Targeted Hyperpolarized Molecular Beacons for Colorectal Cancer Detection

摘要 在美国，结直肠癌是第三大死因。早期诊断是癌症的核心 关心。通常，只有大于5毫米的肿瘤才能使用现有技术进行成像，这限制了早期诊断的能力。 诊断。我们提出的“超极化分子信标”结构将显著提高 利用多个扩增步骤并结合多种结合亲和力和特异性来检测癌症 具有超极化磁共振(HP MR)敏感性的抗体。抗体具有很高的亲和力 他们的蛋白质靶点，还有几个被批准用于癌症治疗。超极化分子信标将 利用基于抗体的分子靶向和杠杆&GT；通过超极化将灵敏度提高10,000倍 磁共振技术创造了一种高灵敏的结直肠癌早期检测方法。在惠普分子信标中， 抗体附着在催化超极化小分子转化的蛋白质上；因此， 超极化化合物的代谢物只有在报告者存在的情况下才能观察到。我们会附上 一种以植物为基础的蛋白质，位于抗体的N端，可识别人类粘蛋白(MUC1)。MUC1 蛋白与结直肠癌的肿瘤增殖、侵袭和转移呈正相关。我们的 建议的MUC1抗体可特异性识别很大一部分MUC1。惠普分子信标将 通过多个MUC1抗体与一个MUC1蛋白结合来增强信号幅度，催化扩增 通过使用超极化的信号和增强。因此，我们将创造一个高度亲和力的 MUC1靶向超极化分子信标，评价其在动物模型中检测结直肠癌的能力 并将HP分子信标的谱系扩展到其他细胞表面标记，以开发多重 分子灯塔，以识别不同患者群体中结直肠癌表型的全部谱系。 这种方法将显著提高核磁共振靶向分子成像的能力，并可以 在不同的癌症系统中很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.