MR Signal Amplification for Receptor Imaging

MRAmp策略最初设计的目的是提高MR的分子敏感性 通过同时在两个水平上调制MR信号输出来成像：1)目标特异性：一对 受体靶向的酶共定位于特定的组织间隔，并且由于酶的活性 互补，使低分子顺磁性底物能够快速修饰，从而导致 它们在反应部位的局部滞留；以及2)敏感性：局部滞留引起放大的MR信号 由高的局部浓度密度和增加的顺磁产物的弛豫度所产生 酶促反应。我们在使MRamp技术更接近临床方面已经标志着主要的里程碑 翻译内容包括：1)人类病理内源性髓过氧化物酶活性的MRI表现 以及在各种疾病模型中的表达；2)癌症模型中受体表达的成功成像。MRamp就是其中之一 在现有的能够检测两个蛋白质标记(受体)共表达的为数不多的技术中。 除了MRI，我们最近还探索了使用µPET-CT进行共表达成像的可行性。通过实现一个 扩展的多模式成像方法(BLI、MRI和µPET-CT)，我们以前发现了溶骨性和 非溶骨性三阴性乳腺癌(TNBC)表型 关键基因转录本。这里提出的新阶段的研究将包括优化双重受体 TNBC两个重要生物标志物的成像策略及其在活体成像中的应用 EGFR和PD-L1过表达。成像这些关键标记在TNBC中共表达的能力 肿瘤有望提供一种新的、高度可量化和易于解释的诊断成像方法 它可用于(1)检测转移扩散，(2)选择患者进行靶向治疗和(3)监测 在治疗过程中的治疗反应或抵抗。除了简化对 接受现有癌症治疗的患者，这种新的方法可以加快对研究的测试 新药正在进行临床试验，从而加快了有希望的TNBC新疗法的批准。我们最初的目标将是 筛选新型嵌合小分子催化剂底物，以选择最高MR和PET信号的候选者 使用我们的酶依赖成像系统进行放大。我们之前曾发表过关于在中国制造的进展 我们设计了MR可检测的基于顺磁性Mn(II)的超氧化物歧化酶模拟物，并将进一步 利用他们的力量作为工具，使我们的MRAmp系统微型化。这种小型化可能会被证明是 在体内标记和跟踪细胞外小泡(EV)的能力现在被认为是 肿瘤的转移性扩散，如TNBC。因此，这项提议的第二个主要目标将是 使用我们的双受体、高敏感性酶互补方法进行内源性EVS。

The MRamp strategy was initially designed with the goal of improving the molecular sensitivity of MR imaging by modulating the MR signal output on two levels simultaneously: 1) target specificity: a pair of receptor-targeted enzymes co-localize in the specific tissue compartment and due to enzymatic activity complementation, enable rapid modification of low molecular weight paramagnetic substrates which results in their local retention at the reaction site; and 2) sensitivity: local retention gives rise to an amplified MR signal generated by both high local concentration density and increased relaxivity of the paramagnetic products of the enzymatic reaction. We have marked major milestones in bringing the MRamp technique closer to clinical translation including: 1) demonstration of MRI of endogenous myeloperoxidase activity in human pathology and in various disease models; 2) successful imaging of receptor expression in cancer models. MRamp is one of the few existing techniques enabling the detection of the co-expression of two protein markers (receptors). We recently explored co-expression imaging feasibility with µPET-CT in addition to MRI. By implementing an expanded multi-modality imaging approach (BLI, MRI and µPET-CT), we previously identified osteolytic and non-osteolytic triple-negative breast cancer (TNBC) phenotypes and characterized them using the analysis of key gene transcripts. The new phase of research proposed here, will include the optimization of a dual receptor imaging strategy and its application to in vivo imaging of two critically important biomarkers of TNBC, i.e. overexpressed EGFR and PD-L1. The ability to image the co-expression of these critical markers in TNBC tumors is expected to provide a new, highly quantifiable and easily interpretable diagnostic imaging method that can be used to (1) detect metastatic spread, (2) select patients for targeted therapies and (3) monitor therapeutic response or resistance over the course of treatment. In addition to simplifying the monitoring of patients undergoing existing cancer treatments, this new methodology could speed testing of investigational new drugs in clinical trials thus expediting approval of promising new TNBC therapies. Our initial goal will be to screen novel chimeric small molecule catalyst-substrates, to select candidates for highest MR and PET signal amplification using our enzyme dependent imaging system. We have previously published on inroads made in our design of MR detectable paramagnetic Mn(II)-based superoxide dismutase mimetics and will further harness their power as tools for miniaturizing our MRamp system. Such miniaturization may prove essential for the ability to tag and track extracellular vesicles (EV) in vivo which are now believed to be a key element in the metastatic spread of cancers such as TNBC. Therefore, a second major goal of this proposal will be to image endogenously occurring EVs using our dual receptor, high sensitivity enzyme complementation approach.