Synthesis and Pre-Clinical Evaluation of Targeted, Iron-Based MRI Contrast Agents

靶向铁基 MRI 造影剂的合成和临床前评估

• 批准号: 7620200
• 负责人: RAPHAEL G RAPTIS
• 金额: $ 8.89万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7620200
• 关键词: Affinity; Aftercare; Binding; Biological Assay; Bromides; CD44 gene; Cancer Model; Carbohydrates; Cell Line; Cell surface; Chemistry; Clinical; Clinical Trials; Colorectal Cancer; Complex; Contrast Media; Coupled; Cyclodextrins; Detection; Development; Diagnostic Imaging; Disease; Disease remission; Doctor of Philosophy; Dose; Drug Formulations; Early Diagnosis; Excipients; Family member; Future; Gadolinium; Glucosamine; Goals; Gynecologic; Human; Hyaluronic Acid; Image; Imaging Techniques; In Vitro; Intervention; Invasive; Iron; Lead; Length; Ligands; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of ovary; Mesothelium; Methods; Modality; Modeling; Molecular; Monitor; Neoplasm Metastasis; Newly Diagnosed; Non-Invasive Cancer Detection; Nude Mice; Operative Surgical Procedures; Ovarian Carcinoma; Patients; Peritoneal; Peritoneum; Pharmaceutical Preparations; Play; Positioning Attribute; Proteoglycan; RNA Splicing; Relapse; Residual Neoplasm; Risk Factors; Role; Screening for Ovarian Cancer; Screening procedure; Series; Serum; Signal Transduction; Solubility; Specimen; Staging; Survival Rate; Therapeutic; Time; Title; Toxic effect; Treatment Protocols; Tumor Burden; Tumor Debulking; Tumor Tissue; Ultrasonography; University of Texas M D Anderson Cancer Center; Validation; Variant; Water; X-Ray Computed Tomography; Xenograft Model; Xenograft procedure; abstracting; aptamer; aqueous; base; cellular oncology; expectation; human disease; implantation; improved; intraperitoneal; iron oxide; novel; ovarian neoplasm; pre-clinical; professor; prognostic; research clinical testing; response; stoichiometry; tumor

TITLE: Full Project A - Synthesis and Pre-Clinical Evaluation of Targeted, Iron-Based MRI Contrast Agents to Enhance Ovarian Cancer Detection and Treatment Scheduling CO-LEADERS: MDACC - Jim Klostergaard, Ph.D., Professor, Department of Molecular & Cellular Oncology UPRCCC - Raphael G. Raptis, Ph.D., Professor, Department of Chemistry ABSTRACT Ovarian cancer remains the most lethal gynecologic malignancy, with only incremental improvements in survival rates over the last decades. Due to the absence of appropriate screening targets and clearly-defined risk factors for the majority of ovarian cancers, carcinomatous involvement of the peritoneum is already present in the majority of newly-diagnosed patients; ominously, this tumor burden alone frequently determines survival. Non-invasive detection of early therapeutic responses of ovarian cancer already in the peritoneum in the contexts of minimal residual disease following debulking, as well as detection of the earliest evidence of relapse of such disease after treatment-induced remission, might prove invaluable for optimal patient management and treatment intervention. Specifically, for this pre-clinical proposal, we plan to model the clinical scenarios of both initial treatment monitoring of stage III/IV patients, as well as the detection of their earliest relapse to signal the need for further intervention. A key aspect of future validation would be comparison to CA-125 levels (or to other markers that may have been developed in the interim), both during entry into remission and as a prognostic indicator of relapse. Currently, ovarian cancer monitoring typically depends on a combination of serum CA-125 and diagnostic imaging, most frequently computed tomography or ultrasound, and in this setting magnetic resonance imaging (MRI) is a comparatively under-utilized modality. We propose that with improved use of targeted contrast agents (CAs), MRI could play a valuable role in monitoring. The overarching hypotheses that form the basis for this proposal are 1) that iron-based MR CAs will be superior to those based on gadolinium (Gd) and superparamagnetic iron oxides (SPIOs), 2) that in preclinical ovarian cancer models, our novel iron-cluster-based CAs will enhance MR imaging capabilities compared to current technigues, and 3) that tumor-targeted CAs will provide superior detection of tumors compared to non-targeted CAs. In this proposal, we will synthesize and evaluate a novel series of Fe-based MRI CAs to attempt to enhance detection of ovarian tumors disseminated to the peritoneum. The focus will be on human ovarian carcinoma/nude mouse xenograft models, using intraperitoneal (i.p.) implantation. These tumor models reflect numerous relevant aspects of the human disease, and are high expressors of the cell-surface proteoglycan, CD44, which is over-expressed on as many as 90% of human ovarian carcinoma specimens. In the clinical scenario, CD44 expression on tumor tissue would be confirmed at the time of surgical debulking. Hyaluronic acid (HA), a component of the peritoneal mesothelium, is a ligand of CD44. HA will be conjugated to a CA "module" to create a novel lead formulation of a CA, specifically targeted to CD44(+) tumors. Specific aims for the proposed studies include: 1) To evaluate the ability of non-targeted as well as targeted formulations of the proprietary lead Fe8-compound and its water-soluble conjugates to enhance MR imaging of i.p. human ovarian carcinoma xenograft models; 2) To develop/select thioaptamers with high affinity for CD44 family members, parental and/or selected splice variants; and 3) To synthesize appropriate chemically functionalized derivatives of the lead Fe8-cluster, which will allow the attachment of the anti-CD44 aptamers; to determine whether the CD44 aptamer-Fe8-cluster conjugate improves the MR imaging sensitivity of i.p. CD44(+) ovarian carcinoma xenografts, by comparison to the HA-Fe8 CA, as well as to non-targeted complexes. Our goal and expectation is that at the end of this study, we will be in a position to select a lead CA formulation for further pre-clinical development and to subsequently follow a track to clinical evaluation. With recent clinical trial results demonstrating compelling evidence for the use of i.p-based drug treatment protocols, the availability of such MRI CAs and the associated improvements in sensitivity for non-invasive, serial imaging of peritoneal tumor burden may find a significant clinical niche in CD44(+) tumors where current diagnostic imaging techniques are suboptimal (e.g. colorectal cancer peritoneal metastases).

标题：完整项目A -靶向铁基MRI造影剂的合成和临床前评价 增强卵巢癌检测和治疗计划的药物 共同负责人：MDACC - Jim Klostergaard博士，教授，分子与化学系 细胞肿瘤学 UPRCCC - Raphael G. Raptis博士，化学系教授 摘要 卵巢癌仍然是最致命的妇科恶性肿瘤， 生存率在过去几十年。由于缺乏适当的筛选目标和明确的 作为大多数卵巢癌的危险因素，已经存在腹膜的癌性浸润 在大多数新诊断的患者中;不幸的是，这种肿瘤负荷常常决定生存。 腹膜内卵巢癌早期治疗反应的非侵入性检测 减积后微小残留病的情况，以及检测到最早的证据， 这种疾病在治疗诱导缓解后复发，对于最佳患者可能证明是无价的， 管理和治疗干预。 具体来说，对于这个临床前提案，我们计划对初始治疗的临床场景进行建模 监测III/IV期患者，以及检测他们最早的复发，以表明需要进一步的治疗。 干预未来验证的一个关键方面将是与CA-125水平（或与 可能是在过渡期发展的），在进入缓解期期间和作为预后指标， 复发目前，卵巢癌监测通常取决于血清CA-125和 诊断成像，最常见的是计算机断层扫描或超声，在这种情况下，磁 共振成像（MRI）是一种相对未充分利用的模态。我们建议，通过改进使用 靶向造影剂（CA），MRI可以发挥有价值的作用，在监测。 构成该提议基础的总体假设是：1）铁基MR CA将 上级于基于钆（Gd）和超顺磁性氧化铁（SPIO）的那些，2）在临床前 卵巢癌模型，我们的新型铁簇基CA将增强MR成像能力 与现有技术相比，3）肿瘤靶向CA将提供上级肿瘤检测 与非目标CA相比。 在这个提议中，我们将合成和评估一系列新的铁基MRI CA， 增强对扩散至腹膜的卵巢肿瘤的检测。重点将放在人类卵巢 癌/裸鼠异种移植模型，使用腹膜内（i. p.）置入这些肿瘤模型反映了 人类疾病的许多相关方面，并且是细胞表面蛋白聚糖的高表达者， CD 44在多达90%的人卵巢癌标本中过度表达。在 在临床情况下，肿瘤组织上的CD 44表达将在手术减积时得到证实。 透明质酸（HA）是腹膜间皮细胞的一种成分，是CD 44的配体。HA将结合 CA“模块”，以创建CA的新型先导制剂，特异性靶向CD 44（+）肿瘤。 具体的研究目标包括：1）评价非靶向以及 专有的铅Fe 8-化合物及其水溶性共轭物的靶向制剂，以增强MR 人卵巢癌异种移植模型的腹腔内成像; 2）开发/选择具有高亲和力的硫代适体 对于CD 44家族成员、亲本和/或选择的剪接变体;和3）为了合成适当的 化学官能化的铅Fe 8-簇的衍生物，这将允许抗-CD 44 以确定CD 44适体-Fe 8-簇缀合物是否改善MR成像灵敏度 通过与HA-Fe 8 CA以及非靶向的 配合物 我们的目标和期望是，在本研究结束时，我们将能够选择一个主要CA 用于进一步临床前开发的制剂，并随后跟踪临床评价。与 最近的临床试验结果证明了使用基于IP的药物治疗方案的令人信服的证据， 这种MRI CA的可用性以及非侵入性连续成像灵敏度的相关改善 腹膜肿瘤负荷的增加可能会在CD 44（+）肿瘤中发现一个重要的临床小生境， 成像技术是次优的（例如结肠直肠癌腹膜转移）。