Nanocage System for Endoscopic Imaging and Staging of Pancreatic Cancer

描述（由申请人提供）：对于胰腺癌的早期检测和准确分期，确实迫切需要改进成像技术。此外，靶向治疗，包括针对肿瘤部位的图像引导化疗药物释放，将减少对健康细胞的有害副作用，大大提高治疗效果，同时减轻患者的痛苦。目前有几种成像方式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任何远处转移的存在，而EUS用于肿瘤分期和预测血管浸润。EUS是一门精美的艺术，只有经验丰富的内镜超声医师进行了至少100次EUS检查，通常被信任可以评估和分期胰腺癌。改进这些EUS设备并最终实现胰腺肿瘤成像对于临床医生正确评估患者治疗策略至关重要。我们的研究计划的总体目标是双重的：1）开发分子敏感的靶向纳米笼系统（NCS），包括成像造影剂，治疗剂或两者; 2）开发一种复杂的体内成像技术-用NCS增强的内窥镜光声和超声（EPAUS）成像-这将允许诊断，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（仅使用造影剂）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）设计和构建用于胰腺癌EPAUS成像的靶向的、分子敏感的NCS; B）设计和构建EPAUS成像系统的实验室原型;以及c）初步证明NCS增强的EPAUS成像可用于胰腺癌的早期检测和准确分期。阐述了这三个拟议的目标，核心的NCS是一个可生物降解的聚合物基质的聚（乳酸-共-乙醇酸）（PLGA）。银纳米笼将围绕聚合物核并赋予光声成像的造影剂性质。该纳米笼将通过将聚（乙二醇）（PEG）链连接到外部而与网状内皮系统屏蔽。最后，整个系统将通过将胰腺癌抗原特异性抗体附着到外部来靶向。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胰腺癌的增强成像。EPAUS成像设备的实验室原型将基于与多通道超声成像系统和可调谐脉冲激光源接口的内窥镜线性阵列超声探头。最后，开发的NCS增强的EPAUS系统将使用具有含有不同浓度NCS的癌症模拟内含物的组织模拟体模、组织培养细胞体模和胰腺癌的异种小鼠模型进行测试。EPAUS图像将与组织学切片相关，并与组织样本的免疫组织化学分析进行比较。 公共卫生相关性：胰腺癌的早期发现和准确分期是一个明确和迫切需要改进的成像技术。此外，靶向治疗，包括针对肿瘤部位的图像引导化疗药物释放，将减少对健康细胞的有害副作用，大大提高治疗效果，同时减轻患者的痛苦。目前有几种成像方式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任何远处转移的存在，而EUS用于肿瘤分期和预测血管浸润。

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.