SUPERHYDROPHOBIC DRUG LOADED BUTTRESSES FOR PREVENTION OF LUNGTUMOR RECURRENCE

摘要 * 该提案描述了一种创新的生物材料解决方案，以解决手术后局部复发的问题。 非小细胞肺癌尽管手术，大约22%的早期患者发展为局部区域性 复发归因于剩余的隐匿性局部残留疾病。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的肿瘤细胞来丧失肺功能 保持在手术切除边缘附近。我们的解决方案是将支撑物钉入切除边缘 在该过程中，为了：1）在受控的环境中递送延长的高局部浓度的抗癌剂， 2）将残留的癌组织（和区域淋巴结）封闭，以防止 吻合时漏气。这种新型生物材料/手术方法通过允许外科医生 以在有效治疗任何潜在的残余肿瘤负荷的同时去除较少的肺组织。我们描述了独特的 电纺聚合物非织造网，由此聚合物组合物和本体超疏水 特性（即，抗润湿并具有高表观接触角）控制药物释放。拟议 实验将检验这样的假设，即局部递送已建立的（紫杉醇和顺铂）和新的（紫杉醇和顺铂）。 （eupenifelden）剂通过3-D超疏水支撑，具有可控的润湿性，将提供 持续释放和细胞毒性大于60天。我们进一步假设双重药物- 加载的（例如，紫杉醇和顺铂）支持将降低局部复发率，延长生存期 在患者来源肺癌异种移植物（PDX）手术模型中， 局部区域药物递送，而没有不良的全身作用或受损的局部愈合。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 实验设计已经确立，重要的跨学科合作和专业知识已经到位 来解决这些假设。这个五年计划的具体目标是：目标1。表征润湿性 单一的和组合的疏水（紫杉醇或Eupenifelden）和亲水（紫杉醇）的释放速率和释放动力学 （顺铂）剂的超疏水性支撑物以及对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疗效和药效学特征 体外对切除的患者来源的肺肿瘤的反应;以及，目的3.评价载药的疗效 超疏水支撑物在预防肺癌切除术后复发中的作用 异种移植物（PDX）鼠模型以及评估安全性、局部组织愈合和药物耐受性。 植入支撑物后的药代动力学/生物分布。

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.