Ultra-Responsive "ON/OFF" Fluorescent Nanoprobes for Cancer Molecular Imaging

用于癌症分子成像的超响应“开/关”荧光纳米探针

• 批准号: 8193961
• 负责人: Jinming Gao
• 金额: $ 36.57万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-05 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193961
• 关键词: A549; Angiogenesis Inhibitors; Angiogenic Switch; Animals; Biological Markers; Blood; Blood Circulation; Blood Vessels; Cell Surface Receptors; Data; Development; Diagnosis; Dyes; Early Endosome; Electron Transport; Endosomes; Endothelial Cells; Endothelium; Energy Transfer; Fluorescence; Fluorescent Probes; Goals; Homo; Image; Imaging Techniques; Immunohistochemistry; Integrins; Lipids; Literature; Lysosomes; Magnetic Resonance Imaging; Maleimides; Malignant Neoplasms; Maps; Measurement; Measures; Micelles; Microscopic; Modeling; Molecular; Molecular Target; Mus; Neoplasm Metastasis; Optics; Output; Physiological; Play; Polymers; Research; Rhodamine; Role; Screening for cancer; Sensitivity and Specificity; Series; Signal Transduction; Specificity; Stimulus; Testing; Time; Tissues; Tumor Angiogenesis; Vascular Endothelial Cell; Vascular Endothelial Growth Factor Receptor-2; analog; angiogenesis; base; carcinogenesis; copolymer; cyclo(S,S)KYGCRGDWPC; design; experience; extracellular; improved; in vivo; millimeter; molecular imaging; nanoparticle; nanoprobe; pre-clinical; radiotracer; receptor mediated endocytosis; response; success; therapeutic target; tumor

DESCRIPTION (provided by applicant): Angiogenesis imaging holds considerable promise for early detection of cancer, as well as post-therapy assessment of many new molecular-targeted antiangiogenic therapies. New contrast probes such as small molecular radiotracers, optical probes, and lipid- and polymer-based nanoparticles are intensively investigated to target different biomarkers of angiogenesis. However, low tissue concentrations of intended biomarkers, lack of an amplification strategy to increase signal output, and high background signals are several major limiting factors that hamper the advances of these molecular imaging techniques. The long-term goal of this application is to develop a robust set of tunable fluorescent nanoprobes based on the homo fluorescent resonance energy transfer (homoFRET) and photo-induced electron transfer (PET) mechanisms. The micelle nanoprobes will stay silent (or in the OFF state) with minimum background signals under normal physiological conditions (e.g. blood circulation). Upon specific targeting to angiogenic target (e.g. avb3), these nanoprobes can be turned ON by pH activation (pH 5.0-7.2) inside endosomes/lysosomes after receptor-mediated endocytosis. Our central hypothesis is that a synergized strategy of signal amplification in tumor endothelium and background suppression in blood and pH-activatable micelle (pHAM) nanoprobes will be able to improve the imaging sensitivity and specificity of angiogenesis biomarkers in vascularized tumors in vivo. To test this hypothesis, we will carry out the following specific aims: (1) establish a series of near infrared (NIR) pHAM nanoprobes with tunable transition pH (pHt); (2) evaluate the activation of non-targeted pHAM in acidic tumor microenvironment; (3) establish vascular-targeted pHAM and investigate the intracellular activation of these nanoprobes in tumor endothelial cells; (4) evaluate the specificity and efficacy of targeted pHAM in the imaging of distinctive angiogenesis biomarkers (i.e. VEGFR2, avb3) in tumor-bearing mice in vivo. Successful execution of this research will establish pHAM as a valuable imaging platform to image angiogenesis- specific biomarkers on the tumor endothelium in vivo. These nanoprobes may be particularly useful for the efficacy assessment of molecular-targeted antiangiogenic therapies, where the expression levels of the therapeutic targets (e.g. VEGFR2, avb3) can be directly measured. PUBLIC HEALTH RELEVANCE: This application describes the development of ultra-responsive fluorescent nanoparticles for molecular imaging of angiogenesis biomarkers in preclinical tumor models.

描述（由申请人提供）：血管生成成像对于癌症的早期检测以及许多新的分子靶向抗血管生成疗法的治疗后评估具有相当大的前景。新的造影剂探针，如小分子放射性示踪剂，光学探针，脂质和聚合物为基础的纳米粒子进行了深入研究，以靶向不同的生物标志物的血管生成。然而，预期生物标志物的低组织浓度、缺乏增加信号输出的扩增策略以及高背景信号是阻碍这些分子成像技术进步的几个主要限制因素。本申请的长期目标是开发一套基于同荧光共振能量转移（homoFRET）和光诱导电子转移（PET）机制的可调荧光纳米探针。胶束纳米探针将在正常生理条件（例如血液循环）下保持沉默（或处于关闭状态），具有最小的背景信号。在特异性靶向血管生成靶点（例如avb 3）后，这些纳米探针可以在受体介导的内吞作用后通过内体/溶酶体内的pH激活（pH 5.0-7.2）打开。我们的中心假设是，肿瘤内皮细胞中的信号放大和血液中的背景抑制的协同策略和pH可激活胶束（pHAM）纳米探针将能够提高体内血管化肿瘤中血管生成生物标志物的成像灵敏度和特异性。为了验证这一假设，我们将开展以下具体目标：（1）建立一系列具有可调转变pH（pHt）的近红外（NIR）pHAM纳米探针;（2）评估非靶向pHAM在酸性肿瘤微环境中的活化;（3）建立血管靶向pHAM并研究这些纳米探针在肿瘤内皮细胞中的细胞内活化;（4）建立一系列pHAM纳米探针。（4）评价靶向pHAM在荷瘤小鼠体内特异性血管生成生物标志物（即VEGFR 2、avb 3）成像中的特异性和功效。本研究的成功实施将建立pHAM作为一个有价值的成像平台，在体内肿瘤内皮上成像血管生成特异性生物标志物。这些纳米探针可能特别适用于分子靶向抗血管生成疗法的疗效评估，其中可以直接测量治疗靶标（例如VEGFR 2、avb 3）的表达水平。 公共卫生相关性：本申请描述了用于临床前肿瘤模型中血管生成生物标志物的分子成像的超响应荧光纳米颗粒的开发。