Smart Probes for Imaging Cancer

描述(由申请人提供)： 非侵入性活体成像技术可以极大地方便癌症的检测和治疗。如果体内成像方法能够与治疗无缝结合，那么它们就是最有效的。我们建议开发一种使用变构适配子的新型成像系统，该系统可以交替使用来浓缩癌细胞周围的显像剂或药物。 我们的基于适配子的设计被称为夹具(用于医疗或微量分析程序的顺式/墨迹适配子)。钳为开发变构适配子提供了基本结构，其中一个适配子靶标与钳结合导致位于钳分子另一部分的另一个适配子被激活。第二，激活的适体可以与显像剂或治疗剂结合。 由于HER2是表皮生长因子受体家族中的一员，在许多癌症中都有高表达，因此它将成为SELEX开发新适体的靶点。筛选和优化的HER2适配子将用作钳夹中的变构适配子。因此，HER2与细胞表面的结合将激活第二适配子，该适配子与附着在菊粉等聚合物上的显像剂结合。 变构钳有望为成像提供以下优点：1)由于DNA的小尺寸，相对较快的肾脏清除；2)靶细胞的缓慢释放速率。释放率是价态的反函数。如果细胞表面有多个紧密定位的夹子，就会产生多价区域与靶向显像剂结合，从而导致缓慢的释放速率。 由于夹子将癌细胞表面连接到另一个分子，夹子成像技术可以与多肽前体药物疗法无缝对接，在这种疗法中，蛋白酶的多肽底物被降解，以释放有毒药物。转移癌细胞周围高浓度的蛋白酶，再加上夹子将前体药物集中在细胞周围的能力，将产生与成像无缝结合的更有效的治疗方法。

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.