PSMA activatable MRI contrast agents to improve the detection of prostate cancer

项目摘要/摘要 前列腺癌MRI在前列腺癌的检测、诊断和治疗算法中正变得越来越重要。 里斯姆斯。然而，它的灵敏度和特异度仍然不是最理想的。在专业人士的多参数范例中- Tate MRI，利用现有临床造影剂的对比增强成像组件增加了相对 对考试的敏感度几乎没有增加。我们的长期目标是开发核磁共振造影剂。 针对前列腺癌，认为这是改进前列腺癌磁共振成像的最大潜在机会。这个 这项提案的总体目标是创造和验证新型可激活的聚集型磁共振造影剂 特异性靶向前列腺特异性膜抗原(PSMA)。 我们实现目标的第一个创新战略是专注于开发能够 在病理领域激活和积累。靶向MRI造影剂在体内蓄积 身体是基于单一造影剂-靶点的相互作用一般是不现实的，如极少数例外 生物靶密度不足以支持足够造影剂的积累以产生 可可靠检测的信号随着MRI的增加而增加。我们之前已经开发出可激活的造影剂，其 在细胞死亡(细胞凋亡)的背景下，积累通过酶作用被放大。我们将在这之前的基础上 现在致力于开发造影剂，这种造影剂的积累可以在前列腺癌的背景下放大。 我们的第二个创新策略是利用前列腺特异膜的胞外酶活性 抗原(PSMA)来提供这种扩增。PSMA是一个有吸引力的分子成像靶点，因为它是可靠的 在前列腺癌中过度表达。我们将设计造影剂，使其在被PSMA切割后， 这些药物将通过聚集在感兴趣的细胞外或细胞内而在前列腺癌中积累。 我们的第三个创新策略是将MRI造影剂的开发与前列腺癌的验证结合起来 患者来源异种移植(PDX)模型。分子显像剂的正确验证对于实现以下目标至关重要 稳健的实验结果支持这些药物未来转化为临床使用。以前的工作经常 过度依赖传统的异种移植模型，这些模型在人类发生时是糟糕的癌症模型。 这项拟议研究的意义在于，它展示了一种适用于前几种情况的普遍机制。 用于克服靶向MRI造影剂敏感性限制的细胞酶靶标。这样的工作 有可能提高前列腺核磁共振的灵敏度，并通过这一点改进检测并最终 前列腺癌的治疗。

PROJECT SUMMARY/ABSTRACT Prostate MRI is becoming increasingly critical in prostate cancer detection, diagnosis, and treatment algo- rithms. However, its sensitivity and specificity remain suboptimal. Within the multiparametric paradigm of pros- tate MRI, the contrast enhanced imaging component utilizing existing clinical contrast agents adds relatively little if any increased sensitivity to the examination. We see our long term goal to develop MRI contrast agents targeted to prostate cancer, as representing the largest potential opportunity for improving prostate MRI. The overall objective of this proposal, is to create and validate novel activatable aggregating MRI contrast agents specifically targeted to prostate specific membrane antigen (PSMA). Our first innovative strategy in accomplishing our goal is to focus on developing MRI contrast agents that can activate and accumulate in the area of pathology. Targeted MRI contrast agents whose accumulation within the body is based on single contrast agent-target interactions are in general unrealistic, as with rare exceptions biological target densities are inadequate to support the accumulation of sufficient contrast agent to generate a reliably detectable signal increase with MRI. We have previously developed activatable contrast agents whose accumulation in the setting of cell death (apoptosis) is amplified by enzymatic action. We will build off this prior work to now develop contrast agents whose accumulation can be amplified in the setting of prostate cancer. Our second innovative strategy is to harness the extracellular enzymatic activity of prostate specific membrane antigen (PSMA) to provide this amplification. PSMA is an attractive molecular imaging target as it is reliably overexpressed in prostate cancer. We will design our contrast agents such that after being cleaved by PSMA, these agents will accumulate in prostate cancer either by aggregating outside or inside of the cells of interest. Our third innovative strategy is to couple MRI contrast agent development with validation in a prostate cancer patient derived xenograft (PDX) model. Proper validation of molecular imaging agents is critical for achieving robust experimental results that support future translation of these agents to clinical use. Prior work has often been overly reliant on conventional xenograft models that are poor models of cancer as it occurs in humans. The significance of the proposed research is that it demonstrates a generalizable mechanism applicable to ex- tracellular enzymatic targets for overcoming sensitivity limitations of targeted MRI contrast agents. Such work has the potential to improve the sensitivity of prostate MRI, and through this improve detection and eventually treatment of prostate cancer.