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

PSMA 可激活 MRI 造影剂以改善前列腺癌的检测

• 批准号: 9807165
• 负责人: Andreas Markus Loening
• 金额: $ 23.48万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9807165
• 关键词: Algorithms; Apoptosis; Area; Benign Prostatic Hypertrophy; Biodistribution; Biological; CASP3 gene; Cancer Detection; Cancer Etiology; Cancer Model; Cancer Patient; Cell Culture Techniques; Cell Death; Cells; Cessation of life; Chemistry; Cleaved cell; Clinical; Clinical Research; Contrast Media; Deposition; Detection; Development; Diagnosis; Enzymes; Evaluation; Extracellular Domain; FOLH1 gene; Future; Gadolinium; Goals; Histology; Human; Human body; Image; Image Enhancement; Imaging Techniques; Inductively Coupled Plasma Mass Spectrometry; Inflammation; Injections; Ligands; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Manganese; Methods; Pathology; Pathway interactions; Patients; Performance; Permeability; Phase; Positron-Emission Tomography; Prostate; Prostate Cancer therapy; Public Health; Research; Risk; Screening for Prostate Cancer; Sensitivity and Specificity; Signal Transduction; Slice; Specificity; Study models; Therapeutic; Tissues; Toxic effect; Translating; Translations; Validation; Work; Xenograft Model; Xenograft procedure; base; burden of illness; contrast enhanced; density; design; extracellular; glutamate carboxypeptidase; imaging agent; improved; innovation; interest; men; molecular imaging; mouse model; nanoparticle; novel; overexpression; receptor; receptor density; small molecule; stem; success; targeted agent; targeted imaging; tumor

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.

项目总结/摘要 前列腺MRI在前列腺癌检测、诊断和治疗算法中变得越来越重要， Rithms然而，其灵敏度和特异性仍然不理想。在多参数范式中， 在MRI中，利用现有临床造影剂的对比增强成像组件相对增加了 对检查的敏感性几乎没有增加。我们的长期目标是开发MRI造影剂 靶向前列腺癌，代表了改善前列腺MRI的最大潜在机会。的 本提案的总体目标是创建和验证新型可活化聚集MRI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策略是专注于开发MRI造影剂， 激活并积聚在病理区域。靶向MRI造影剂， 身体是基于单一的造影剂-靶相互作用一般是不现实的，因为很少有例外 生物目标密度不足以支持足够的造影剂的积累 MRI可可靠检测到的信号增加。我们以前已经开发了可激活的造影剂， 在细胞死亡（细胞凋亡）的情况下的积累通过酶促作用被放大。我们将建立在这个先验基础上 现在正在努力开发造影剂，其积累可以在前列腺癌的情况下放大。 我们的第二个创新策略是利用前列腺特异性膜的胞外酶活性， 抗原（PSMA）来提供这种扩增。PSMA是一种有吸引力的分子成像靶标，因为它可靠地 在前列腺癌中过度表达。我们将设计我们的造影剂，使得在被PSMA切割后， 这些试剂将通过聚集在感兴趣的细胞外部或内部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相结合 患者来源的异种移植物（PDX）模型。分子成像剂的正确验证对于实现 强大的实验结果，支持这些药物的临床应用的未来翻译。以前的工作经常 过度依赖于传统的异种移植模型，这些模型是人类发生的癌症的不良模型。 这项研究的意义在于，它展示了一种适用于前 用于克服靶向MRI造影剂的灵敏度限制的跨细胞酶靶。这种工作 有可能提高前列腺MRI的灵敏度，并通过这一提高检测，并最终 前列腺癌的治疗。