Supratherapeutic PTX Buttresses Reduce Locoregional Recurrence Rates Following Surgery for Soft Tissue Sarcomas

超治疗 PTX 支撑可降低软组织肉瘤手术后的局部复发率

• 批准号: 10670441
• 负责人: Yolonda L Colson
• 金额: $ 69.56万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670441
• 关键词: Abdomen; Address; Adjuvant; Adjuvant Therapy; Anatomy; Animal Model; Animals; Antineoplastic Agents; Beds; Binding; Biodistribution; Biomedical Engineering; Carbon Dioxide; Carbonates; Cell Cycle Kinetics; Cell Death; Clinical; Collaborations; Colon Carcinoma; Data; Death Rate; Development; Disease; Distant; Dose; Drug Delivery Systems; Drug Kinetics; Excision; Experimental Designs; Failure; Film; Glycerol; Histologic; Hour; Hydrolysis; Hyperthermia; Implant; In Vitro; Incidence; Invaded; Kidney; Kinetics; Microscopic; Modeling; Mus; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; Organ Preservation; Paclitaxel; Pathology; Patient imaging; Patient-Focused Outcomes; Patients; Pattern; Pelvis; Perioperative; Pharmaceutical Preparations; Phase; Polymers; Prevention; Radiation therapy; Recurrence; Recurrent tumor; Reporting; Resected; Residual state; Retroperitoneal Sarcoma; Retroperitoneal Space; Risk; Site; Soft tissue sarcoma; Solubility; Structure; Succinic Acids; Surface; Surgical Models; Surgical margins; Surgical sutures; Survival Rate; Testing; Therapeutic; Time; Tissues; Tumor Burden; Tumor Debulking; Visceral; X-Ray Computed Tomography; aqueous; biomaterial compatibility; biomedical referral center; caprolactone; chemotherapy; cytotoxicity; efficacy evaluation; esterase; experience; experimental study; flexibility; healing; implantation; improved; in vivo; innovation; intraperitoneal therapy; intravenous administration; mortality; mouse model; novel strategies; patient derived xenograft model; perioperative morbidity; pre-clinical; prevent; safety assessment; sarcoma; side effect; standard of care; systemic toxicity; tumor

PROJECT SUMMARY/ABSTRACT This proposal describes an innovative surgical and bioengineering solution to the challenge of locoregional recurrence for sarcomas. Locoregional recurrence (LRR) is the most common pattern of failure for retroperitoneal, abdominal, and pelvic sarcomas. Despite a macroscopically complete resection, surgical margins are frequently positive on final pathology due to large tumor size and anatomic complexity, resulting in LRR rates of up to 40% even in leading referral centers with expertise in sarcoma. High mortality is commonly due to locoregional disease rather than distant failure, and therefore strategies to improve survival must address LRR. Trials evaluating perioperative and/or intraoperative external beam radiotherapy, single-dose hyperthermic intraperitoneal chemotherapy, and systemic chemotherapy have all failed to demonstrate benefit. Our solution is a surgically implantable buttress to locally deliver high concentrations of a chemotherapeutic drug to the resection bed. Specifically, we describe the first example of an implantable, high-dose chemotherapeutic buttress for biphasic extended paclitaxel (PTX) delivery post-resection. The buttress consists of a compliant poly(caprolactone) (PCL) and poly(1,2-glycerol carbonate) (PGC) polymer blend on a mesh, where PTX is both physically entrapped within and site-specifically conjugated to PGC enabling concentrations as high as 3.3 mg/cm2 (supraPTX-buttress). The proposed experiments will test the hypothesis that the dual release profile combination of fast, but not burst, release of physically entrapped PTX followed by extended release of covalently-bound PTX will: 1) reduce LRR rates and extend survival in patient-derived xenograft (PDX) surgical models; and 2) be safe and feasible for locoregional drug delivery, achieving high local tissue drug levels with minimal systemic delivery when implanted in a large animal along tissue planes and vital structures commonly exposed during clinical cytoreductive sarcoma surgery. 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. supraPTX-buttresses provide an unprecedented opportunity to treat sarcomas with a first-of-its-kind therapy. The specific aims of this five-year proposal are the following. Aim 1 characterizes the PTX release kinetics as well as cytotoxicity and mechanism of action of supraPTX-buttresses against resected patient-derived sarcomas in vitro. Aim 2 evaluates the efficacy of supraPTX-buttresses to prevent sarcoma recurrence following resection in multiple PDX murine models with assessment of safety, local tissue healing, and drug pharmacokinetics/biodistribution after film implantation. Aim 3 assesses the safety, feasibility, perioperative morbidity, and systemic toxicity of supraPTX-buttress implantation in a pre-clinical large animal model of retroperitoneal sarcoma surgery.

项目概要/摘要 该提案描述了一种创新的外科和生物工程解决方案，以应对局部区域的挑战 肉瘤复发。局部区域复发（LRR）是最常见的失败模式 腹膜后、腹部和盆腔肉瘤。尽管宏观上完全切除，手术 由于肿瘤体积大且解剖结构复杂，最终病理结果的切缘经常呈阳性，从而导致 即使在拥有肉瘤专业知识的领先转诊中心，LRR 率也高达 40%。死亡率高是普遍现象 由于局部疾病而不是远处的失败，因此提高生存率的策略必须解决 LRR。评估围手术期和/或术中外照射放疗、单剂量热疗的试验 腹腔化疗和全身化疗均未能显示出疗效。我们的解决方案 是一种可通过手术植入的支撑物，可将高浓度的化疗药物局部输送到 切除床。具体来说，我们描述了可植入的高剂量化疗支撑的第一个例子 用于切除后双相延长紫杉醇 (PTX) 输送。扶壁由顺应性的 聚己内酯 (PCL) 和聚 (1,2-甘油碳酸酯) (PGC) 聚合物共混物在网上，其中 PTX 都是 物理捕获并与 PGC 进行位点特异性结合，使浓度高达 3.3 mg/cm2（supraPTX-支撑）。所提出的实验将检验双重释放曲线的假设 结合快速但不突然释放物理捕获的 PTX，然后延长释放 共价结合的 PTX 将：1) 降低 LRR 率并延长患者来源的异种移植物 (PDX) 的生存期 手术模型； 2）局部药物递送安全可行，实现局部组织高浓度 当沿着组织平面植入大型动物体内时，药物水平具有最小的全身递送，并且 临床细胞减灭肉瘤手术期间通常暴露的重要结构。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。 supraPTX-buttresses 提供了前所未有的机会来治疗肉瘤 首创的疗法。该五年提案的具体目标如下。目标 1 的特点是 PTX释放动力学以及supraPTX-buttresss对切除的细胞毒性和作用机制 体外患者来源的肉瘤。目标 2 评估 supraPTX-buttress 预防肉瘤的功效 多个 PDX 小鼠模型切除后复发，并评估安全性、局部组织愈合、 以及薄膜植入后的药物药代动力学/生物分布。目标 3 评估安全性、可行性、 临床前大型动物中supraPTX-buttress植入的围手术期发病率和全身毒性 腹膜后肉瘤手术模型。