Biocompatible Magnetic Resonance Probes for in vivo Concurrent Profiling of Interstitial Oxygenation, Acidosis and Inorganic Phosphate: Preclinical Application to Cancer

用于体内间质氧合、酸中毒和无机磷酸盐同步分析的生物相容性磁共振探针：在癌症中的临床前应用

• 批准号: 9295138
• 负责人: Benoit Driesschaert
• 金额: $ 7.66万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9295138
• 关键词: Acidosis; Acute; Affinity; Albumins; Alkynes; Award; Azides; Binding; Biological; Biological Assay; Blood; Blood Circulation; Breast Cancer Cell; Breast Cancer Model; Breast Epithelial Cells; Cell Survival; Cells; Chemistry; Chronic; Collaborations; Development; Dose; Electron Spin Resonance Spectroscopy; Endothelial Cells; Folic Acid; Frequencies; Functional Imaging; Future; Goals; Human; Hydrophobic Interactions; Hypoxia; Image; Imaging technology; Immunodeficient Mouse; Impairment; Implant; In Vitro; Integrin alphaVbeta3; Kinetics; Knowledge; Label; Libraries; Ligands; MCF10A cells; MDA MB 231; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Neoplasms; Measurement; Measures; Medicine; Methodology; Modeling; Mono-S; Organic Chemistry; Physiological; Plasma; Property; Scientist; Signal Transduction; Signaling Molecule; Site; Solid Neoplasm; Solubility; Spectrum Analysis; Support System; Technology; Time; Tissues; Toxic effect; Toxicokinetics; Tumor Tissue; Umbilical vein; Validation; Xenograft procedure; anticancer research; aqueous; base; bioimaging; biomacromolecule; biomaterial compatibility; cancer imaging; cancer type; clinically relevant; design; dosage; ethylene glycol; experience; extracellular; improved; in vivo; inorganic phosphate; interstitial; macromolecule; malignant breast neoplasm; mouse model; neoplastic cell; peptidomimetics; phosphonate; pre-clinical; prevent; receptor; skills; spectroscopic imaging; success; tissue oxygenation; tool; tumor; tumor growth; tumor microenvironment; tumorigenesis

PROJECT SUMMARY/ABSTRACT Cancer research has recently experienced a paradigm shift from the seemingly obvious target of tumor cells towards key support systems of cancer, such as the tumor microenvironment (TME). Tissue oxygenation (pO2) and acidosis (pH) are among the most established hallmarks in solid tumor. Recently, extracellular inorganic phosphate (Pi) has been identified as a new signaling molecule of importance in tumorigenesis. This project aims to develop new biocompatible paramagnetic probes suitable for systemic delivery allowing for in vivo concurrent measurement of tissue acidosis (pH), oxygenation (pO2) and Pi concentration in the extracellular compartment (HOPE probes) using electron paramagnetic resonance (EPR)-based technologies. These developments will provide a new unique tool in cancer research allowing for in vivo direct non-invasive measurements and correlation of these important TME parameters. Under SA1, a robust click chemistry approach has been designed to efficiently produce a library of PEGylated HOPE probes. Under SA2, tumor targeting will be achieved upon conjugation of the PEGylated probe to RGD and/or folic acid ligands. The synthesized probes will be evaluated in vitro for their functional sensitivity, spectral properties, toxicity and ability to bind to the targeted biological receptors. Finally, under SA3, we will use a mouse model of human breast cancer to perform toxicokinetic studies, to optimize the probe dose and experimental time window, and to determine the functional sensitivity and tumor targeting efficiency of the probes using low frequency EPR spectroscopy and Overhauser-enhanced magnetic resonance imaging. We anticipate to achieve in vivo functional sensitivity of 1-2 mmHg of pO2, 0.05 units of pH, and 0.1 mM of Pi. We expect the dual targeted approach of the two receptors upregulated in numerous cancer types to improve the contrast between healthy and tumor tissues, and to significantly enhance signal intensity and decrease probe dosage. The completion of this K99/R00 award by the PI will allow him to obtain the necessary tools and skills in EPR-based in vivo spectroscopy and imaging to successfully apply this knowledge to the field of cancer functional imaging; therefore, bridging the interface between synthetic organic chemistry, cancer research and imaging technologies. The successful completion of this project is designed to make a signficant impact on the future of bioimaging applications to medicine.

项目概要/摘要 癌症研究最近经历了范式转变，不再以肿瘤细胞为看似明显的目标 癌症的关键支持系统，例如肿瘤微环境（TME）。组织氧合 (pO2) 和酸中毒 (pH) 是实体瘤最常见的标志之一。近年来，细胞外无机物 磷酸盐（Pi）已被确定为在肿瘤发生中重要的新信号分子。这个项目 旨在开发适合全身递送的新型生物相容性顺磁探针，允许体内 同时测量组织酸中毒 (pH)、氧合 (pO2) 和细胞外 Pi 浓度 使用基于电子顺磁共振 (EPR) 的技术的隔室（HOPE 探头）。这些 发展将为癌症研究提供一种新的独特工具，允许体内直接非侵入性 这些重要 TME 参数的测量和相关性。 SA1 下，强大的点击化学反应 该方法旨在有效地生成聚乙二醇化 HOPE 探针库。 SA2下，肿瘤 聚乙二醇化探针与 RGD 和/或叶酸配体缀合后即可实现靶向。这 合成的探针将在体外评估其功能灵敏度、光谱特性、毒性和 与目标生物受体结合的能力。最后，在SA3下，我们将使用人类的小鼠模型 乳腺癌进行毒代动力学研究，优化探针剂量和实验时间窗，以及 使用低频 EPR 确定探针的功能灵敏度和肿瘤靶向效率 光谱学和欧沃豪瑟增强磁共振成像。我们期望在体内实现 功能灵敏度为 1-2 mmHg pO2、0.05 单位 pH 和 0.1 mM Pi。我们预计双重目标 两种受体在多种癌症类型中上调的方法，以提高健康癌症之间的对比 和肿瘤组织，并显着增强信号强度并减少探针剂量。完成情况 PI获得的K99/R00奖将使他获得基于EPR的体内必要的工具和技能 光谱学和成像成功地将这些知识应用到癌症功能成像领域； 因此，架起了合成有机化学、癌症研究和成像之间的桥梁 技术。该项目的成功完成旨在对未来产生重大影响 生物成像在医学上的应用。