Image-Guided Drug Delivery for Pancreatic Neuroendocrine Tumor.

图像引导胰腺神经内分泌肿瘤的药物输送。

• 批准号: 9302133
• 负责人: Hak Soo Choi
• 金额: $ 67.62万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-16 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302133
• 关键词: Adenocarcinoma; Adipose tissue; Adverse effects; Anatomy; Animal Model; Animals; Binding; Binding Sites; Biodistribution; Biological Markers; Biotechnology; Bladder; Blood Circulation; Blood Vessels; Caliber; Cells; Charge; Chemicals; Chemistry; Clinical; Color; Complex; Contrast Media; Cyclodextrins; Data; Detection; Development; Diagnosis; Diagnostic; Diazoxide; Disease; Dissociation; Dose; Drug Delivery Systems; Drug Kinetics; Duct (organ) structure; Ductal; Early Diagnosis; Early treatment; Endocrine Glands; Evaluation; Excision; Extinction (Psychology); Family suidae; Fluorescence; Fluorouracil; Formulation; Future; Glucagon; Goals; Health; Hormones; Image; Image-Guided Surgery; Imagery; In Vitro; Injectable; Injection of therapeutic agent; Insulin; Intravenous; Islet Cell Tumor; Islets of Langerhans; Kidney; Light; Liver; Location; Lung; Lysine; Malignant - descriptor; Measures; Modeling; Morbidity - disease rate; Mus; NQO1 gene; Near-infrared optical imaging; Neoplasms; Nerve; Neuroendocrine Tumors; Normal Cell; Operating Rooms; Operative Surgical Procedures; Organ; Organism; Pancreas; Performance; Pharmaceutical Preparations; Positron-Emission Tomography; Property; Quinone Reductases; Radiolabeled; Renal clearance function; Resistance; Resources; Serum; Site; Somatostatin; Spleen; Surface; Surgeon; Symptoms; System; Systemic Therapy; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Time; Tissue imaging; Tissues; Toxic effect; Transgenic Organisms; Translating; Translations; Travel; Unresectable; Urine; Validation; Vertebral column; animal data; bioimaging; biomaterial compatibility; cancer diagnosis; cancer type; chemical group; chemotherapeutic agent; chemotherapy; clinical translation; conventional therapy; cost; design; image guided; image guided intervention; image-guided drug delivery; imaging agent; imaging system; improved; in vivo; in vivo Bioassay; innovation; instrumentation; insulinoma; intraoperative imaging; intravenous injection; lymph nodes; nanoprobe; operation; pancreas imaging; pancreatic neoplasm; pre-clinical; preclinical study; preclinical toxicity; prevent; quantum; single photon emission computed tomography; small molecule inhibitor; targeted delivery; targeted imaging; tumor; tumor xenograft; uptake

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.

项目概要/摘要 胰腺神经内分泌肿瘤（PNET）是一种罕见的癌症，起源于朗格汉斯岛， 产生胰高血糖素、胰岛素和生长抑素等重要激素的地方。这些肿瘤是 非常小并且有各种一般症状。大多数 PNET 病例是在以下情况下被诊断出来的： 由于检测的困难，在开发的后期阶段。目前化疗药物缺乏 由于胰腺的复杂功能和组成，治疗 PNET 的任何真正程度的效力， 这阻碍了治疗的特定靶向和递送。因此，手术切除仍然是 治疗的支柱；然而，手术过程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，以近红外 (NIR) 为目标的 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 诊断和改进的治疗干预措施，包括靶向化疗和图像引导肿瘤 切除。本研究的具体目标是开发多功能纳米探针，该探针将 实现 PNET 的瞄准、成像和图像引导干预；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。的影响 这项研究将创建一个创新概念，以应对早期诊断系统的缺乏 PNETs，以及通过将治疗药物系统性地输送到身体部位来产生治疗效果 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组织和患病组织的实时定位，而无需改变组织的外观 手术野。术中成像系统提供手术解剖结构的实时成像（即彩色 视频）和两个独立的近红外荧光通道（700 nm 和 800 nm 发射）。一个近红外 一个通道通常保留用于目标组织（例如肿瘤），而另一个通道则保留用于重要组织 需要避开的部位（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，通过避免生物分子提供无干扰成像 活体中的自发荧光和非特异性器官摄取。！此应用的重点是 多功能纳米探针的开发，因为 NIR 成像系统和 PNET 靶向小型 分子抑制剂已可用于临床前研究。我们描述了系统优化 化学成分，包括表面电荷、全身递送、肿瘤保留和靶向清除 纳米探针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。这将为这些纳米探针未来的快速临床转化奠定基础。