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: 8705515
• 负责人: Jinming Gao
• 金额: $ 35.58万
• 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/8705515
• 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; MDA MB 231; 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; tumor microenvironment

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.

描述（由申请人提供）：血管生成成像在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方面具有相当大的前景。新的对比探针，如小分子放射性示踪剂，光学探针，脂质和聚合物基纳米颗粒被广泛研究，以针对血管生成的不同生物标志物。然而，低组织浓度的预期生物标志物，缺乏放大策略来增加信号输出，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。该应用的长期目标是开发一套基于homo荧光共振能量转移（homoFRET）和光诱导电子转移（PET）机制的可调谐荧光纳米探针。在正常的生理条件下（如血液循环），胶束纳米探针在最小的背景信号下保持沉默（或处于关闭状态）。在特异性靶向血管生成靶点（如avb3）后，这些纳米探针可以在受体介导的内吞作用后，通过内核体/溶酶体内的pH激活（pH 5.0-7.2）开启。我们的中心假设是，肿瘤内皮的信号放大和血液和ph活化胶束（pHAM）纳米探针的背景抑制的协同策略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敏感性和特异性。为了验证这一假设，我们将进行以下具体目标：(1)建立一系列具有可调跃迁pH （pHt）的近红外（NIR） pHAM纳米探针；(2)评价非靶向pHAM在酸性肿瘤微环境中的活化作用；(3)在肿瘤内皮细胞中建立血管靶向pHAM，研究这些纳米探针在细胞内的活化作用；(4)评估靶向pHAM在荷瘤小鼠体内不同血管生成生物标志物（如VEGFR2、avb3）成像中的特异性和有效性。这项研究的成功实施将使pHAM成为一个有价值的成像平台，用于在体内对肿瘤内皮细胞上血管生成特异性生物标志物进行成像。这些纳米探针对于分子靶向抗血管生成疗法的疗效评估可能特别有用，其中治疗靶点（例如VEGFR2， avb3）的表达水平可以直接测量。

项目成果

Synthetic nanovaccines for immunotherapy.

• DOI: 10.1016/j.jconrel.2017.03.033
• 发表时间: 2017-10-10
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Luo M;Samandi LZ;Wang Z;Chen ZJ;Gao J
• 通讯作者: Gao J

Innate Immune Activation by cGMP-AMP Nanoparticles Leads to Potent and Long-Acting Antiretroviral Response against HIV-1.

• DOI: 10.4049/jimmunol.1700972
• 发表时间: 2017-12-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Aroh C;Wang Z;Dobbs N;Luo M;Chen Z;Gao J;Yan N
• 通讯作者: Yan N