Nanocage System for Endoscopic Imaging and Staging of Pancreatic Cancer

描述（由申请人提供）：目前迫切需要改进胰腺癌的早期发现和准确分期的影像学技术。此外，靶向治疗，包括图像引导化疗药物释放直接针对肿瘤部位，将减少有害的副作用对健康细胞，显著提高治疗效果，同时减轻患者的痛苦。目前有几种影像学方法用于胰腺癌的诊断和分期。主要方法包括螺旋计算机断层扫描（CT）和超声内镜（EUS）。螺旋CT通常用于初步检测胰腺肿块和远处转移的存在，而EUS用于肿瘤分期和预测血管侵犯。EUS是一门艺术，通常只有经验丰富且至少进行过100次EUS检查的超声医师才能评估和分期胰腺癌。改善这些EUS设备并最终对胰腺肿瘤成像对临床医生正确评估患者治疗策略至关重要。我们研究计划的总体目标是双重的：1)开发分子敏感，靶向纳米笼系统（NCSs），包括成像造影剂，治疗剂，或两者兼有；2)开发一种复杂的体内成像技术-内镜光声和超声（EPAUS）成像与NCSs增强-将允许诊断，疾病表征和更精确的胰腺癌分期。然而，目前的项目重点是开发静脉注射靶向NCS（仅含造影剂）和内窥镜光声和超声成像，用于胰腺癌的早期检测和可靠分期。因此，本文提出的工作旨在a)设计和构建靶向的、分子敏感的胰腺癌EPAUS成像ncs；b)设计并搭建EPAUS成像系统的实验室样机；c)初步证明ncs增强EPAUS成像可用于胰腺癌的早期发现和准确分期。在阐述这三个目标的基础上，NCS的核心是一种可生物降解的聚乳酸-羟基乙酸（PLGA）聚合物基质。银纳米笼将包围聚合物芯，赋予造影剂光声成像的特性。这种纳米笼将通过将聚乙二醇（PEG）链连接到外部来屏蔽网状内皮系统。最后，整个系统将通过将针对胰腺癌抗原的抗体附着到外部来定位。当与定制设计的EPAUS成像设备结合使用时，最终的纳米笼系统将提供增强的胰腺癌成像。EPAUS成像设备的实验室原型将基于内窥镜、线性阵列超声探头、多通道超声成像系统和可调谐脉冲激光源的接口。最后，开发的NCS增强EPAUS系统将使用含有不同浓度NCS的癌症模拟内含物的组织模拟模型、组织培养细胞模型和胰腺癌异种小鼠模型进行测试。EPAUS图像将与组织切片相关联，并与组织样本的免疫组织化学分析相比较。

DESCRIPTION (provided by applicant): There is a definite and urgent need for improved imaging techniques for early detection and accurate staging of pancreatic cancer. Furthermore, targeted therapy, consisting of image guided chemotherapeutic drug release directed at the tumor site, will reduce harmful side effects on healthy cells, dramatically improving treatment efficacy while relieving patient suffering. Several imaging modalities are currently used to diagnose and stage pancreatic cancer. Primary methods include helical computed tomography (CT) and endoscopic ultrasound (EUS). Helical CT is generally used to initially detect the presence of a pancreatic mass and any distant metastasis, while EUS is used for tumor staging and predicting vascular invasion. EUS is a fine art and only highly experienced endosonographers who have performed at least 100 EUS examinations are generally trusted to evaluate and stage pancreatic cancer. Improving these EUS devices and ultimately the imaging of pancreatic tumors is critical for clinicians to properly assess patient treatment strategies. The overall goal of our research program is two-fold: 1) to develop molecular sensitive, targeted nanocage systems (NCSs) encompassing either imaging contrast agents, therapeutic agents, or both; and 2) to develop a sophisticated in-vivo imaging technology - endoscopic photoacoustic and ultrasound (EPAUS) imaging augmented with NCSs - that will allow for diagnosis, disease characterization and more precise staging of pancreatic cancer. The current project, however, is focused on development of both an intravenously injectable targeted NCS (with contrast agents only) and endoscopic photoacoustic and ultrasound imaging for early detection and reliable staging of pancreatic cancer. Therefore, the work proposed here aims to a) design and build the targeted, molecularly sensitive NCSs for EPAUS imaging of pancreatic cancer; b) design and build a laboratory prototype of the EPAUS imaging system; and c) initially demonstrate that the NCS-augmented EPAUS imaging can be used for early detection and accurate staging of pancreatic cancer. Elaborating on these three proposed aims, the core of NCS is a biodegradable polymer matrix of poly(lactic-co-glycolic) acid (PLGA). A silver nanocage will surround the polymer core and impart contrast agent properties for photoacoustic imaging. This nanocage will be shielded from the reticuloendothelial system by attachment of poly(ethylene glycol) (PEG) chains to the exterior. Finally, the entire system will be targeted by attaching antibodies, specific to pancreatic cancer antigens, also to the exterior. The final nanocage system will provide enhanced imaging of pancreatic cancer when used in conjunction with a custom designed EPAUS imaging device. The laboratory prototype of an EPAUS imaging device will be based on an endoscopic, linear array ultrasound probe interfaced with a multi-channel ultrasound imaging system and tunable pulsed laser source. Finally, the developed NCS-augmented EPAUS system will be tested using tissue-mimicking phantoms with cancer-simulating inclusions containing various concentrations of NCS, tissue culture cell phantoms, and xenographic mouse models of pancreatic cancer. The EPAUS images will be correlated with histological slides and compared with immunohistochemical analysis of tissue samples. PUBLIC HEALTH RELEVANCE: There is a definite and urgent need for improved imaging techniques for early detection and accurate staging of pancreatic cancer. Furthermore, targeted therapy, consisting of image guided chemotherapeutic drug release directed at the tumor site, will reduce harmful side effects on healthy cells, dramatically improving treatment efficacy while relieving patient suffering. Several imaging modalities are currently used to diagnose and stage pancreatic cancer. Primary methods include helical computed tomography (CT) and endoscopic ultrasound (EUS). Helical CT is generally used to initially detect the presence of a pancreatic mass and any distant metastasis, while EUS is used for tumor staging and predicting vascular invasion.