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

基于 pHLIP 的药物，用于手术前、术中和术后成像和治疗

• 批准号: 8900751
• 负责人: Dustin Wayne Demoin
• 金额: $ 5.24万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8900751
• 关键词: Alder plant; American; Animals; Area; Bacteriorhodopsins; Binding; Biological; Biopsy; Blood; Breast Cancer Cell; Cancer Etiology; Cancerous; Cell Surface Receptors; Cell membrane; Cell surface; Cells; Cessation of life; Characteristics; Chelating Agents; Clinical; Development; Diagnosis; Diagnostic; Disease; Dose; Dose-Limiting; Drug Targeting; Ensure; Exhibits; Fluorescent Probes; Future; Glucose; Goals; Growth; Hepatobiliary; Image; Imaging Device; In Vitro; Injection of therapeutic agent; Kidney; Label; Lead; Malignant - descriptor; Malignant Neoplasms; Memorial Sloan-Kettering Cancer Center; Mentors; Metabolic Pathway; Metabolism; Metals; Operative Surgical Procedures; Optics; Organ; Parents; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Physicians; Positron; Positron-Emission Tomography; Postoperative Period; Procedures; Production; Property; Proteins; Qualifying; Radiation; Radioactive; Radioactivity; Radioisotopes; Radiopharmaceuticals; Reagent; Research; Research Personnel; Scanning; Solubility; Structure; Surgeon; Technology; Testing; Therapeutic; Time; Tissues; Toxic effect; Training; Translations; Tumor Tissue; United States; Variant; Woman; Work; base; cancer cell; chemical synthesis; cycloaddition; design; extracellular; fluorescence imaging; fluorodeoxyglucose; fluorophore; functional group; glucose metabolism; imaging agent; improved; in vivo; innovation; interest; malignant breast neoplasm; molecular imaging; mouse model; novel; physical property; public health relevance; radiosensitive; research study; success; tumor; uptake; urinary

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.

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。1。确定患者癌症增殖的程度仍然是一个未满足的临床需求。有时，需要进行多次扫描和活检来确定肿块是否正在增大，或者对于特定患者来说仅仅是正常的。目前的扫描利用分子成像剂来靶向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中。最常用的 PET 放射性药物 [18F]-FDG 已用于确定哪些细胞消耗葡萄糖的速度高于其他细胞，但也被葡萄糖代谢升高的健康组织所吸收。 pH（低）插入肽 - pHLIP 不利用细胞表面受体或常见代谢途径，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。2 PHLIP 是细菌视紫红质蛋白的一部分，在不同 pH 值下具有三种截然不同的二级结构：1) 在碱性 pH 值下为未折叠（非螺旋）二级结构； 2) 更加有序的未折叠（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。利用当今的技术，可以用光学或 PET 扫描仪检测到的荧光分子或放射性金属来标记 pHLIP。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 依赖性二级结构，以允许 pHLIP 仅针对低 pH 癌细胞。该项目分为三部分：1）改进用于外科手术环境的荧光标记pHLIP（pHLIP-FL）制剂的设计和化学合成； 2) 创建新的变体，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) 成像剂 (pHLIP-PET)； 3) 研究 pHLIP 在预靶向方法 (pHLIP-PT) 中的使用，以限制成像和治疗期间肾脏的放射性剂量。纪念斯隆-凯特琳癌症中心 (MSKCC) 的指导和先前的成功将为实现这些研究目标提供帮助，并提供培训以培养全面发展、见多识广的独立癌症研究人员。