VALIDATION OF FLUORESCENT DEOXYGLUCOSE (2-NBDG) IN TUMORS

描述(申请人提供)：一种新的d-葡萄糖的荧光类似物2-[N-(7-nitrobenz-2-oxa-1，3-diaxol-4-yl)amino]-2-deoxyglucose(2-NBDG)是最近开发的，但尚未被表征为癌细胞摄取葡萄糖的标志。验证这种新的示踪剂作为浅表肿瘤光学成像的葡萄糖类似物可能会对浅表肿瘤的临床和临床前成像产生重大影响。如果这种新的示踪剂的行为类似于18-氟标记的2-脱氧葡萄糖(FDG)，后者正成为正电子发射断层扫描(PET)肿瘤代谢成像的金标准，我们可能会改变浅表肿瘤的检测和诊断方式，并产生一种低成本的早期发现浅表肿瘤的筛查方法。这一验证也可能对动物研究产生重大影响，因为这将是唯一一种用于小动物代谢成像的葡萄糖类似物验证。该项目的总体目标是首先验证2-NBDG作为恶性肿瘤细胞标志物的使用(第一阶段)，然后开发体内方法和荧光光学仪器，用于商业化，可用于通过简单的光学仪器经济地监测2-NBDG摄取(第二阶段)。为阶段I提出的2个特定目标：1)使用荧光显微镜和荧光分光光度法来评估和表征荧光葡萄糖类似物2-NBDG在体外模型恶性肿瘤细胞系和正常、非恶性肿瘤细胞中的摄取特性，以阐明在选定的模型恶性肿瘤细胞系(3个系)和正常、非恶性肿瘤细胞中2-NBDG摄取过程的动力学特性，以及2)通过直接比较2-NBDG的摄取与放射性标记的2-葡萄糖摄取(已建立的金标准)来验证使用荧光葡萄糖类似物2-NBDG作为探针来识别恶性肿瘤细胞，通过放射性同位素分析，在相同的细胞系中；以及最初在动物组织中的摄取。通过将2-NBDG的摄取与标准的放射性标记类似物进行比较，将验证2-NBDG作为每个细胞系的可靠探针的使用。评估第一阶段成功完成的终点是肿瘤细胞对2-NBDG的摄取与放射性标记的2-脱氧葡萄糖相当。随着这一阶段的成功完成，我们建议研究2-NBDG在小鼠浅表肿瘤模型中体内成像的可行性，并开发非侵入性检测这些肿瘤的仪器。

DESCRIPTION (provided by applicant): A new fluorescent analogue of d-glucose, 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose (2-NBDG), was recently developed, but has not been characterized as a marker of glucose uptake in cancer cells. Validating this new tracer as a glucose analogue for optical imaging of superficial tumors may have a major impact on clinical and preclinical imaging of superficial tumors. If this new tracer is shown to behave similarly to the 18-fluorine-labeled 2-deoxyglucose (FDG), which is becoming the gold standard for metabolic imaging of tumors by positron-emission topography (PET), we may change the way superficial tumors are detected and diagnosed and produce a low cost screening method for early detection of superficial tumors. This validation may also have a major impact on animal studies since it would be the only glucose analogue validation for metabolic imaging in small animals. The overall goal of the project is to validate first the use of 2-NBDG as a marker of malignant tumor cells (Phase I) and then to develop in vivo methods and fluorescence optical instrumentation, for commercialization, that can be used to\economically monitor 2-NBDG uptake via simple optical instrumentation (Phase II). 2 Specific Aims proposed for Phase I: 1) to assess and characterize the uptake properties of the fluorescent glucose analogue, 2-NBDG, in model malignant tumor cell lines and in normal, non-malignant cells in vitro using fluorescence microscopy and spectrofluorimetry to elucidate the kinetic properties of the 2-NBDG uptake process in selected model malignant tumor cell lines (3 lines) and in normal, non-malignant cells, and 2) to validate the use of the fluorescent glucose analogue, 2-NBDG, as a probe to identify malignant tumor cells by directly comparing the uptake of 2-NBDG with the uptake of radiolabeled 2-dexoyglucose (an established "gold" standard), by radioisotopic analysis, in the same cell lines; and initial uptake in animal tissues. By comparing 2-NBDG uptake with that of the standard, radiolabeled analogue, the use of 2-NBDG as a reliable probe for each cell line will be validated. The end points for assessing successful completion of Phase I is the demonstration of uptake of 2-NBDG in tumor cells comparable to radiolabeled 2-deoxyglocose. Following a successful completion of this phase, we propose to study the feasibility of in-vivo imaging of 2-NBDG in mice models of superficial tumors, and develop instrumentation to detect these tumors non-invasively.