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

点击翻译按钮获取中文摘要

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.