(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(申请人提供)：目前的活体成像设备可以检测到1毫米3大小的肿瘤，即107个细胞。能够检测到比目前可能的肿瘤小2-3个数量级的微小肿瘤的能力将对癌症的治疗产生深远的影响，因为早期检测癌症对于增加患者的生存机会以及检测现有癌症患者的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属性的化学探针，例如过度表达的表面抗原或增强的血管通透性。血管生成开关，即肿瘤生长到足以诱导局部血管生成，从而增加局部血管通透性的现象，发生在肿瘤大小约1-2mm3时。因此，目前的靶向分子成像方法在血管生成开关被激活后，固有地检测到大于1mm3的肿瘤。我们独特而创新的癌症检测方法是使用MRI追踪单核细胞和间充质干细胞(MSCs)在非常小的肿瘤中的渗透情况。事实上，在肿瘤发生的最早阶段，单核细胞和间充质干细胞的浸润是其特点。基于MRI的细胞跟踪已被证明有助于可视化细胞在体内对多种损伤和疾病模型的渗透。简而言之，细胞可以在体外或直接在 在活体中使用磁性粒子，通过局部调制磁共振成像图像生成背后的物理机制来实现对它们的检测。我们率先将临床上可行的、可生物降解的微米级氧化铁颗粒(MPIO)用于细胞MRI。由于MPIO的负载效率，可以用非常高的铁水平标记细胞，从而能够在动物体内检测到单个细胞。因此，我们希望开发一种使用MRI来灵敏和特异地检测少量浸润性细胞，识别非常小的肿瘤的方案。癌症的早期发现 对于提高患者的存活率以及检测现有癌症患者中更多和更小的转移至关重要。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好的血脑屏障后面的小肿瘤，那么同样的细胞很可能会渗透到身体其他部位的肿瘤中。因此，当我们在这项提案中研究胶质瘤时，该方案可以扩大到研究不同的癌症类型。这项拟议工作最具原创性的方面是我们对肿瘤检测的根本不同的方法。我们没有使用有针对性的化学试剂，而是依靠两种不同类型细胞的已知和证明的营养行为来检测非常小的肿瘤。本质上，这些细胞为您做了艰苦的工作，穿透大脑并迁移到正确的位置，再加上我们在体内的单细胞检测能力，我们预计将超过107个细胞或1 mm3肿瘤的检测极限2-3个数量级。在人类中基于MRI的细胞跟踪正在被接受，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。