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与癌症相关死亡的第二大原因，但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未满足的临床需求。有时，需要进行多次扫描和活检以确定肿块是否在扩大或仅对于该特定患者而言是正常的。电流扫描利用靶向过度表达细胞表面受体在癌组织上的分子成像剂。这些细胞表面受体在较低的丰度下也发现了非癌组织。最常用的PET放射性药物[18F] -FDG已被用来确定哪些细胞以比其他细胞更高的葡萄糖消耗，但在葡萄糖代谢升高的健康组织中也被吸收。 pH（低）插入肽 - phlip-特别是针对低细胞外pH的细胞，而不是利用细胞表面受体或常见的代谢途径，这是所有癌细胞的常见特征。不同pH的二次结构截然不同：1）基本pH下展开的（非螺旋）二级结构； 2）一个有序的展开（非螺旋）二级结构，可以与中性pH下的细胞表面相互作用； 3）可以在酸性pH下插入细胞膜中的α螺旋二级结构。通过今天的技术，可以在光学或宠物扫描仪中检测到用荧光分子或放射性金属进行phlip标记。合成的pHLIP变体 - 与荧光分子或带有放射性金属的螯合剂结合 - 必须保留pH依赖性二级结构，以允许Phlip仅靶向低pH癌细胞。该项目的三倍：1）改善荧光标记的phlip（phlip-fl）代理的设计和化学合成，用于手术环境； 2）创建新的变体，以保留父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）调查在预先计算方法（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。纪念斯隆 - 凯特林癌症中心（MSKCC）的指导和先前的成功将为实现这些研究目标以及培训提供帮助，以产生全面且知情的独立癌症研究员。