(PQC5 in RFA-CA-12-020) Using MR phase to detect ferritin tagged breast cancer ce

（RFA-CA-12-020 中的 PQC5）利用 MR 相检测铁蛋白标记的乳腺癌细胞

• 批准号: 8684314
• 负责人: JIANI HU
• 金额: $ 19.84万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8684314
• 关键词: Address; Biological; Cancer Detection; Cancer Patient; Cells; Clinical; Complex; Contrast Media; Detection; Disseminated Malignant Neoplasm; Early Diagnosis; Ferritin; Fibroblasts; Figs - dietary; Future; Goals; Homing; Human; Image; Imaging Techniques; Iron; Label; Life; Magnetic Resonance Imaging; Malignant Neoplasms; Neoplasm Metastasis; Normal tissue morphology; Oncogenic; Organelles; Organism; Pattern; Phagocytes; Phase; Predisposition; Primary Neoplasm; Property; Proteins; Proto-Oncogene Proteins c-myc; Reagent; Research; Resolution; Safety; Signal Transduction; Site; Source; Stem cells; Techniques; Testing; Therapeutic; Time; Toxic effect; Tropism; Variant; Viral; base; cancer cell; cell type; clinical application; ferritin labeling; imaging modality; improved; in vitro Model; in vivo; in vivo imaging; induced pluripotent stem cell; iron oxide; malignant breast neoplasm; mouse model; nanoparticle; novel; public health relevance; tumor

DESCRIPTION (provided by applicant): Early detection of ultra-small cancer is important, particularly early metastatic cancer detection, and can save the lives of breast cancer patients with existing therapies. The three core issues in developing a clinically feasible imaging technique are clinical suitability, safety, and sensitivity. We propose to develop a novel cellular MRI technique that combines the MRI phase blooming effect, the property of ferritin, and the tropism effect of certain cells towards tumors to address these three core issues simultaneously. MRI is a favorable imaging modality in clinical settings. However, to be imaged by MRI, cells need to be labeled with MRI detectable tags first. Ferritin is an ideal MRI tag because of its unique biological and MRI properties. Unlike superparamagnetic iron oxide (SPIO) nanoparticles which can only be internalized natively by phagocytic cells, cells in almost all living organisms have their natural ways to interact with ferritin, and ferritin has its natural wa to deal with irons. Like SPIO, ferritin can store a large amount of Fe3+ (up to 4500) and offers stronger contrast effects on MRI than conventional contrast agents. To detect an ultra-small object that is two to three orders of magnitude smaller than those currently detected with conventional MRI, we propose to use the susceptibility related blooming effect of MR phase. Unlike MR magnitude information, MR phase information had been largely discarded due to its high sensitivity to susceptibility, and recent studies have been focused on how to minimize/remove phase blooming effects or to correct them for T2*-magnitude imaging. We propose to do just the opposite: enhancing blooming effects in phase to detect ultra-small objects. The underlying assumption is that the MR phase blooming effect can spatially extend to two to three orders of the original size of the object. To detect tumors using phase blooming effect, we need to induce a susceptibility change specifically within tumor. Preliminary study indicates the capability of 4T1-piPSCs (protein induced pluripotent stem cells reprogrammed from breast cancer line 4T1) to migrate to not only primary but also metastatic tumors without migrating to the normal tissues. To that end, we hypothesize that by injecting QQ-ferritin labeled 4T1-piPSCs the susceptibility in tumors can be selectively enhanced, creating blooming effects that can be utilized to detect tumors that are two to three orders of magnitude smaller than those currently detected with MRI. Our specific aims are: 1) to demonstrate the phase blooming effect is of two to three orders of the original object in in vitro models, and 2) to demonstrate te feasibility of imaging an ultra-small object that is two to three orders smaller than those currenty detected in a 4T1 mouse model in vivo. Although exclusively using 4T1-piPSC as the testing cell in this project, the proposed blooming effect and QQ ferritin based novel cellular MRI technique is developed for imaging all types of cells in the future, including research based or clinically proved therapeutic cells with tropism effects.

描述（由申请人提供）：超小肿瘤的早期检测非常重要，特别是早期转移性癌症检测，可以挽救现有治疗乳腺癌患者的生命。开发临床可行的成像技术的三个核心问题是临床适用性、安全性和灵敏度。我们建议开发一种新的细胞 MRI技术结合了MRI相位晕效应、铁蛋白的特性和某些细胞对肿瘤的向性效应，同时解决了这三个核心问题。MRI是临床环境中有利的成像模式。然而，要通过MRI成像，细胞需要首先用MRI可检测的标签进行标记。铁蛋白因其独特的生物学和MRI特性而成为理想的MRI标记物。与只能被吞噬细胞天然内化的超顺磁性氧化铁（SPIO）纳米颗粒不同，几乎所有生物体中的细胞都有其与铁蛋白相互作用的天然方式，而铁蛋白也有其处理铁的天然方式。与SPIO一样，铁蛋白可以储存大量的Fe 3+（高达4500），并在MRI上提供比传统造影剂更强的造影效果。为了检测比目前用常规MRI检测到的那些小两到三个数量级的超小对象，我们建议使用MR相位的磁化率相关的晕染效应。与MR幅度信息不同，MR相位信息由于其对磁化率的高灵敏度而在很大程度上被丢弃，并且最近的研究集中在如何最小化/去除相位模糊效应或针对T2* 幅度成像校正相位模糊效应。我们建议做相反的事情：在相位上增强开花效应以检测超小物体。基本假设是MR相位模糊效应可以在空间上延伸到对象的原始尺寸的两到三个数量级。为了利用相位开花效应检测肿瘤，我们需要在肿瘤内特异性地诱导敏感性变化。初步研究表明，4 T1-piPSC（从乳腺癌细胞系4 T1重编程的蛋白质诱导的多能干细胞）不仅能够迁移到原发性肿瘤，而且能够迁移到转移性肿瘤，而不会迁移到正常组织。为此，我们假设，通过注射QQ-铁蛋白标记的4 T1-piPSC，可以选择性地增强肿瘤的易感性，产生开花效应，可用于检测比目前用MRI检测到的肿瘤小两到三个数量级的肿瘤。我们的具体目标是：1）在体外模型中证明相位模糊效应是原始物体的两到三个数量级，以及2）证明在体内对比当前在4 T1小鼠模型中检测到的那些小两到三个数量级的超小物体成像的可行性。尽管在该项目中仅使用4 T1-piPSC作为测试细胞，但开发了所提出的基于开花效应和QQ铁蛋白的新型细胞MRI技术，用于在未来对所有类型的细胞进行成像，包括基于研究或临床证明的具有向性效应的治疗细胞。