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.

项目摘要/摘要 该提案描述了一种创新的外科手术和生物工程解决方案 肉瘤的复发。局部区域复发（LRR）是最常见的失败模式 腹膜后，腹部和骨盆肉瘤。尽管有宏观的完整切除，但手术 由于较大的肿瘤大小和解剖复杂性，边缘经常对最终病理呈阳性，从而导致 LRR的率即使在肉瘤专业知识的领先推荐中心也高达40％。高死亡率通常是 由于局部疾病而不是遥远的失败，因此提高生存的策略必须解决 LRR。评估围手术期和/或术中外束放射疗法的试验，单剂量高温 腹膜内化疗和全身化疗都未能证明有益。我们的解决方案 是一种手术植入的支撑 切除床。具体而言，我们描述了可植入的高剂量化学治疗支柱的第一个例子 用于分离后双相延伸紫杉醇（PTX）递送。该支撑包括一个合规的 聚（Caprolactone）（PCL）和聚（1,2-甘油碳酸盐）（PGC）聚合物在网格上的聚合物混合物，其中PTX均为PTX 物理陷入内部并特定于PGC，使浓度高达3.3 mg/cm2（supraptx buttress）。提出的实验将测试双重释放曲线的假设 快速而不是破裂的组合，释放物理陷入的PTX，然后延长释放 共价结合的PTX将：1）降低LRR速率并延长患者衍生异种移植物（PDX）的存活率 手术模型； 2）安全可行，可用于局部药物输送，达到高局部组织 当在组织平面植入大型动物时，全身传递最小的药物水平， 在临床细胞减少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，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。 supraptx buttresses提供了一个前所未有的机会，可以用 首先疗法。该五年提案的具体目的是以下。 AIM 1表征 PTX释放动力学以及细胞毒性和对切除的骨头的作用机理 体外患者衍生的肉瘤。 AIM 2评估Supraptx的功效以防止肉瘤 在多个PDX鼠模型中切除后的复发，并评估安全性，局部组织愈合， 膜植入后的药物药代动力学/生物分布。 AIM 3评估安全性，可行性， 围手术期的发病率和在临床前大动物中植入Supraptx的全身毒性 腹膜后肉瘤手术的模型。