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

描述(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，但在美国女性中是最常见的癌症。确定患者癌症增殖的程度仍然是一个未得到满足的临床需求。有时，需要进行多次扫描和活检，以确定肿块是增大了还是对特定患者来说只是正常的。目前的扫描利用分子显像剂来靶向癌症组织上过度表达的细胞表面受体。这些细胞表面受体也存在于丰度较低的非癌组织中。最常用的PET放射性药物[18F]-FDG已被用于确定哪些细胞比其他细胞消耗葡萄糖的速度更快，但也被葡萄糖代谢升高的健康组织所吸收。PHLIP是细菌视紫红质蛋白的一部分，在不同的pH下有三种非常不同的二级结构：1)在碱性pH下的未折叠(非螺旋)二级结构；2)在中性pH下可以与细胞表面相互作用的更有序的展开(非螺旋)二级结构；以及3)在酸性pH下可以插入细胞膜的α-螺旋二级结构。利用今天的技术，用可以在光学或PET扫描仪中检测到的荧光分子或放射性金属标记PHLIP是可能的。人工合成的PHLIP变体-连接到荧光分子或具有放射性金属的螯合剂-必须保留依赖于pH的二级结构，以便PHLIP仅针对低pH值的癌细胞。该项目有三个方面：1)改进用于外科设备的荧光标记PHLIP(PHLIP-FL)试剂的设计和化学合成；2)创造保留母体PHLIP分子的物理性质并包括正电子发射断层扫描(PET)显像剂(PHLIP-PET)的新变体；以及3)研究PHLIP在预靶向方法(PHLIP-PT)中的使用，以在成像和治疗期间限制肾脏的放射性剂量。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，并为培养一名全面和知情的独立癌症研究人员提供培训。

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.