Biocompatible Magnetic Resonance Probes for in vivo Concurrent Profiling

项目摘要/摘要 癌症研究最近经历了一个范式的转变，从看似明显的肿瘤细胞目标 针对癌症的关键支持系统，如肿瘤微环境(TME)。组织氧合(PO2) 和酸中毒(PH)是实体瘤最明确的特征之一。最近，胞外无机物 磷酸盐(PI)已被认为是一种新的在肿瘤发生中起重要作用的信号分子。这个项目 旨在开发新的生物兼容顺磁探针，适用于全身给药，允许体内 组织酸中毒(PH)、氧合(PO2)和胞外PI浓度的同步测量 舱室(希望探头)使用基于电子顺磁共振(EPR)的技术。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研究 这些重要的TME参数的测量和关联。在SA1下，强劲的点击化学 该方法被设计成高效地产生聚乙二醇化的HOPE探针库。在SA2下，肿瘤 靶向将在聚乙二醇化的探针与RGD和/或叶酸配体偶联后实现。这个 人工合成的探针将在体外进行功能灵敏度、光谱特性、毒性和 与目标生物受体结合的能力。最后，在SA3中，我们将使用人类的老鼠模型 乳腺癌进行毒代动力学研究，优化探针剂量和实验时间窗口，以及 用低频EPR测定探针的功能敏感性和肿瘤靶向效率 光谱学和奥弗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毫米汞柱的氧分压、0.05单位的酸碱度和0.1毫米波的等电点。我们预计会有双重目标 两种受体在多种癌症类型中上调以改善健康对照的方法 和肿瘤组织，并显著增强信号强度和减少探头剂量。完成度 由PI颁发的K99/R00奖将使他能够在基于EPR的体内获得必要的工具和技能 光谱学和成像，成功地将这一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桥梁 技术。这一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。

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.