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.
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.
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