IMAGING PROSTATE CANCER BY MRI/PET WITH PSMA-TARGETED PROBES

使用 PSMA 靶向探针通过 MRI/PET 对前列腺癌进行成像

• 批准号: 7956999
• 负责人: XIAOFENG SUN
• 金额: $ 0.89万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7956999
• 关键词: Age; American Cancer Society; Androgens; Animal Model; Animals; Antigen Targeting; Arsenic; Behavior; Biodistribution; Biopsy; Cancer Detection; Cancer Etiology; Cells; Cessation of life; Computer Retrieval of Information on Scientific Projects Database; Data; Detection; Dextrans; Diagnosis; Diagnostic Imaging; Digital Rectal Examination; Ethnic group; Evaluation; Excretory function; Family history of; Funding; Glutamate Carboxypeptidase II; Goals; Grant; Half-Life; Hand; Image; Imaging Techniques; In Vitro; Incubated; Institution; Isotopes; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Metabolic; Metabolism; Methods; Modality; Monoclonal Antibodies; Mus; Nanoconjugate; Neoplasm Metastasis; Non-Invasive Cancer Detection; PC3 cell line; PSA screening; Positron; Positron-Emission Tomography; Preparation; Procedures; Property; Prostate; Prostatic Neoplasms; Protocols documentation; RNA; Radio; Radiopharmaceuticals; Rattus; Research; Research Personnel; Resolution; Resources; Role; Screening for Prostate Cancer; Screening procedure; Sensitivity and Specificity; Serum; Source; Staging; Techniques; Testing; Tissues; Transrectal Ultrasound; United States; United States National Institutes of Health; Urine; X-Ray Computed Tomography; Xenograft Model; Xenograft procedure; aptamer; base; cancer diagnosis; checkup examination; clinical practice; dextran; follow-up; imaging modality; imaging probe; improved; in vivo; iron oxide; men; molecular imaging; mouse model; nanoparticle; nanosized; novel; novel strategies; research clinical testing; subcutaneous; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this project is to synthesize and characterize PSMA-targeted nano-conjugates; evaluate in vivo behavior of the nanoconjugates in normal and prostate tumor bearing mice; and apply the nanoconjugates to noninvasive MRI/PET imaging of prostate cancer. In the United States, prostate cancer (PCa) has been consistently the second leading cause of cancer-related deaths of men. Currently the American Cancer Society recommends annual checkups with the prostate-specific antige test and the digital rectal examination for the early detection of PCa in men at certain ages based on their ethnic groups and family history. Although the routine PSA-based screening has been introduced to the diagnosis of PCa over two decades and has become probably the most common clinical test of cancer, it is still in debate about the benefit of the PSA screening and the upper limit of normal PSA values. On the other hand, the PCa biopsies routinely performed with transrectal ultrasound cannot warrant a definitive stage of PCa because PCa can be isoechoic and indistinguishable from the surrounding tissues. Therefore it is of great significance to develop new techniques for the non-invasive detection of PCa with high sensitivity and specificity. Among the non-invasive imaging modalities, computed tomography (CT) has been traditionally used to evaluate the extent of local PCa, more recently magnetic resonance imaging (MRI) has also joined the clinical practices for more accurate staging of PCa as the MRI techniques rapidly evolve. Because CT and MRI are typically anatomical imaging techniques, they are inherently short of sensitivity as compared to the functional/metabolic imaging modalities, such as positron emission tomography (PET). However, the most commonly used PET radiopharmaceutical, 18F-FDG, is not quite successful at identifying PCa (until PCa becomes metastatic) as it is in the detection of other tumors because of the low glycolytic rate of PCa and high background due to the normal excretion of 18F-FDG through urine. To date, the role of PET in prostate cancer has not been established. The goal of this proposal is to explore a new approach that will combine the advantages of MRI and PET for the diagnostic imaging and staging of PCa. We propose to dope positron-emitting isotopes to superparamagnetic iron oxide nanoparticle to make nanosized dual MRI/PET probes for the detection of PCa by multi-modality (anatomical MRI plus functional PET) molecular imaging approaches, so that the sensitivity and specificity of PCa diagnosis could be significantly improved. In this proposal, we choose arsenic-74 due to its low endpoint positron energy (0.94 MeV) that provides higher spatial resolution of PET, and its relatively long half-life (17.77 days) that allows us to carry out the procedures of making the dual-modality imaging probes. In perspective, the long half-life also allows global delivery of such imaging probes. Two prostate specific membrane antigen (PSMA) targeting molecules (a new PSMA monoclonal antibody and a novel PSMA-targeting RNA aptamer) will be used to construct the PSMA-targeted nano-conjugates. Three animal models (intra-femoral, subcutaneous, and orthotopic) using two prostate cancer cell lines, C4-2 and PC-3 cells, will be used for the imaging probe evaluations in this proposal, because C4-2 is an androgen responsive cell expressing PSMA and PC-3 is PSMA-devoid AIPCa cell that will serve as negative control. Two specific objectives are arranged in this project: Objective I. Preparation/characterization of 77/74As-doped iron oxide nanoparticles and construction of PSMA-targeted nano-conjugates; and Objective II. Evaluation of the PSMA-targeted nano-conjugates in PCa xenograft mouse models via the conventional biodistribution and small animal MRI and PET imaging methods. In Objective I, we will establish protocols to prepare dextran-coated 77/74As-doped iron oxide nanoparticles and PSMA-targeted nano-conjugates. We plan to make four PSMA-targeted nano-conjugates by covalently attaching the two targeting molecules to the dextran-coated 77/74As-doped iron oxide nanoparticles with sizes of 25 nm and 35 nm, for the studies in the Objective II. The in vitro stability will be determined by incubating the nano-conjugates with fresh rat serum over 48 h and follow-up radio-HPLC analysis. The tumor-targeting property of the nano-conjugates will be evaluated in C4-2 and PC-3 xenograft models (subcutaneously in the flank) by the conventional biodistribution method. The nano-conjugates that show optimal behavior in vitro and in vivo and tumor-targeting property will be further evaluated by small animal MRI and PET imaging in two C4-2 xenograft models (orthotopic and intra-femoral) for the detection of localized and metastatic tumors. Both biodistribution and small animal imaging results will be compared with the respective PSA data. We anticipate the PSMA-targeted nano-conjugates will be able to serve as dual-modality imaging probes and provide higher sensitivity and specificity for PCa detection than either of the single-modality imaging approaches and the PSA test.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本项目的目标是合成和表征以PSMA为靶点的纳米结合物；评估纳米结合物在正常和前列腺癌荷瘤小鼠的体内行为；并将纳米结合物应用于前列腺癌的无创性MRI/PET成像。在美国，前列腺癌(PCA)一直是男性癌症相关死亡的第二大原因。目前，美国癌症协会建议每年进行前列腺特异性抗前列腺癌检查和直肠指检，以便根据特定年龄的男性的种族和家族史及早检测出前列腺癌。虽然基于PSA的常规筛查已被引入到前列腺癌的诊断中，并可能成为最常见的癌症临床检查，但对于PSA筛查的益处和正常PSA值的上限仍存在争议。另一方面，常规的经直肠超声进行的前列腺癌活检不能保证明确的前列腺癌分期，因为前列腺癌可能是等回声的，与周围组织无法区分。因此，开发高灵敏度、高特异度的PCa无创检测新技术具有重要意义。在非侵入性成像方法中，传统上使用计算机断层扫描(CT)来评估局部PCa的范围，最近随着MRI技术的快速发展，磁共振成像(MRI)也加入到临床实践中来，以更准确地对PCa进行分期。由于CT和MRI是典型的解剖成像技术，与正电子发射断层扫描(PET)等功能/代谢成像方式相比，它们固有地缺乏敏感性。然而，最常用的PET放射性药物，18F-FDG，在识别PCa(直到PCa发生转移)时并不是很成功，因为它在检测其他肿瘤方面是因为PCa的糖酵解率低，而且18F-FDG的本底很高，因为18F-FDG通过尿液正常排泄。到目前为止，PET在前列腺癌中的作用还没有确定。该方案的目的是探索一种新的方法，将MRI和PET的优势结合起来，用于PCa的诊断、成像和分期。我们建议将发射正电子的同位素掺杂到超顺磁性纳米氧化铁颗粒中，制成纳米级的MRI/PET双探针，用于多模式(解剖MRI+功能PET)分子成像方法检测PCa，从而显著提高PCa诊断的敏感性和特异性。 在这项提议中，我们选择砷-74是因为它的低端正电子能量(0.94 MeV)提供了更高的PET空间分辨率，并且它的半衰期相对较长(17.77天)，使我们能够进行制造双模式成像探针的过程。从长远来看，较长的半衰期也允许这种成像探头在全球范围内交付。两种前列腺特异性膜抗原(PSMA)靶向分子(一种新的PSMA单抗和一种新型的PSMA靶向RNA适配子)将被用来构建PSMA靶向的纳米结合物。使用两种前列腺癌细胞系C4-2和PC-3的三种动物模型(股内、皮下和原位)将用于本方案中的成像探针评估，因为C4-2是表达PSMA的雄激素反应细胞，而PC-3是PSMA缺失的AIPCA细胞，将作为阴性对照。 本项目安排了两个具体目标： 目的一、77/74As掺杂纳米氧化铁纳米颗粒的制备、表征及PSMA靶向纳米结合物的构建；二、通过常规生物分布、小动物MRI和PET成像方法，评价PSMA靶向纳米结合物在小鼠前列腺癌移植模型中的应用。 在目标I中，我们将建立制备葡聚糖包覆的77/74As掺杂的氧化铁纳米颗粒和聚甲基丙烯酸甲酯靶向纳米偶联物的方案。我们计划通过将两个靶向分子共价连接到尺寸分别为25 nm和35 nm的葡聚糖包被的77/74As掺杂的氧化铁纳米颗粒上来制备四个PSMA靶向纳米结合物，用于目标II的研究。通过将纳米结合物与新鲜大鼠血清孵育48小时和后续的放射-高效液相分析来确定其体外稳定性。纳米结合物的肿瘤靶向性将在C4-2和PC-3异种移植模型中(侧部皮下)用常规的生物分布方法评估。在两种C4-2异种移植模型(原位和股骨内)中，显示出最佳的体内外行为和肿瘤靶向性的纳米结合物将通过小动物MRI和PET成像进行进一步评估，以检测局部和转移肿瘤。生物分布和小动物成像结果将与各自的PSA数据进行比较。我们预计，以PSMA为靶点的纳米结合物将能够作为双模式成像探针，并提供比单模式成像方法和PSA测试更高的灵敏度和特异性来检测PCA。