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

题目：完整项目A -靶向，铁基MRI造影剂的合成和临床前评价

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).