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（由申请方提供）：胰腺癌是美国第三大常见胃肠道恶性肿瘤，也是第四大癌症死亡原因。三分之二的胰腺癌患者在诊断时具有放射学可检测的转移性疾病。在无转移性疾病的患者中，手术可使5年总生存率达到15-25%。然而，接受不完全（边缘阳性）切除的患者的生存率仍然很低，现有数据表明，这些患者的生存期与接受放化疗治疗的局部晚期、手术不可切除疾病患者的生存期没有差异。一些研究表明，除了淋巴结状态，边缘切除状态是一个非常重要的预后因素（在一些研究中，最重要的），边缘阳性切除强烈预测早期复发和短期生存。此外，术后放化疗治疗不能克服边缘阳性切除所带来的不良预后。由于这些原因，手术应限于那些能够成功进行边缘阴性切除的患者。然而，在现实中，许多患者仍然接受边缘阳性切除术。提高切缘阴性切除可能性的努力集中在术前影像学的改善上，这些影像学可以辨别局部肿瘤生长的程度（特别是沿着腹膜后切缘），以允许准确的预处理分期和分期特异性治疗的发展。一种方法是使用严格的术前影像学标准来定义一组“边缘可切除”胰腺癌患者，然后为他们提供术前放化疗治疗。将边缘可切除癌症转化为边缘阴性可切除癌症的可能性被认为小于30%。我们提出了一种在手术时使用血管靶向的、近红外（NIR）吸收纳米壳来识别和治疗阳性边缘的方法，所述近红外吸收纳米壳在手术前全身递送至肿瘤，使用纳米壳积聚的术中NIR窄带成像来识别残留疾病，以及该残留疾病的光热消融。如果影像学和治疗有足够的特异性，这种联合技术可能会克服一些由切缘阳性的手术切除所带来的不良预后。该提案的具体目标包括：（1）设计、优化和验证原型NIR窄带成像系统，以识别实体肿瘤切除边缘中预期的纳米壳的积聚。(2)通过与新生血管抗原偶联来制造和优化肿瘤特异性积聚的纳米壳。这些血管靶向纳米壳将表征其体外和体内结合亲和力以及体内生物分布。将定义胰腺肿瘤模型中蓄积的最佳给药参数。(3)评价NIR窄带成像和光热消融治疗在微小残留病动物模型中的联合应用。用于成像和消融的术中程序将与胰蛋白酶转染的胰腺癌细胞的生物发光成像相结合，用于在4周内无创监测肿瘤再生长。 公共卫生关系：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金纳米壳来识别和治疗阳性胰腺癌边缘。这些纳米壳将在手术前全身递送到肿瘤。术中将使用近红外窄带成像对其进行可视化，以识别残留病变。随后，该残留疾病将通过对含有累积的纳米壳的场的近红外照射来光热消融。因此，该提案概述了一种使用纳米壳作为成像探针和治疗有效载荷的残留边缘的集成成像和治疗方法。