Agents for Specific NMR and SQUID Imaging of Prostate Cancer

描述（由申请人提供）：我们将使用一种结合磁共振成像（MRI）和超导量子干涉器件（SQUID）成像的新型成像方法，开发用于前列腺癌检测和分期的急需的非侵入性磁显像剂。开发前列腺癌检测的新方法很重要，因为它是美国男性最常见的癌症之一，目前的检测方法导致多达40%的接受前列腺切除术的患者分期不准确。目前还没有一种影像学方法能够特异性地检测和分期囊外或转移性前列腺癌。我们的目标是通过开发基于磁性显像剂的敏感检测方法来解决这个问题，这种显像剂可以特异性地靶向并结合癌细胞。这些药物将由附着在超顺磁性氧化铁纳米颗粒（SPIONs）上的特定细胞表面识别配体组成，可以通过MRI和SQUID成像检测到。这些药物将靶向的细胞表面标记包括前列腺特异性膜抗原（PSMA）、前列腺干细胞抗原（PSCA）、神经紧张素受体（NTR）和与血管生成密切相关的整合素（α -v- β -3）。为了确定哪种药物对前列腺癌的特异性检测效果最好，我们将利用人类前列腺癌细胞系建立体外和体内生物学模型。这些标志物的表达水平将通过RT-PCR和流式细胞术在一系列人类前列腺癌细胞系（LNCaP、DU-145、PC-3和C4-2，以及从前列腺切除术标本中培养的细胞系）中进行评估。成像剂与这些细胞的结合将在体外通过MRI和SQUID进行测量，以选择能够为SQUID检测提供最佳MRI对比度和最高磁场的显像剂或显像剂组合。同样的细胞系将用于在裸鼠体内诱导原发性和转移性前列腺肿瘤，MRI和SQUID检测将用于确定这些静脉注射药物在体内定位和识别疾病的敏感性和特异性。这项工作将为我们的下一个目标：通过MRI和SQUID成像对人类原发性和转移性前列腺癌的检测和分期进行这些药物的临床试验提供全面的了解。通俗地说：我们的目标是开发一种方法来成像前列腺肿瘤，并确定他们是良性还是恶性的MRI。所提出的方法将比针活检更准确，侵入性更小。

DESCRIPTION (provided by applicant): We will develop critically-needed, non-invasive magnetic imaging agents for prostate cancer detection and staging, using a novel imaging approach that combines Magnetic Resonance Imaging (MRI) and Superconducting Quantum Interference Device (SQUID) imaging. Developing new methods for prostate cancer detection is important because it is one of the most common American-male cancers, and current detection methods result in inaccurate staging in as many as 40% of patients undergoing prostate resection. No imaging method currently exists which is specific for detecting and staging extracapsular or metastatic prostate cancer. We aim to address this problem by developing sensitive detection methods based on magnetic imaging agents that specifically target and bind to cancer cells. These agents will consist of specific cell surface recognition ligands attached to superparamagnetic iron oxide nanoparticles (SPIONs), which can be detected by both MRI and SQUID imaging. The cell surface markers these agents will target include Prostate Specific Membrane Antigen (PSMA), Prostate Stem Cell Antigen (PSCA), the Neurotensin Receptor (NTR), and an integrin intimately involved in angiogenesis (alpha-v-beta-3). To determine which agent performs the best for the specific detection of prostate cancer, we will develop in vitro and in vivo biological models, using human prostate cancer cell lines. Expression levels for these markers will be evaluated by RT-PCR and flow cytometry in a series of human prostate cancer cell lines (LNCaP, DU-145, PC-3, and C4-2, and lines developed in house from prostatectomy specimens). The binding of the imaging agents to these cells will be measured in vitro by MRI and SQUID to select the agents or combination of agents that will provide the best MRI contrast and the highest magnetic field for SQUID detection. The same cell lines will then be used to induce primary and metastatic prostate tumors in nude mice, and MRI and SQUID detection will be used to determine the sensitivity and specificity of these intravenous agents for locating and identifying disease in vivo. The proposed work will provide the thorough understanding needed for our next goal: clinical trials of these agents for the detection and staging of primary and metastatic prostate cancer in humans by MRI and SQUID imaging. Lay terms: We aim to develop a method to image prostate tumors and determine whether they are benign or cancerous using MRI. The proposed method would be more accurate and less invasive than needle biopsy.