Image-Guided Drug Delivery for Pancreatic Neuroendocrine Tumor.

项目总结/摘要 胰腺神经内分泌肿瘤（PNTH）是一种罕见的癌症类型，起源于胰岛， 其中产生重要的激素，包括胰高血糖素、胰岛素和生长抑素。这些肿瘤 极小且有多种一般症状。大多数的PNS病例是在 在发展的后期阶段，因为这种检测的困难。目前的化疗药物缺乏 由于胰腺的复杂功能和组成， 其阻止了治疗剂的特异性靶向和递送。因此，手术切除仍然是 然而，手术期间肿瘤的可视化一直是一个重大挑战。 我们的假设是，多功能纳米探针，目标PNIPs与近红外（NIR） 荧光和放射成像，将提供敏感，特异性和实时图像指导的早期 诊断和改进的治疗干预，包括靶向化疗和图像引导肿瘤 切除术本研究的具体目标是开发多功能纳米探针， 使靶向，成像和图像引导的介入PNTs;细胞的评价 靶向纳米探针的机制和生物分布;以及肿瘤特异性 用于图像引导干预的纳米探针，包括化疗和图像引导手术。的影响 这项研究将创造一个创新的概念，以面对缺乏诊断系统的早期阶段， 通过全身性递送治疗药物至受试者以产生治疗效果。 胰腺 当与适当的术中成像系统一起使用时，650至900 nm的NIR荧光 可以为外科医生提供正常和病变组织的实时定位，而不会改变 外科领域。术中成像系统提供手术解剖结构的实时成像（即，颜色 视频）和两个独立通道的NIR荧光（700 nm和800 nm发射）。1份近红外 通道通常为目标组织保留（例如，肿瘤），而另一个保留用于重要组织， 需要避免（例如，神经、血管、淋巴结等）。近红外荧光，与此配对 仪器和靶向造影剂，通过避免生物分子干扰提供无干扰成像 自体荧光和非特异性器官吸收在活的有机体。此应用程序的重点是 开发多功能纳米探针，因为近红外成像系统和PNET靶向小 分子抑制剂已经可用于临床前研究。我们描述了系统的优化， 化学组成，包括表面电荷、全身递送、肿瘤保留和靶向药物的清除。 通过使用体外和体内生物测定和生物成像，以及临床前验证， 大型动物。这将为未来这些纳米探针的快速临床翻译奠定基础。

PROJECT SUMMARY/ABSTRACT Pancreatic neuroendocrine tumors (PNETs) are a rare type of cancer that originate in the islets of Langerhans, where important hormones including glucagon, insulin, and somatostatin are produced. These tumors are extremely small and have a variety of general symptoms. Most cases of PNETs are diagnosed when they are in the later stages of development because of this difficulty of detection. Current chemotherapeutic agents lack any real degree of potency in treating PNETs because of complex functions and compositions of pancreas, which prevents specific targeting and delivery of therapeutics. Therefore, surgical resection remains the mainstay of treatment; however, visualization of tumors during operation has been a major challenge. Our hypothesis is that multifunctional nanoprobes, that target PNETs with near-infrared (NIR) fluorescence and radioimaging, will provide sensitive, specific, and real-time image-guidance for early diagnosis and improved therapeutic interventions, including targeted chemotherapy and image-guided tumor resection. The specific aims of this study are focused on developing multifunctional nanoprobes which will enable the targeting, imaging, and image-guided intervention of PNETs; the evaluation of the cellular mechanism and biodistribution of the targeted nanoprobes; and the translation of the tumor-specific nanoprobes for image-guided interventions including chemotherapy and image-guided surgery. The impact of this study will be the creation of an innovative concept to confront the lack of diagnostic systems for early stage PNETs, and the creation of a therapeutic effect through the systemic delivery of therapeutic drugs to the pancreas. When used with an appropriate intraoperative imaging system, NIR fluorescent light from 650 to 900 nm can provide surgeons with real-time localization of normal and diseased tissue, without changing the look of the surgical field. The intraoperative imaging system provides real-time imaging of surgical anatomy (i.e., color video) and two independent channels of NIR fluorescent light (700 nm and 800 nm emission). One NIR channel is typically reserved for a target tissue (e.g., tumor) while the other is reserved for vital tissue that needs to be avoided (e.g., nerves, blood vessels, lymph nodes, etc.). NIR fluorescence, paired with this instrumentation and targeted contrast agents, provides interference-free imaging by avoiding biomolecular autofluorescence and nonspecific organ uptake in the living organism.!The focus of this application is on the development of multifunctional nanoprobes, because the NIR imaging system and a PNET-targeted small molecule inhibitor are already available for preclinical studies. We describe the systematic optimization of chemical composition, including surface charge, systemic delivery, tumor retention, and clearance for targeted nanoprobes through the use of in vitro and in vivo bioassays and bioimaging, as well as preclinical validation in large animals. This will set the stage for rapid clinical translation of these nanoprobes in the future.