Targeted Hyperpolarized Molecular Beacons for Colorectal Cancer Detection

摘要 结直肠癌是美国第三大死亡原因。早期诊断是癌症的核心 在乎通常，使用现有技术只能对大于5 mm的肿瘤进行成像，限制了早期诊断的能力。 诊断.我们提出的结构，“超极化分子信标”，将显着增加的能力， 通过利用几个扩增步骤并结合通用的结合亲和力和特异性来检测癌症， 超极化磁共振（HP MR）灵敏度的抗体。抗体具有高亲和力 他们的蛋白质靶点，其中一些被批准用于癌症治疗。超极化分子信标 利用基于抗体的分子靶向和杠杆作用> 10，000倍的灵敏度增强通过超极化 MR技术为结直肠癌的早期诊断提供了一种高灵敏度的方法。在HP分子信标中， 抗体附着于催化超极化小分子转化的蛋白质;因此， 超极化化合物的代谢物仅在报道分子存在下观察到。我们将附上 一种基于植物的蛋白质连接到识别人粘蛋白（MUC 1）的抗体的N末端。MUC1 蛋白质与结直肠癌的肿瘤增殖、侵袭和转移正相关。我们 所提出的MUC 1抗体特异性识别MUC 1的大部分。HP分子信标 通过多个MUC 1抗体与一个MUC 1蛋白结合，催化扩增， 通过使用超极化来增强信号。因此，我们将创造一个高亲和力 MUC 1靶向超极化分子信标，评估其在动物模型中检测结直肠癌的能力 并将HP分子信标库扩展到其他细胞表面标记，以开发多路复用的 分子信标，以识别不同患者人群中的结直肠癌表型的全部库。 这种方法将显著提高MRI中靶向分子成像的能力， 在不同的癌症系统中容易与其他抗体复制。

ABSTRACT Colorectal cancer is the third leading cause of death in the United States. Early diagnosis is central to cancer care. Often, only tumors greater than 5 mm can be imaged using existing technologies, limiting the ability of early diagnosis. Our proposed constructs, "hyperpolarized molecular beacons,” will significantly increase the ability of detecting cancer by utilizing several amplification steps and combining the versatile binding affinity and specificity of antibodies with the sensitivity of hyperpolarized Magnetic Resonance (HP MR). Antibodies have high affinity to their protein targets, and several are approved for cancer treatment. Hyperpolarized molecular beacons will utilize antibody based molecular targeting and leverage >10,000-fold sensitivity enhancement by hyperpolarized MR technique to create a highly sensitive early detection method forcolorectal cancer. In a HP molecular beacon, an antibody is attached to a protein that catalyzes the conversion of hyperpolarized small molecules; therefore, metabolites of the hyperpolarized compounds are only observed in the presence of the reporter. We will attach a plant based protein to the N-terminus of an antibody that recognizes human mucin protein (MUC1). MUC1 protein positively correlates with tumor proliferation, invasiveness, and metastasis in colorectal cancer. Our proposed MUC1 antibody specifically recognizes a large section of MUC1. The HP molecular beacon will enhance signal amplitude through multiple MUC1 antibodies binding to one MUC1 protein, catalytic amplification of the signal and enhancement through the use of hyperpolarization. We will therefore, create a high affinity MUC1 targeted hyperpolarized molecular beacon, evaluate its ability to detect colorectal cancer in animal models and will expand the repertoire of HP molecular beacons to other cell surface markers to develop a multiplexed molecular beacon to recognize the full repertoire of colorectal cancer phenotypes in diverse patient populations. This methodology will significantly increase the capability of targeted molecular imaging in MRI and can be readily replicated with other antibodies in different cancer systems.