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.

项目总结/摘要 癌症研究最近经历了一个范式的转变，从肿瘤细胞这一看似明显的目标 癌症的关键支持系统，如肿瘤微环境（TME）。组织氧合（pO 2） 和酸中毒（pH）是实体瘤中最确定的标志之一。最近，细胞外无机 磷酸盐（Pi）已被鉴定为在肿瘤发生中重要的新的信号分子。这个项目 目的是开发新的生物相容性顺磁探针，适用于全身递送， 同时测量组织酸中毒（pH）、氧合（pO 2）和细胞外Pi浓度 使用基于电子顺磁共振（EPR）的技术，在隔室（HOPE探针）中进行分析。这些 这些发展将为癌症研究提供一种新的独特工具， 这些重要的TME参数的测量和相关性。在SA 1下，稳健的点击化学 已经设计了一种方法来有效地产生PEG化HOPE探针的文库。在SA 2下，肿瘤 当PEG化探针与RGD和/或叶酸配体偶联时将实现靶向。的 合成探针将在体外评估其功能灵敏度、光谱特性、毒性和 与靶生物受体结合的能力。最后，在SA 3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 光谱和Overhauser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 pO 2、0.05单位pH和0.1 mM Pi。我们预计双重目标 在许多癌症类型中上调的两种受体的方法，以改善健康 和肿瘤组织，并显著增强信号强度和降低探针剂量。完成 PI授予的K99/R 00奖项将使他能够获得基于EPR的体内研究所需的工具和技能 光谱学和成像，成功地将这些知识应用于癌症功能成像领域; 因此，在合成有机化学、癌症研究和成像之间架起了一座桥梁， 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