Image-Guided Drug Delivery for Pancreatic Neuroendocrine Tumor.

项目摘要/摘要 胰腺神经内分泌肿瘤(PNETs)是一种罕见的癌症，起源于朗格汉斯的胰岛， 在那里产生重要的荷尔蒙，包括胰升糖素、胰岛素和生长抑素。这些肿瘤是 体型极小，有多种一般症状。大多数PNETs病例是在确诊时诊断出来的 在开发的后期阶段，由于这种检测的困难。目前的化疗药物缺乏 由于胰腺的复杂功能和成分，在治疗PNETs方面有任何实际的效力， 这阻止了特定的靶向和治疗药物的输送。因此，手术切除仍然是 然而，手术中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，即以近红外(NIR)为靶标的PNET 荧光和放射成像，将为早期诊断提供灵敏、特异和实时的图像指导 诊断和改进治疗干预措施，包括靶向化疗和影像引导肿瘤 切除手术。这项研究的具体目标是开发多功能纳米探测器，它将 实现PNETs的靶向、成像和图像引导干预；评估细胞 靶向纳米探针的机制和生物分布；肿瘤特异性基因的翻译 用于图像引导干预的纳米探针，包括化疗和图像引导手术。网络的影响 这项研究将创造一个创新的概念，以应对早期诊断系统的缺乏 PNETs，并通过系统地将治疗性药物输送到 胰腺。 当与适当的术中成像系统配合使用时，650至900 nm的近红外荧光灯 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的实时成像(即，彩色 视频)和两个独立的近红外荧光灯(700 nm和800 nm发射)。一个近红外光谱 通道通常预留给目标组织(例如肿瘤)，而另一个通道预留给 需要避免(如神经、血管、淋巴结节等)。近红外荧光，与此配对 仪器和靶向造影剂，通过避免生物分子提供无干扰成像 活体中的自发荧光和非特异性器官摄取。！这一应用的重点是 多功能纳米探针的开发，因为近红外成像系统和PNET靶向的小 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 化学成分，包括表面电荷、全身给药、肿瘤滞留和靶向清除 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.