(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）：当前的体内成像方式可以检测1 mm3大小或107个细胞的肿瘤。检测到非常小的肿瘤的能力，比目前可能小的2-3个数量级（104-105个细胞； 0.001-0.01 mm3），将对癌症治疗产生深远的影响，因为早期发现癌症对于增加患者的存活机会以及在现有癌症患者中发现更多和较小的转移酶的生存机会至关重要。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，例如表面过表达的表面抗原或增强的血管渗透性。血管生成开关是肿瘤生长足够大以诱导局部血管生成的现象，因此增加了局部脉管系统的渗透性，发生在肿瘤大小〜1-2 mmm3处。因此，在激活血管生成开关后，当前的靶向分子成像方法固有地检测到大于1 mm3的肿瘤。 我们检测癌症的独特而创新的方法是使用MRI跟踪单核细胞和间质干细胞（MSC）的浸润到很小的肿瘤中。实际上，在最早的阶段，肿瘤发生以单核细胞和MSC浸润为特征。事实证明，基于MRI的细胞跟踪对于可视化细胞的渗透ITO众多损伤和疾病模型在体内有用。简而言之，可以在体外或直接标记细胞 带有磁性颗粒的体内，通过局部调节MRI图像产生背后的物理学来实现其检测。我们率先使用了临床上可行的可生物降解的微米大小的氧化铁（MPIO）颗粒作为细胞MRI。由于MPIO的负载效率，可以将细胞用非常高的铁水平标记，从而使动物体内单个细胞的检测。因此，我们期望开发一种使用MRI敏感和特异性检测浸润细胞数量少的方案，从而鉴定出非常小的肿瘤。 癌症的早期检测 对于增加患者的生存率以及在现有癌症患者中发现更多和较小的转移至关重要。如果确实具有磁性标记的单核细胞和MSC可以瞄准完整BBB后面的小肿瘤，那么相同细胞可以在体内其他区域浸润肿瘤的可能性很高。因此，尽管我们正在研究该提案中的神经胶瘤，但可以扩大方案以研究不同的癌症类型。拟议工作的最原始方面是我们从根本上不同的肿瘤检测方法。我们没有使用靶向化学剂，而是依靠已知和证明的2种不同细胞类型的营养行为来检测非常小的肿瘤。从本质上讲，细胞在穿透大脑并迁移到正确的位置与我们的体内单细胞检测能力相结合时，这些细胞为您付出了艰苦的工作，我们期望以2-3个尺寸的级别击败检测极限F 107细胞，或1 mm3肿瘤。人类基于MRI的细胞跟踪正在获得接受，如果成功，我们在这里提出的MRI方案在大鼠的早期肿瘤检测中具有潜力。