Smart Probes for Imaging Cancer

用于癌症成像的智能探针

• 批准号: 6615949
• 负责人: RICHARD T HAMILTON
• 金额: $ 10.7万
• 依托单位: APTALOGIC, INC
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6615949
• 关键词: bioimaging /biomedical imaging; biomedical equipment development; biotechnology; imaging /visualization /scanning; neoplasm /cancer diagnosis; noninvasive diagnosis; nucleic acid probes; nucleic acid sequence; oligonucleotides; oncogenes; peptides; prodrugs; technology /technique development

DESCRIPTION (provided by applicant): Detection and treatment of cancer can be greatly facilitated by noninvasive in vivo imaging techniques. In vivo imaging methods are most effective if they can be seamlessly tied to therapies. We propose to develop a novel imaging system using allosteric aptamers that can be used alternately to concentrate either an imaging agent or a drug around a cancer cell. Our aptamer-based design is referred to as a CLAMP (cis-/inked aptamers for medical or microanalytical procedures). CLAMPs provide the basic structure for developing allosteric aptamers in which the binding of one aptamer target to the CLAMP results in activation of another aptamer that is located in another part of the CLAMP molecule. The second, activated aptamer can then bind an imaging agent or a therapeutic agent. Because of HER2, a member of the epidermal growth factor receptor family, is highly expressed in many cancers, it will be the target for evolving a new aptamer by SELEX. The selected and optimized HER2 aptamer will be used as the allosteric aptamer in the CLAMP. Thus, binding of HER2 to the cell surface will activate the second aptamer that binds the imaging agent which is attached to a polymer such as inulin. The allosteric CLAMPs are expected to provide the following advantages for imaging: 1) relatively rapid renal clearance due to the small size of the DNA and 2) slow release rates from the target cells. Release rates are an inverse function of the valency. The availability of more than one closely located CLAMP on the cell surface will create multivalent regions for binding to the targeted imaging agent, resulting in slow release rates. Because the CLAMP will link the cancer cell surface to another molecule, the CLAMP imaging technology can be seamlessly interfaced with peptide prodrug therapies in which the peptide substrates of proteases are degraded to release a toxic drug. The high concentration of proteases that surround metastatic cancer cells, combined with the ability of the CLAMP to concentrate the prodrug around the cells, will result in more effective therapies that are seamless with imaging.

描述（由申请人提供）： 非侵入性体内成像技术可以极大地促进癌症的检测和治疗。如果体内成像方法可以与治疗无缝结合，那么它们是最有效的。我们建议开发一种新的成像系统，使用变构适体，可以交替使用，以集中无论是成像剂或药物周围的癌细胞。 我们的基于适体的设计被称为CLAMP（用于医学或微量分析程序的顺式/连接适体）。CLAMP提供了用于开发变构适体的基本结构，其中一种适体靶标与CLAMP的结合导致位于CLAMP分子的另一部分中的另一种适体的活化。然后，第二活化适体可以结合成像剂或治疗剂。 由于表皮生长因子受体家族的成员HER 2在许多癌症中高度表达，因此它将成为通过SELEX进化新适体的靶点。选择和优化的HER 2适体将用作CLAMP中的变构适体。因此，HER 2与细胞表面的结合将激活结合成像剂的第二适体，所述成像剂附着于聚合物如菊粉。 预期变构CLAMP为成像提供以下优点：1）由于DNA的小尺寸，相对快速的肾清除和2）从靶细胞的缓慢释放速率。释放速率是化合价的反函数。细胞表面上多于一个紧密定位的CLAMP的可用性将产生用于结合靶向成像剂的多价区域，导致缓慢的释放速率。 由于CLAMP将癌细胞表面连接到另一个分子，CLAMP成像技术可以与肽前药疗法无缝连接，其中蛋白酶的肽底物被降解以释放有毒药物。围绕转移性癌细胞的高浓度蛋白酶，结合CLAMP将前药集中在细胞周围的能力，将导致更有效的治疗，与成像无缝。