The 3D whole Body Distribution of NIR transferrin using FRET tomography imaging

描述（由申请人提供）：转铁蛋白是一种众所周知的铁结合蛋白，它通过与转铁蛋白受体的结合负责将铁带入细胞。此外，由于转铁蛋白受体在肿瘤中表达上调，已被广泛用作抗癌药物传递系统的载体。靶向给药是一种重要的、有前途的癌症有效治疗方法。我们的主要目标是使用3D全身断层成像来可视化受体介导的转铁蛋白细胞摄取。为了实现这一目标，我们建议利用转铁蛋白受体的同二聚体性质，并采用荧光共振能量转移（FRET）在体内成像组织吸收近红外（NIR）铁结合转铁蛋白的能力。我们将使用全身多光谱时间分辨荧光分子层析成像（FMT）成像平台来测量体内和3D的受体二聚化。总之，我们将检测和成像体内受体介导的nir -转铁蛋白细胞摄取，以定量检测基于转铁蛋白的靶向递送系统，用于诊断和治疗。该建议超越了目前的标准方法，纳入了最先进的临床前光学成像方法，以定量评估膜结合受体的二聚化，例如：转铁蛋白受体，通过监测FRET。FRET FMT成像以非侵入性但在体内的方式工作，使定量数据易于获得，以前所未有的特异性和敏感性定位和测量受体介导的转铁蛋白细胞摄取量。这项研究计划的长期目标是开发一种新的临床模式，以识别个体癌症中由受体二聚化激活的受体途径。这种非侵入性技术是缺乏的，但它将深刻地影响患者的管理，因为它允许设计一种个体化的治疗方案，该方案只包括那些靶向并阻断特定肿瘤中激活的受体途径的药物，以实现积极和成功的治疗。

DESCRIPTION (provided by applicant): Transferrin is a well known iron-binding protein, which is responsible for carrying iron into the cells via its binding to the transferrin receptor. Moreover, transferrin has been widely used as carrier for anti-cancer drug delivery systems since the transferrin-receptor is upregulated in tumors. Targeted delivery is an important and promising approach for the development of effective therapy in cancer applications. Our main goal is to use 3D whole body tomographic imaging to visualize the receptor-mediated transferrin cellular uptake. Towards this goal, we propose to capitalize on the homodimeric nature of the transferrin receptor and employ Fluorescence Resonance Energy Transfer (FRET) to image in vivo the ability of tissues to take up near-infrared (NIR) iron-bound transferrin. We will use a whole body multispectral time-resolved fluorescence molecular tomography (FMT) imaging platform to measure receptor dimerization in vivo and in 3D. In summary, we will detect and image in vivo receptor-mediated NIR-transferrin cell uptake for the quantitative detection of the transferrin-based targeted delivery systems for diagnostic and therapeutic use. This proposal leapfrogs over current standard approaches to incorporate the most advanced pre-clinical optical imaging approach to assess quantitatively the dimerization of membrane-bound receptors, e,.g. transferrin receptor, by monitoring FRET. FRET FMT imaging works in a non-invasive but in vivo manner, making quantitative data readily available to localize and measure the amount of receptor-mediated transferrin cellular uptake with unprecedented specificity and sensitivity. The long term goal of this research program is to develop a new clinical modality to identify receptor pathways that are activated by receptor dimerization in an individual's cancer. Such non-invasive technique is lacking but will profoundly impact patient management by allowing to devise an individualized therapeutic regimen consisting only of those drugs that will target and block the receptor pathways that are activated in that particular tumor for aggressive and successful therapy.