SUPERHYDROPHOBIC DRUG LOADED BUTTRESSES FOR PREVENTION OF LUNGTUMOR RECURRENCE

用于预防肺部肿瘤复发的超疏水载药支撑

• 批准号: 10331020
• 负责人: Yolonda L Colson
• 金额: $ 46.83万
• 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/10331020
• 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 *该提案描述了手术后局部复发问题的创新生物材料解决方案 用于非小细胞肺癌。尽管进行了手术，但大约22％的早期患者发展了局部区域 复发归因于剩余的隐秘局部残留疾病。这个问题是由于尝试最小化而引起的 通过去除尽可能少的肺组织和从微观肿瘤细胞中去除肺功能的丧失 在手术切除边缘附近。我们的解决方案是一个支撑，将其列入切除余地 在过程中，to：1）在受控的 携带残留癌（和区域淋巴结）的组织的方式； 2）密封组织以防止 钉子时漏气。这种新颖的生物材料/外科手术方法通过允许外科医生改变范例 在有效治疗任何潜在的残留肿瘤负担的同时，去除较少的肺组织。我们描述了独特的 电纺多聚合物非编织网格，从而聚合物组成和散装超疏水性 特性（即抵抗润湿并具有很高的表观接触角）控制药物释放。提议 实验将检验以下假设，即已建立的局部递送（紫杉醇和顺铂）和新的 （Eupenifelden）通过具有控制性润湿性的3-D超疏水性支柱的代理商将负担得起 持续释放和细胞毒性超过60天。我们进一步假设一种双重药物 已加载（例如紫杉醇和顺铂）的支架将降低局部复发率并延长生存率 在患者来源的肺癌异种移植（PDX）手术模型中，证明是安全可行的 局部药物输送，没有不良全身影响或局部愈合受损。重要的是， 大量的初步数据支持拟议的研究，特征良好的材料和严格的材料 建立了实验设计，并建立了基本的跨学科合作和专业知识 解决这些假设。该五年提案的具体目的是：目标1。表征润湿 单一和联合疏水（紫杉醇或Eupenifelden）和亲水性的速率和释放动力学 （顺铂）来自超疏水撑杆的药物以及离体肺组织上的密封能力；目的 2。研究单一和双药的超疏水胸罩的功效和药效学分析 反应在体外对切除的患者衍生的肺部肿瘤的反应；以及目标3。评估载有药物的功效 在患者衍生的切除术后预防肺癌复发方面的超疏水支撑 异种移植（PDX）鼠模型以及评估安全性，局部组织愈合和药物 植入后的药代动力学/生物分布。