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.

项目总结/摘要 该提案描述了一种创新的手术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， 由于肿瘤大小和解剖结构的复杂性，在最终病理学检查中，边缘经常是阳性的， 即使在具有肉瘤专业知识的领先转诊中心，LRR率也高达40%。高死亡率通常是 由于局部疾病，而不是遥远的失败，因此提高生存率的策略必须解决 LRR。评价围手术期和/或术中外照射放疗、单剂量热疗 腹腔内化疗和全身化疗都没有显示出益处。我们的解决方案 是一种可手术植入的支撑物，用于将高浓度的化疗药物局部递送到患者的 切除床具体来说，我们描述了第一个例子，植入式，高剂量化疗支持 用于切除术后的双相延长紫杉醇（PTX）递送。支撑物由柔顺的 聚（己内酯）（PCL）和聚（1，2-甘油碳酸酯）（PGC）聚合物共混物，其中PTX是 物理截留在PGC内并与PGC位点特异性缀合，使浓度高达3.3 mg/cm 2（PTX支撑物上）。所提出的实验将检验双重释放曲线 物理包埋的PTX的快速但非突发释放，随后是紫杉醇的延长释放的组合。 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）中的存活 手术模型;和2）对于局部药物递送是安全和可行的，实现高局部组织 当沿沿着组织平面植入大型动物体内时， 在临床细胞减灭肉瘤手术中经常暴露的重要结构。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。supraPTX-支撑物提供了一个前所未有的机会， 第一种治疗方法这个五年计划的具体目标如下。目标1描述了 PTX释放动力学以及supraPTX-支撑物对切除肿瘤的细胞毒性和作用机制 患者源性肉瘤的体外研究。目的2评价supraPTX-支撑物预防肉瘤的有效性 在多种PDX鼠模型中切除后的复发，并评估安全性、局部组织愈合， 和膜植入后的药物药代动力学/生物分布。目的3评估安全性，可行性， 在临床前大型动物中植入supraPTX-支撑物的围手术期发病率和全身毒性 腹膜后肉瘤手术模型。