(PQC5) MRI of magnetically labeled immune/stem cells for early tumor detection

(PQC5) 磁性标记免疫/干细胞的 MRI 用于早期肿瘤检测

• 批准号: 8686986
• 负责人: Erik Shapiro
• 金额: $ 21.05万
• 依托单位: MICHIGAN 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: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8686986
• 关键词: Angiogenic Switch; Animals; Area; Behavior; Biology; Brain; Brain Neoplasms; Cancer Detection; Cell Count; Cells; Chemical Agents; Chemicals; Clinical; Clinical Research; Coupled; Detection; Diffusion; Disease; Disease model; Distal; Drops; Early Diagnosis; Endothelial Cells; Environment; Generations; Genetic Models; Glioma; Grant; Hepatic Stellate Cell; Histology; Home environment; Human; Image; Immune; In Vitro; Infiltration; Injury; Iron; Label; Location; Magnetic Resonance Imaging; Magnetism; Malignant Neoplasms; Mesenchymal Stem Cells; Methodology; Modeling; Monitor; Motivation; Neoplasm Metastasis; Particle Size; Patients; Penetration; Permeability; Physics; Property; Protocols documentation; Publications; Rattus; Reporting; Roentgen Rays; Role; Route; Screening for cancer; Sensitivity and Specificity; Signal Transduction; Staging; Stem cells; Surface Antigens; Survival Rate; Therapeutic; Therapeutic Intervention; Time; Tissues; Ultrasonography; Vascular Permeabilities; Work; angiogenesis; base; cancer diagnosis; cancer therapy; cancer type; cell type; clinical practice; design; imaging modality; in vivo; in vivo imaging; innovation; iron oxide; macrophage; molecular imaging; monocyte; nanometer; nanoparticle; overexpression; particle; prevent; public health relevance; research study; success; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Current in vivo imaging modalities can detect tumors of 1 mm3 size, or 107 cells. The ability to detect very small tumors, 2-3 orders of magnitude smaller than currently possible (104 - 105 cells; 0.001 - 0.01 mm3), would have a profound impact on cancer treatment as early detection of cancer is critical both for increasing survival chances of the patient, as well as for also detecting more and smaller metastases in patients with existing cancer. The typical molecular imaging approach to detecting cancer is to use a chemical probe targeted against some phenotypic property, such as an overexpressed surface antigen, or enhanced vascular permeability. The angiogenic switch, the phenomenon by which the tumor grows large enough to induce local angiogenesis, and hence increases the permeability of the local vasculature, occurs at tumor size ~ 1-2 mm3. As such, current targeted molecular imaging approaches inherently detect tumors larger than 1 mm3, after the angiogenic switch has been activated. Our unique and innovative approach for detection of cancer is to use MRI to track the infiltration of monocytes and mesenchymal stem cells (MSCs) into very small tumors. Indeed, tumorigenesis, in its earliest stages, is marked by monocyte and MSC infiltration. MRI-based cell tracking has proven useful for visualizing the infiltration of cells ito numerous injury and disease models, in vivo. In short, cells can be labeled in vitro or directly in vivo with magnetic particles, enabling their detection by locally modulating the physics behind image generation in MRI. We have pioneered the use of clinically viable, biodegradable micron sized particles of iron oxide (MPIOs) for cellular MRI. Due to the loading efficiency of MPIOs, cells can be labeled with very high iron levels, allowing the detection of single cells in vivo in animals. Hence, we expect to develop a protocol for using MRI to sensitively and specifically detect low numbers of infiltrating cells, identifying very small tumors. Early detection of cancer is critical for increasing survival of the patient, as well as for also detecting more and smaller metastases in patients with existing cancer. If indeed magnetically labeled monocytes and MSCs can target small tumors behind the intact BBB, then there would be a high likelihood that the same cells can infiltrate tumors in other areas of the body. Thus, while we are studying glioma in this proposal, the protocol could be broadened to investigate different cancer types. The most original aspect of the proposed work is our fundamentally different approach to tumor detection. Rather than using targeted chemical agents, we are relying on the known and demonstrated trophic behaviors of 2 different cell types, to detect very small tumors. In essence, the cells do the hard work for you, in penetrating the brain and migrating to the correct locations Coupled with our in vivo single cell detection capabilities, we expect to beat the detection limit f 107 cells, or 1 mm3 tumors by 2-3 orders of magnitude. MRI-based cell tracking in humans is gaining acceptance, and if successful, the MRI protocols we propose here for early tumor detection in rats have potential in humans.

描述（由申请人提供）：目前的体内成像模式可以检测1 mm 3大小或107个细胞的肿瘤。检测非常小的肿瘤（比目前可能的小2-3个数量级（104 - 105个细胞; 0.001 - 0.01mm3））的能力将对癌症治疗产生深远的影响，因为癌症的早期检测对于增加患者的存活机会以及检测患有现有癌症的患者中更多和更小的转移都是至关重要的。检测癌症的典型分子成像方法是使用针对某些表型特性的化学探针，例如过表达的表面抗原或增强的血管通透性。血管生成转换是肿瘤生长到足以诱导局部血管生成的现象，因此增加了局部血管系统的渗透性，发生在肿瘤大小约1-2 mm 3时。因此，在血管生成开关被激活后，目前的靶向分子成像方法固有地检测大于1 mm 3的肿瘤。 我们独特而创新的癌症检测方法是使用MRI跟踪单核细胞和间充质干细胞（MSC）向非常小的肿瘤中的浸润。事实上，肿瘤发生在其最早阶段以单核细胞和MSC浸润为标志。基于MRI的细胞跟踪已被证明可用于可视化细胞浸润到许多损伤和疾病模型，在体内。简而言之，可以在体外或直接在细胞中标记细胞。 体内的磁性粒子，使他们的检测，通过局部调制背后的MRI图像生成的物理。我们率先使用临床上可行的，可生物降解的氧化铁（MPIO）微米级颗粒进行细胞MRI。由于MPIO的负载效率，细胞可以用非常高的铁水平标记，从而允许在动物体内检测单细胞。因此，我们希望开发一种使用MRI敏感和特异性检测少量浸润细胞的方案，以识别非常小的肿瘤。 早期发现癌症 对于增加患者的存活率，以及对于检测患有现有癌症的患者中更多和更小的转移是至关重要的。如果磁性标记的单核细胞和间充质干细胞确实可以靶向完整的血脑屏障后面的小肿瘤，那么同样的细胞很可能会浸润身体其他区域的肿瘤。因此，当我们在这项提案中研究神经胶质瘤时，该方案可以扩展到研究不同的癌症类型。这项工作最具原创性的方面是我们从根本上不同的肿瘤检测方法。我们不使用靶向化学试剂，而是依赖于2种不同细胞类型的已知和已证实的营养行为来检测非常小的肿瘤。从本质上讲，细胞为您做艰苦的工作，穿透大脑并迁移到正确的位置再加上我们的体内单细胞检测能力，我们预计将超过107个细胞或1 mm 3肿瘤的检测限2-3个数量级。基于MRI的人类细胞跟踪正在获得认可，如果成功，我们在这里提出的用于大鼠早期肿瘤检测的MRI方案在人类中具有潜力。