Targeted Hyperpolarized Molecular Beacons for Colorectal Cancer Detection

用于结直肠癌检测的靶向超极化分子信标

• 批准号: 10696093
• 负责人: Pratip K. Bhattacharya
• 金额: $ 20.25万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10696093
• 关键词: Acids; Affinity; Ammonia; Animal Cancer Model; Animal Model; Animals; Antibodies; Antibody Affinity; Antibody Specificity; Binding; Biological Assay; Biological Markers; Blood Circulation; Blood Vessels; Cancer Detection; Carbon; Carbon Dioxide; Cause of Death; Cell surface; Circulation; Colorectal Cancer; Detection; Diameter; Early Diagnosis; Enzymes; Event; Hour; Human; Hydrolysis; Image; Label; Lesion; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Neoplasms; Membrane Glycoproteins; Metabolic; Methodology; Molecular; Molecular Target; Mucins; National Institute of Biomedical Imaging and Bioengineering; Neoplasm Metastasis; Phenotype; Plants; Prognosis; Proliferating; Proteins; Reaction; Relaxation; Reporter; Signal Transduction; Site; System; Tandem Repeat Sequences; Techniques; Technology; Time; Tissue imaging; United States; Urea; Urease; cancer care; cancer therapy; colorectal cancer screening; detection method; detection sensitivity; experimental study; extracellular; in vivo imaging; innovation; interest; molecular imaging; nanoparticle; patient population; patient prognosis; receptor; small molecule; spectroscopic imaging; tumor

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.

抽象的 结直肠癌是美国第三大死亡原因，早期诊断对于癌症至关重要。 通常，使用现有技术只能对大于 5 毫米的肿瘤进行成像，这限制了早期诊断的能力。 我们提出的“超极化分子信标”结构将显着提高诊断能力。 通过利用多个扩增步骤并结合多功能结合亲和力和特异性来检测癌症 具有超极化磁共振 (HP MR) 敏感性的抗体具有高亲和力。 超极化分子信标将用于癌症治疗。 利用基于抗体的分子靶向，并利用超极化使灵敏度提高 >10,000 倍 MR 技术创建了一种高灵敏度的结直肠癌早期检测方法 在 HP 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； 超极化化合物的代谢物仅在报告者存在的情况下才能观察到，我们将附上。 一种植物蛋白连接到识别人粘蛋白蛋白 (MUC1) 的抗体的 N 端。 蛋白质与结直肠癌的肿瘤增殖、侵袭性和转移呈正相关。 提出的 MUC1 抗体特异性识别 MUC1 的大部分 HP 分子信标。 通过多种 MUC1 抗体与一种 MUC1 蛋白结合，催化放大，增强信号幅度 因此，我们将通过使用超极化来增强信号和增强亲和力。 MUC1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 并将将 HP 分子信标的全部范围扩展到其他细胞表面标记，以开发多路复用 分子信标可识别不同患者群体中结直肠癌表型的全部信息。 该方法将显着提高 MRI 中靶向分子成像的能力，并且可以 很容易在不同的癌症系统中与其他抗体一起复制。

项目成果

Post-Acquisition Hyperpolarized 29Silicon Magnetic Resonance Image Processing for Visualization of Colorectal Lesions Using a User-Friendly Graphical Interface.

使用用户友好的图形界面进行采集后超极化 29 硅磁共振图像处理，实现结直肠病变的可视化。

• 发表时间: 2022-03-01
• 作者: McCowan, Caitlin V;Salmon, Duncan;Hu, Jingzhe;Pudakalakatti, Shivanand;Whiting, Nicholas;Davis, Jennifer S;Carson, Daniel D;Zacharias, Niki M;Bhattacharya, Pratip K;Farach
• 通讯作者: Farach