Pre-clinical quantitation of ovarian cancer tumor burden using Magnetic Particle Imaging and non-dilutive cell labeling

描述（由申请人提供）：卵巢癌是妇科癌症导致死亡的主要原因，并且经常在晚期出现，此时它已经转移到整个腹膜腔。靶向这些转移性肿瘤的新化疗策略的开发已经取得了重大进展，然而临床前研究无法无创和准确地测量肿瘤负荷。我们建议开发一种新的成像技术，结合两个新兴的和互补的技术，磁粒子成像（MPI）和磁内共生体（ME）。前者是一种新型的成像扫描仪，能够在零背景下对铁进行深层组织成像，这使得它在MRI由于无法区分铁与正常解剖特征而难以区分的情况下具有价值。后者是一类新的用于标记和跟踪细胞的造影剂，基于富铁趋磁细菌，具有潜在的 以解决通过细胞分裂稀释造影剂的长期问题。该组合将允许基于注射外源性肿瘤细胞的临床前肿瘤模型在体内跟踪整个身体的几代细胞，而不考虑局部生理学。首先，我们计划优化MPI硬件，使其适应趋磁细菌的特定特性（目标1），通过改变激发频率（考虑到磁小体的较长旋转时间）和检测电子器件（以提高灵敏度）。同时，我们将对ME进行基因工程改造，以产生磁小体（含铁细胞器），这些磁小体具有有效MPI所需的最佳尺寸和形状（目标2）。初步结果表明，通过这些修改，应该可以定量监测卵巢癌小鼠动物模型中的癌症植入、生长、转移和药物反应，我们计划在目标3中对此进行评估。我们预计MRI（用于解剖参考）和MPI（用于铁的高灵敏度检测）的组合将产生信息丰富的体内图像数据，可用于量化转移性卵巢肿瘤负荷，并且也适用于涉及干细胞或肿瘤细胞的其他临床前细胞跟踪应用。

DESCRIPTION (provided by applicant): Ovarian cancer is the primary cause of mortality resulting from gynecological cancer, and frequently presents at a late stage when it has metastasized throughout the peritoneal cavity. There has been significant progress in the development of new chemotherapeutic strategies to target these metastatic tumors, however pre-clinical studies suffer from an inability to non-invasively and accurately measure the tumor burden. We propose to develop a new imaging technique that combines two emergent and complementary technologies, Magnetic Particle Imaging (MPI) and Magneto- Endosymbionts (MEs). The former is a new type of imaging scanner that enables deep- tissue imaging of iron with zero background, making it valuable in cases where MRI would struggle due to an inability to differentiate iron from normal anatomic features. The latter is a new class of contrast agent for labeling and tracking cells, based on iron-rich magnetotactic bacteria, which has the potential to solve a long-standing issue of contrast agent dilution through cell division. The combination will allow preclinical tumor models based on injection of exogenous tumor cells to be tracked in vivo for several cell generations throughout the body, irrespective of local physiology. First we plan to optimize the MPI hardware to adapt it to the specific properties of magnetotactic bacteria (Aim 1), by changing the excitation frequency (to take into account the longer rotational times of magnetosomes) and detection electronics (to improve sensitivity). Concurrently, we will genetically engineer MEs to produce magnetosomes (iron containing organelles) which are at the optimal size and shape required for efficient MPI (Aim 2). Preliminary results suggest that with these modifications it should be possible to quantitatively monitor cancer implantation, growth, metastases, and pharmaceutical response in a mouse animal model of ovarian cancer, and we plan to evaluate this in Aim 3. We expect that a combination of MRI (for an anatomic reference) and MPI (for high sensitivity detection of the iron) will produce information-rich in vio image data that can be used to quantify metastatic ovarian tumor burden, and which will also be applicable for other preclinical cell tracking applications involving stem or tumor cells.