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical; Collaborations; Curative Surgery; Data; Diagnosis; Dose; Drops; Drug Combinations; Drug Controls; Drug Delivery Systems; Drug Kinetics; Drug usage; Evaluation; Excision; Experimental Designs; Family suidae; Fiber; Freedom; Human; Hydrophobicity; Immunocompetent; Impairment; In Vitro; Kinetics; Lobectomy; Lung; Lung Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Measures; Microscopic; Morbidity - disease rate; Non-Small-Cell Lung Carcinoma; North America; Operative Surgical Procedures; Paclitaxel; Patients; Pharmaceutical Preparations; Pharmacodynamics; Polymers; Prevention; Procedures; Property; Recurrence; Regimen; Resected; Residual Cancers; Residual Tumors; Risk; Safety; Site; Solubility; Specimen; Structure; Structure of parenchyma of lung; Surgeon; Surgical Models; Survival Rate; Testing; Tissues; Tumor Burden; Wettability; Xenograft procedure; aqueous; base; biomaterial compatibility; cancer recurrence; chemotherapy; cytotoxicity; draining lymph node; drug efficacy; efficacy evaluation; experimental study; flexibility; healing; hydrophilicity; implantation; improved; in vivo; innovation; lung cancer cell; lung preservation; malignant breast neoplasm; mechanical properties; mouse model; neoplastic cell; novel; novel anticancer drug; novel strategies; palliative; patient derived xenograft model; prevent; pulmonary function; response; seal; side effect; standard of care; success; surgery outcome; tumor; user-friendly

ABSTRACT *This proposal describes an innovative biomaterials solution to the problem of local recurrence following surgery for non-small cell lung cancer. Despite surgery, approximately 22% of early-stage patients develop locoregional recurrence attributed to remaining occult local residual disease. This problem results from attempts to minimize the loss of pulmonary function by removing as little lung tissue as possible and from microscopic tumor cells remaining near the surgical resection margin. Our solution is a buttress, which is stapled into the resection margin during the procedure, to: 1) deliver prolonged high local concentrations of anti-cancer agents in a controlled manner to the tissue harboring the residual cancer (and regional lymph nodes); and 2) seal the tissue to prevent air leaks upon stapling. This novel biomaterials/surgical approach changes the paradigm by allowing the surgeon to remove less lung tissue while treating any potential residual tumor burden effectively. We describe unique electrospun polymeric non-woven meshes whereby the polymer composition and the bulk superhydrophobic property (i.e., resist wetting and have high apparent contact angles) control drug release. The proposed experiments will test the hypothesis that local delivery of established (paclitaxel & cisplatin) and new (eupenifelden) agents via a 3-D superhydrophobic buttress, possessing controlled wettability, will afford sustained release and cytotoxicity for greater than 60 days. We further hypothesize that a dual drug- loaded (e.g., paclitaxel & cisplatin) buttress will reduce locoregional recurrence rates and extend survival in a patient-derived lung cancer xenograft (PDX) surgical model, and prove to be safe and feasible for locoregional drug delivery without adverse systemic effects or impaired local healing. Importantly, substantial preliminary data support the proposed studies, well-characterized materials and rigorous experimental designs are established, and essential cross-disciplinary collaborations and expertise are in place to address the hypotheses. The specific aims of this five-year proposal are: Aim 1. Characterize the wetting rates and the release kinetics of single and combined hydrophobic (paclitaxel or eupenifelden) and hydrophilic (cisplatin) agents from superhydrophobic buttresses as well as the sealing capability on ex vivo lung tissue; Aim 2. Investigate efficacy and pharmacodynamic profiling of single and dual drug-loaded superhydrophobic buttress response against resected patient-derived lung tumors in vitro; and, Aim 3. Evaluate the efficacy of drug-loaded superhydrophobic buttresses in preventing lung cancer recurrence following resection in a patient-derived xenograft (PDX) murine model as well as assess the safety, local tissue healing, and drug pharmacokinetics/biodistribution after buttress implantation.

抽象的 *该提案描述了一种创新的生物材料解决方案，解决手术后局部复发的问题 用于非小细胞肺癌。尽管进行了手术，大约 22% 的早期患者仍会出现局部区域性病变 复发归因于残留的隐匿性局部残留病。这个问题是由于试图最小化 通过尽可能少地切除肺组织和微小肿瘤细胞来丧失肺功能 保留在手术切除边缘附近。我们的解决方案是使用支撑物，将其钉入切除边缘 在手术过程中，目的是：1）在受控的环境中长时间提供局部高浓度的抗癌药物。 含有残留癌症的组织（和区域淋巴结）的方式； 2) 密封组织以防止 装订时漏气。这种新颖的生物材料/手术方法改变了范式，允许外科医生 去除更少的肺组织，同时有效治疗任何潜在的残留肿瘤负担。我们描述独特的 静电纺丝聚合物非织造网，其中聚合物组合物和本体超疏水性 特性（即抗润湿性和具有高表观接触角）控制药物释放。拟议的 实验将检验现有药物（紫杉醇和顺铂）和新药物的局部递送的假设 (eupenifelden) 试剂通过 3-D 超疏水支撑，具有受控的润湿性，将提供 持续释放和细胞毒性超过60天。我们进一步假设双重药物- 负载（例如紫杉醇和顺铂）支撑将降低局部复发率并延长生存期 在患者来源的肺癌异种移植（PDX）手术模型中，并被证明是安全可行的 局部药物输送不会产生不良的全身效应或损害局部愈合。重要的是， 大量的初步数据支持拟议的研究、充分表征的材料和严格的 实验设计已经建立，重要的跨学科合作和专业知识已经到位 来解决假设。该五年提案的具体目标是： 目标 1. 表征润湿特性 单一和组合疏水性（紫杉醇或 eupanifelden）和亲水性药物的速率和释放动力学 （顺铂）超疏水支撑剂以及离体肺组织的密封能力；目的 2. 研究单载药和双载药超疏水支撑物的功效和药效学分析 对切​​除的患者来源的肺肿瘤的体外反应；目标 3. 评估载药药物的功效 超疏水支撑物在预防肺癌切除术后复发方面的作用 异种移植 (PDX) 小鼠模型以及评估安全性、局部组织愈合和药物 支撑植入后的药代动力学/生物分布。