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

描述（由申请人提供）：目前的体内成像方式可以检测到1mm3大小的肿瘤，或107个细胞。检测非常小的肿瘤的能力，比目前可能的小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，因为癌症的早期检测对于增加患者的生存机会至关重要，对于在现有癌症患者中检测更多和更小的转移也是至关重要的。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，例如过度表达的表面抗原或增强的血管通透性。血管生成开关（angiogenesis switch）是指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，发生在肿瘤大小为1-2 mm3的地方。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跟踪单核细胞和间充质干细胞（MSCs）向非常小的肿瘤的浸润。事实上，肿瘤发生在其早期阶段，以单核细胞和间充质浸润为特征。基于核磁共振成像的细胞跟踪已被证明可用于可视化细胞在许多损伤和疾病模型中的浸润。简而言之，细胞可以在体外或直接在体内进行标记

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.