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，但却是美国女性中最常见的癌症。确定患者中癌症增殖的程度仍然是未满足的临床需求。有时，需要多次扫描和活检来确定肿块是否正在扩大或只是正常的特定患者。目前的扫描利用分子成像剂，目标是癌组织上过度表达的细胞表面受体。这些细胞表面受体也以较低丰度存在于非癌组织上。最常用的PET放射性药物[18 F]-FDG已被用于确定哪些细胞以高于其他细胞的速率消耗葡萄糖，但也被葡萄糖代谢升高的健康组织吸收。pH（低）插入肽- pHLIP -特异性靶向具有低细胞外pH的细胞，而不是利用细胞表面受体或常见代谢途径，这是所有癌细胞的共同特征。2 PHLIP，细菌视紫红质蛋白的一部分，在不同pH下具有三种非常不同的二级结构：1）未折叠的（非螺旋）二级结构在碱性pH值; 2）有点更有序的展开（非螺旋）二级结构，其可以在中性pH下与细胞表面相互作用;和3）α-用荧光素分子或放射性金属标记pHLIP，可以在光学或PET扫描仪中检测到，在今天的技术下是可能的合成的pHLIP变体-与荧光分子或具有放射性金属的螯合剂缀合-必须保留pH依赖性二级结构，以允许pHLIP仅靶向低pH癌细胞。该项目有三个方面：1）改进荧光标记pHLIP的设计和化学合成2）创建保留母体pHLIP分子的物理性质并包括正电子发射断层扫描（PET）成像剂的新变体（pHLIP-PET）;和3）研究在预靶向方法（pHLIP-PT）中使用pHLIP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为实现这些研究目标提供帮助，并提供培训，以培养全面和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.