pHLIP-based agents for pre-, intra-, and post-operative imaging and therapy of br

描述（由申请人提供）：乳腺癌是美国女性癌症相关死亡的第二大原因，但也是美国女性中最常见的癌症。确定患者的肿瘤增殖程度仍然是一个未满足的临床需求。有时，需要多次扫描和活检来确定肿块是否扩大或仅仅是正常的。目前的扫描利用分子显像剂靶向癌组织上过表达的细胞表面受体。这些细胞表面受体在非癌组织中也以较低的丰度存在。最常用的PET放射性药物[18F]-FDG已被用于确定哪些细胞以比其他细胞更高的速率消耗葡萄糖，但也会在葡萄糖代谢升高的健康组织中被吸收。pH（低）插入肽（pHLIP）不利用细胞表面受体或常见的代谢途径，而是专门针对细胞外pH值低的细胞，这是所有癌细胞的共同特征philip是细菌视紫红质蛋白的一部分，在不同的pH值下具有三种非常不同的二级结构：1)在碱性pH值下具有未折叠（非螺旋）的二级结构；2)一种更有序的未折叠（非螺旋）二级结构，可以在中性pH下与细胞表面相互作用；3) α -螺旋二级结构，可以在酸性ph下插入细胞膜。利用今天的技术，可以用光学或PET扫描仪检测到的荧光分子或放射性金属标记phillip。合成的pHLIP变体-与荧光分子或放射性金属螯合剂结合-必须保留pH依赖的二级结构，以允许pHLIP仅针对低pH值的癌细胞。该项目有三个方面：1)改进用于手术环境的荧光标记pHLIP （philips - fl）试剂的设计和化学合成；2)创造新的变体，保留母体pHLIP分子的物理特性，并包括正电子发射断层扫描（PET）显像剂（pHLIP- PET）；3)研究pHLIP在预靶向方法（philips - pt）中的使用，以限制成像和治疗期间对肾脏的放射性剂量。在纪念斯隆-凯特琳癌症中心（MSKCC）的指导和先前的成功将有助于实现这些研究目标，并培养出一名全面、知情的独立癌症研究人员。

DESCRIPTION (provided by applicant): Breast cancer is the second leading cause of cancer related deaths in women in the United States, but is the most common cancer among American women.1. Determining the extent of cancer proliferation in patients is still an unmet clinical need. Sometimes, multiple scans and biopsies are required to determine if masses are enlarging or are merely normal for that specific patient. Current scans utilize molecular imaging agents that target over- expressed cell surface receptors on cancerous tissues. These cell surface receptors are also found on non- cancerous tissues in lower abundance. The most commonly used PET radiopharmaceutical, [18F]-FDG, has been used to determine which cells are consuming glucose at a higher rate than others, but also gets taken up in healthy tissues with elevated glucose metabolism. Instead of utilizing cell surface receptors or common metabolic pathways, pH (low) insertion peptide - pHLIP - specifically targets cells with low extracellular pH, which is a common characteristic of all cancer cells.2 PHLIP, a portion of the bacteriorhodopsin protein, has three very different secondary structures at varying pH: 1) an unfolded (non-helical) secondary structure at basic pH; 2) a somewhat more ordered unfolded (non-helical) secondary structure that can interact with cell surfaces at neutral pH; and 3) an alpha-helical secondary structure that can insert into a cell membrane at acidic pH. Labeling of pHLIP with florescent molecules or radioactive metals that can be detected in optical or PET scanners is possible with today's technology. The synthetic pHLIP variations - conjugated to fluorescent molecules or chelators with radioactive metals - must retain the pH dependent secondary structure to allow pHLIP to only target low pH cancer cells. This project is three-fold: 1) improve the design and chemical synthesis of fluorescently labeled pHLIP (pHLIP-FL) agents for use in surgical settings; 2) create new variations that retain the physical properties of the parent pHLIP molecule and include positron emission tomography (PET) imaging agents (pHLIP- PET); and 3) investigate the use of pHLIP in a pretargeting approach (pHLIP-PT) to limit the dose of radioactivity to the kidneys during imaging and therapy. The mentoring and prior successes at Memorial Sloan-Kettering Cancer Center (MSKCC) will provide help in achieving these research goals as well as training to produce a well-rounded and informed independent cancer researcher.