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）：血管生成成像对早期癌症的早期发现以及对许多新的分子靶向抗血管生成疗法的疗法具有相当大的希望。对新的对比探针，例如小分子放射性示例，光学探针以及基于脂质和聚合物的纳米颗粒，以靶向不同的生物学生物形象。但是，预期生物标志物的低组织浓度，缺乏增加信号输出的放大策略以及高背景信号是妨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基于Homo荧光共振能量转移（Homofret）和光诱导的电子传递（PET）机制，开发一组可调的荧光纳米探针。胶束纳米探针将在正常生理条件下（例如血液循环）保持沉默（或处于OFF状态）。在特定靶向血管生成靶标（例如AVB3）时，可以通过受体介导的内吞作用后内体/溶酶体内部/溶酶体内部pH激活（pH 5.0-7.2）打开这些纳米探针。我们的中心假设是，肿瘤内皮中信号扩增的协同策略以及血液和pH-激活胶束（PHAM）纳米探针的背景抑制将能够提高活体血管生物形成的血管生成生物形成的成像敏感性和特异性。为了检验这一假设，我们将执行以下特定目的：（1）建立一系列具有可调过渡pH（PHT）的近红外（NIR）PHAM纳米探针； （2）评估酸性肿瘤微环境中非靶向PHAM的激活； （3）建立靶向血管的PHAM并研究肿瘤内皮细胞中这些纳米探针的细胞内激活； （4）评估靶向PHAM在体内承重肿瘤小鼠中独特的血管生成生物形象成像（即VEGFR2，AVB3）成像中的特异性和功效。这项研究的成功执行将建立PHAM作为一个有价值的成像平台，以对体内肿瘤内皮上的血管生成 - 特定生物标志物进行图像。这些纳米探针可能对于分子靶向的抗血管生成疗法的有效评估特别有用，在该抗血管生成疗法中，可以直接测量治疗靶标的表达水平（例如VEGFR2，AVB3）。

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