SUPERHYDROPHOBIC DRUG LOADED BUTTRESSES FOR PREVENTION OF LUNGTUMOR RECURRENCE

摘要 *这项建议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 治疗非小细胞肺癌。尽管做了手术，大约22%的早期患者会发生局灶性病变。 复发归因于残留的隐匿性局部残留病。此问题是由于试图最小化 切除尽可能少的肺组织和显微镜下的肿瘤细胞而导致的肺功能的丧失 留在手术切除边缘附近。我们的解决方案是一个支撑物，它被钉在切除边缘 在该过程中，为了：1)在受控条件下长期给予局部高浓度的抗癌药物 如何处理残留癌组织(和区域淋巴结)；以及2)密封组织以防止 装订时漏气。这种新的生物材料/外科手术方法改变了范式，允许外科医生 在有效治疗任何潜在的残留肿瘤负担的同时，减少肺组织的切除。我们描述了独特的 电纺聚合物无纺网，其中聚合物组成和本体超疏水 控制药物释放的性能(即耐湿性和高表观接触角)。建议数 实验将验证这样的假设，即已建立的(紫杉醇和顺铂)和新的 (Eupenifelden)试剂通过三维超疏水支撑物，具有可控的润湿性，将提供 缓释性和细胞毒性大于60天。我们进一步假设一种双重药物- 负载(如紫杉醇和顺铂)支撑物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，并被证明是安全和可行的 局部给药，无全身不良反应或损害局部愈合。重要的是 大量的初步数据支持拟议的研究，材料特征良好，严谨 建立了实验设计，并建立了必要的跨学科协作和专业知识 来解决这些假说。这个五年计划的具体目标是：目标1.描述湿润的特征 单一及复合疏水性(紫杉醇或优培酮)和亲水性药物的释放速率和释放动力学 (顺铂)超疏水基托制剂以及对体外肺组织的封闭能力；目的 2.单、双药超疏水支撑剂的药效及药效学研究 对切除患者来源的肺肿瘤的体外反应；以及，目的3.评价载药的疗效 超疏水支撑物预防肺癌术后复发1例 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 支架植入后的药代动力学/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.