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: 8111805
• 负责人: Sunil Krishnan
• 金额: $ 15.75万
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111805
• 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; Radiosurgery; 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 cancer cells; 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(申请人提供)：胰腺癌是美国第三大常见的胃肠道恶性肿瘤，也是导致癌症死亡的第四大原因。三分之二的胰腺癌患者在诊断时有放射学可检测到的转移性疾病。在没有转移性疾病的患者中，手术可以提供15%-25%的5年总存活率。然而，接受不完全(切缘阳性)切除的患者的存活率仍然很低，现有数据表明，这些患者的生存时间与接受放化疗的局部晚期、不能手术切除的疾病患者没有什么不同。一些研究表明，除淋巴结状态外，切缘状态是一个非常重要的预后因素(在一些研究中，是最重要的)，切缘阳性切除强烈预测早期复发和短期生存。此外，术后放化疗并不能克服切缘阳性切除带来的不良预后。由于这些原因，手术应该仅限于那些能够成功地接受切缘阴性切除的患者。然而，在现实中，许多患者仍然接受切缘阳性切除。提高切缘阴性切除的可能性的努力主要集中在改进术前成像，以识别局部肿瘤生长的程度(特别是沿着腹膜后边缘)，以便进行准确的预处理分期和开发针对不同阶段的治疗方法。一种方法是使用严格的术前影像标准确定一组“边缘可切除”的胰腺癌患者，然后为他们提供术前化疗和放射治疗。据信，将交界性可切除癌症转变为切缘阴性可切除癌症的可能性不到30%。我们提出了一种在手术时识别和治疗阳性切缘的方法，使用手术前系统输送到肿瘤的血管靶向的近红外(NIR)吸收纳米壳，使用术中纳米壳堆积的近红外窄带成像来识别残留疾病，并对这种残留疾病进行光热消融。考虑到影像和治疗的足够特异性，这种联合技术可能会克服切缘阳性的手术切除带来的一些不良预后。这项建议的具体目标包括：(1)设计、优化和验证一个原型近红外窄带成像系统，以识别实体肿瘤切除边缘预期的纳米壳堆积。(2)通过与新生血管抗原的偶联，制备和优化肿瘤特异性聚集的纳米壳。这些以血管为靶标的纳米壳将被表征为它们在体外和体内的结合亲和力以及在体内的生物分布。将定义在胰腺肿瘤模型中积累的最佳剂量参数。(3)评价近红外窄带成像与光热消融治疗微小残留病动物模型的联合应用。术中成像和消融的程序将与荧光素酶转基因的胰腺癌细胞的生物发光成像相结合，以非侵入性监测肿瘤在4周内的再生长。 与公共卫生相关：R21将开发一种方法，在手术时使用血管靶向、近红外吸收金纳米壳来识别和治疗阳性胰腺癌切缘。这些纳米壳将在手术前被系统地输送到肿瘤上。它们将在术中使用近红外窄带成像进行可视化，以识别残留疾病。随后，这种残留的疾病将通过含有积累的纳米壳的场的近红外照明被光热消融。因此，这项建议概述了一种使用纳米贝壳作为成像探针和治疗有效载荷的残留边缘的综合成像和治疗方法。