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

描述(申请人提供)：早期发现超小癌症非常重要，特别是早期发现转移癌，可以用现有的治疗方法挽救乳腺癌患者的生命。开发临床可行的成像技术的三个核心问题是临床适用性、安全性和敏感性。我们建议开发一种新的细胞 MRI技术结合了MRI的时相开花效应、铁蛋白的特性以及某些细胞对肿瘤的趋向性效应，以同时解决这三个核心问题。在临床环境中，MRI是一种良好的影像检查方法。然而，为了通过MRI进行成像，细胞需要首先被MRI可检测的标签标记。铁蛋白具有独特的生物学和MRI特性，是一种理想的MRI标记。与只能被吞噬细胞自然内化的超顺磁性氧化铁(SPIO)纳米粒子不同，几乎所有活着的生物体中的细胞都有其与铁蛋白相互作用的自然方式，而铁蛋白有其天然的Wa来处理铁。与SPIO一样，铁蛋白可以储存大量的Fe3+(高达4500)，并且比传统造影剂在MRI上提供更强的对比效果。为了探测到比目前用常规MRI检测到的小两到三个数量级的超小目标，我们建议使用与磁化率相关的MR相位光晕效应。与MR震级信息不同的是，MR相位信息由于其对敏感性的高度敏感性而在很大程度上被丢弃，最近的研究集中在如何最小化/消除相晕效应或对T2*震级成像进行校正。我们建议做相反的事情：增强同相光晕效应，以探测超微小物体。基本的假设是，MR相晕效应可以在空间上扩展到物体原始大小的两到三个数量级。为了利用相位开花效应来检测肿瘤，我们需要在肿瘤内诱导特定的敏感性变化。初步研究表明，4T1-piPSCs(从乳腺癌4T1重新编程的蛋白诱导的多能干细胞)不仅可以迁移到原发肿瘤，还可以迁移到转移瘤，而不迁移到正常组织。为此，我们假设，通过注射QQ-铁蛋白标记的4T1-piPSCs，可以选择性地增强肿瘤的敏感性，产生开花效应，可以用于检测比目前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晕效应是原始物体的两到三个数量级，以及2)证明在体内成像比在4T1小鼠模型中检测到的超小物体小两到三个数量级的超小物体的可行性。虽然在本项目中只使用4T1-PIPSC作为测试细胞，但所提出的布隆效应和基于QQ铁蛋白的新型细胞磁共振技术是为未来所有类型的细胞成像而开发的，包括基于研究或临床证明具有趋向性效应的治疗细胞。

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.