Integrated Imaging and Photothermal Ablation of Pancreatic Cancer Resection Margi

胰腺癌切除 Margi 的综合成像和光热消融

• 批准号: 7789709
• 负责人: Sunil Krishnan
• 金额: $ 22.46万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7789709
• 关键词: Ablation; Address; Affinity; Animal Model; Antigens; Binding; Biodistribution; Bioluminescence; Biomedical Engineering; Blood Circulation; Blood Vessels; Cancer Etiology; Cancer Patient; Cessation of life; Clinical; Collaborations; Coupled; Data; Development; Diagnosis; Disease; Dose; Evaluation; Excision; Gold; Heating; Image; Imaging Techniques; In Vitro; Intravenous; Light; Lighting; Luciferases; Malignant Neoplasms; Malignant neoplasm of pancreas; Methods; Modeling; Neoplasm Metastasis; Nodal; Operative Surgical Procedures; Pathology; Patients; Postoperative Period; Probability; Prognostic Factor; Radiation Oncology; Recurrence; Research Personnel; Resectable; Resected; Residual Neoplasm; Residual Tumors; Residual state; Retroperitoneal Space; Risk; Site; Solid Neoplasm; Specificity; Specimen; Staging; Surgeon; Survival Rate; System; Techniques; Texas; Therapeutic; Thermal Ablation Therapy; Time; Tissues; Tumor Angiogenesis; Universities; University of Texas M D Anderson Cancer Center; Unresectable; Work; austin; cancer cell; design; gastrointestinal; imaging probe; improved; in vivo; nanoshell; neovascular; neovasculature; non-invasive monitor; operation; outcome forecast; pancreatic neoplasm; particle; prototype; public health relevance; targeted delivery; tumor; tumor growth

DESCRIPTION (provided by applicant): Pancreatic cancer is the third most common gastrointestinal malignancy and the fourth leading cause of cancer death in the US. Two-thirds of all pancreatic cancer patients have radiographically detectable metastatic disease at the time of diagnosis. Among patients without metastatic disease, surgery confers a 15-25% rate of 5-year overall survival. However, the survival rate remains poor for patients who undergo an incomplete (margin-positive) resection, and the available data suggest that the survival duration of these patients is no different from that of patients with locally advanced, surgically unresectable disease treated with chemoradiation. Several studies have suggested that in addition to nodal status, margin resection status is a very important prognostic factor (in some studies, the most important) and that a margin-positive resection strongly predicts early recurrence and short survival. Furthermore, postoperative chemoradiation therapy does not overcome the unfavorable prognosis conferred by a margin-positive resection. For these reasons, surgery should be limited to patients who can successfully undergo a margin-negative resection. In reality, however, many patients still undergo margin-positive resections. Efforts to improve the likelihood of obtaining margin-negative resections have focused on improvements in preoperative imaging that can discern the extent of local tumor growth (especially along the retroperitoneal margin) to allow accurate pretreatment staging and the development of stage-specific therapies. One approach has been to define a subset of patients with "borderline resectable" pancreatic cancer using rigorous preoperative imaging criteria, and to then offer them preoperative chemoradiation therapy. The likelihood of converting a borderline resectable cancer to a margin-negative resectable cancer is believed to be less than 30%. We propose a method to identify and treat positive margins at the time of surgery using vascular- targeted, near-infrared (NIR) absorbing nanoshells delivered systemically to the tumor prior to surgery, the use of intraoperative NIR narrowband imaging of nanoshell accumulations to identify residual disease, and photo-thermal ablation of this residual disease. Given sufficient specificity of imaging and therapy, this combined technique may overcome some of the poor prognosis conferred by surgical resections with positive margins. The specific aims of this proposal include: (1) To design, optimize, and validate a prototype NIR narrowband imaging system to identify accumulations of nanoshells expected in the resection margins of solid tumors. (2) To fabricate and optimize nanoshells for tumor-specific accumulation by conjugation to neovascular antigens. These vascular-targeted nanoshells will be characterized for their in vitro and in vivo binding affinity, and in vivo biodistribution. Optimal dosing parameters for accumulation in a pancreatic tumor model will be defined. (3) To evaluate the combination of NIR narrowband imaging and photothermal ablative therapy in an animal model of minimal residual disease. An intraoperative procedure for imaging and ablation will be coupled to bioluminescence imaging of luciferase-transfected pancreatic cancer cells for non- invasive monitoring of tumor regrowth over a 4-week period. PUBLIC HEALTH RELEVANCE: This R21 will develop a method to identify and treat positive pancreatic cancer margins at the time of surgery using vascular-targeted, near-infrared absorbing gold nanoshells. These nanoshells will be delivered systemically to the tumor prior to surgery. They will be visualized intraoperatively using near-infrared narrowband imaging to identify residual disease. Subsequently, this residual disease will be photo-thermally ablated by near-infrared illumination of the field containing accumulated nanoshells. Therefore, this proposal outlines a method for integrated imaging and therapy of residual margins using nanoshells as both the imaging probe and the therapeutic payload.

描述（由申请人提供）：胰腺癌是美国第三大常见的胃肠道恶性肿瘤，也是美国癌症死亡的第四个主要原因。在诊断时，所有胰腺癌患者中有三分之二在射线照相中可检测到。在没有转移性疾病的患者中，手术赋予5年总生存率15-25％。但是，接受不完整（边缘阳性）切除的患者的存活率仍然很差，并且可用的数据表明，这些患者的生存持续时间与接受化学疗法治疗的局部晚期，手术不可切除的疾病的患者没有什么不同。几项研究表明，除了淋巴结状态外，边缘切除状态是一个非常重要的预后因素（在某些研究中，最重要的是最重要的），并且边缘阳性切除强烈预测早期复发和短期生存率。此外，术后化学放疗疗法并不能克服边缘阳性切除所赋予的不利预后。由于这些原因，手术应仅限于可以成功接受边缘阴性切除的患者。但是，实际上，许多患者仍在进行保证金阳性的切除术。改善获得边缘阴性切除术的可能性的努力集中在术前成像的改进上，这些成像可以辨别局部肿瘤生长的程度（尤其是沿腹膜后边缘），以允许准确的预处理分期和阶段特异性疗法的发展。一种方法是使用严格的术前成像标准来定义具有“可切除”胰腺癌患者的子集，然后为他们提供术前化学放疗治疗。据信，将临界分解癌转化为可切除癌症的可能性小于30％。我们提出了一种在手术时使用靶向的，近红外（NIR）吸收纳米壳的方法来识别和治疗阳性边缘的方法，该纳米壳会在手术前系统地传递到肿瘤，使用纳米壳的术中NIR NIR NIR窄带成像，以识别残留疾病，并鉴定出这种残留疾病的残留疾病。鉴于成像和治疗的足够特异性，这种联合技术可能会克服一些由阳性缘阳性的手术切除术赋予的一些不良预后。该提案的具体目的包括：（1）设计，优化和验证原型NIR窄带成像系统，以确定实体瘤切除缘中预期的纳米壳的积累。 （2）通过结合与新血管抗原的结合来制造和优化纳米壳以肿瘤特异性积累。这些靶向血管的纳米壳的体外和体内结合亲和力以及体内生物分布的特征。将定义在胰腺肿瘤模型中积累的最佳给药参数。 （3）评估NIR窄带成像和光热消融疗法的组合，在最小残留疾病的动物模型中。用于成像和消融的术中方法将与荧光素酶转染的胰腺癌细胞的生物发光成像耦合，以在4周期间非侵入性监测肿瘤再生。 公共卫生相关性：该R21将开发一种方法，在手术时使用血管靶向的，近红外吸收的金纳米壳，以识别和治疗胰腺癌阳性。这些纳米壳将在手术前系统地递送到肿瘤。它们将使用近红外窄带成像进行术中可视化，以识别残留疾病。随后，这种残留疾病将通过含有累积纳米壳的田间的近红外照明在光中烧光。因此，该提案概述了使用纳米壳作为成像探针和治疗有效载荷整合成像和治疗残留边缘的方法。