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uPAR Targeted in Vivo Molecular Magnetic Resonance Imaging of....

uPAR 靶向体内分子磁共振成像......

基本信息

批准号：
8382624
负责人：
Hui Mao
金额：
$ 15.56万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8382624
关键词：
Address Affinity Anatomy Animals Area Arts Binding Biodistribution Biological Markers Biological Process Biomedical Engineering Blood Circulation Breast Cancer Cell Breast Cancer Detection Breast Cancer Early Detection Breast Cancer Model Cancer Biology Cancer Center Cancer Patient Cell Communication Cell Surface Receptors Cell surface Cells Chemicals Chemistry Clinical Clinical Oncology Contrast Media Contrast Sensitivity Data Detection Development Diagnostic Imaging Disease Distant Metastasis Drug Formulations Drug Kinetics Dyes Enhancers Epithelial Cells Funding Future Goals Human Image In Vitro Institutes Interdisciplinary Study Investigation Label Lead Liver Magnetic Resonance Imaging Magnetism Malignant Neoplasms Mammary Neoplasms Mammary gland Maps Medical Medical Imaging Methods Modeling Modification Molecular Molecular Target Mus Nanotechnology Neoplasm Metastasis Operative Surgical Procedures Organ Pathway interactions Peptide Fragments Peptides Plasma Play Polymers Primary Neoplasm Property Radiology Specialty Receptor Cell Relative (related person)Research Research Personnel Resolution Resources Role Sensitivity and Specificity Signal Transduction Specificity Spleen Surface Technology Testing Time Tissues Toxic effect Transgenic Mice Transgenic Organisms Translating Tumor Tissue Urokinase Urokinase Plasminogen Activator Receptor Work Xenograft Model Yang angiogenesis base biomaterial compatibility cancer cell cancer imaging carboxyl group cell motility chemical synthesis clinical Diagnosis clinical application cytotoxicity design experience imaging modality imaging probe improved in vivo iron oxide malignant breast neoplasm molecular imaging molecular/cellular imaging nanocrystal nanomaterials nanoparticle nanoprobe neoplastic cell novel oncology optical imaging outcome forecast particle receptor research study soft tissue surface coating tumor tumor xenograft uptake

项目摘要

Project #3 is developed to address the critical needs of novel molecular imaging approaches for early detection of breast cancer. We have identified a moleculer target, urokinase plasminogen activator receptor (uPAR) for receptor targeted MR imaging of breast cancer. uPAR is highly expressed in human breast cancer cells at levels of 14,000 to 500,000 uPAR/cell relative to 2,500/cell in normal mammary epithelial cells. An increased level of uPAR is considered to be associated with tumor aggressiveness, the presence of distant metastasis and poor prognosis. Previous studies have shown that the amino terminal fragment (ATF) peptide of uPAR is responsible for recognition and specific binding to the tumor cell. We propose to develop a uPAR-targeted paramagnetic iron oxide (IO) nanoparticle imaging probe for molecular Magnetic Resolnance Imaging (MRI) of breast cancer. This imaging strategy takes advantages of our experience and ability to produce the ATF in large quantity, our technology of formulating and synethsizing IO nanoparticles for optimal MRI contrast via T2- shortening effect and the chemistry of functionalizing particle surface for conjugating tumor targeting peptides. Given the capability of uPAR targeting with the ATF peptide and strong MRI contrast induced by IO nanoparticles, we hypothesize that this receptor-targeted MRI probe may lead to the accumulation of ATF conjugated IO nanoparticles in the tumor, producing sufficient contrast to detect tumors with elevated level of uPAR. Our preliminary data demonstrated that this breast cancer targeted molecular MRI can be achieved in a mouse mammary tumor model. Specific aims of this project are: 1) to optimize the method for conjugating the ATF peptide to IO nanoparticles and to examine the specificity of the uPAR targeted-imaging probe in normal and breast cancer cells in vitro; 2) to investigate the specificity and sensitivity of uPAR targeted ATF-IO nanoparticles in detection of breast cancer using mouse mammary tumor, human tumor xenograft, and transgenic tumor models; 3) to examine the biodistribution and toxicity of ATF-IO nanoparticles; and 4) to characterize MRI contrast properties of ATF-IO nanoparticles and to develop imaging methods appropriate for imaging of receptor targeted IO nanoprobes in vivo. It is anticipated that this tumor receptor-targeted MRI probe and imaging method can improve the specificity of breast cancer imaging be translated to clinical applications in the future.

项目 #3 的开发是为了满足早期新型分子成像方法的关键需求乳腺癌的检测。我们已经确定了一个分子靶标，尿激酶纤溶酶原激活剂用于乳腺癌受体靶向 MR 成像的受体 (uPAR)。 uPAR 高表达于人乳腺癌细胞的 uPAR 水平为 14,000 至 500,000 个/细胞，而正常细胞为 2,500 个/细胞乳腺上皮细胞。 uPAR 水平升高被认为与肿瘤相关侵袭性、远处转移的存在和预后不良。先前的研究表明 uPAR 的氨基末端片段 (ATF) 肽负责识别和特异性与肿瘤细胞结合。我们建议开发一种针对 uPAR 的顺磁性氧化铁 (IO) 用于乳腺癌分子磁共振成像 (MRI) 的纳米颗粒成像探针。这成像策略利用我们大量生产 ATF 的经验和能力，我们通过 T2- 配制和合成 IO 纳米粒子以实现最佳 MRI 对比度的技术用于结合肿瘤靶向的缩短效应和功能化颗粒表面的化学肽。鉴于 uPAR 具有 ATF 肽靶向能力和强 MRI 对比诱导通过 IO 纳米颗粒，我们假设这种受体靶向 MRI 探针可能会导致 ATF 结合的 IO 纳米粒子在肿瘤中积聚，产生足够的对比度以进行检测 uPAR 水平升高的肿瘤。我们的初步数据表明，这种乳腺癌靶向分子 MRI 可以在小鼠乳腺肿瘤模型中实现。本次活动的具体目标项目有： 1) 优化 ATF 肽与 IO 纳米粒子的缀合方法，并体外检查 uPAR 靶向成像探针在正常细胞和乳腺癌细胞中的特异性； 2) 研究uPAR靶向ATF-IO纳米粒子在检测中的特异性和敏感性使用小鼠乳腺肿瘤、人类肿瘤异种移植物和转基因肿瘤模型研究乳腺癌； 3）考察ATF-IO纳米颗粒的生物分布和毒性； 4) 表征 MRI ATF-IO 纳米颗粒的对比特性并开发适合成像的成像方法体内受体靶向IO纳米探针的研究。预计这种针对肿瘤受体的 MRI 探针影像学方法可以提高乳腺癌影像学的特异性并转化为临床未来的应用。