Polymer chelate conjugates for diagnostic cancer imaging

描述（由申请人提供）：本研究项目的目的是合成和开发新型靶向纳米钆（III）螯合物，作为安全、有效和肿瘤特异性造影剂，用于磁共振成像（MRI）诊断癌症成像。FDA批准的临床MRI造影剂是非特异性试剂。高剂量通常用于实现准确的癌症诊断。然而，最近有报道称，高剂量的钆基造影剂可在某些肾功能障碍患者中引起潜在致命的肾源性全身纤维化。我们相信，有效的肿瘤特异性造影剂可以显著降低用于精确癌症检测的注射剂量，因此，极大地减少钆基造影剂的毒副作用。我们建议设计、合成和评价肿瘤特异性肽靶向纳米Gd-DO 3A缀合物作为新型靶向MRI造影剂用于诊断癌症成像。靶向造影剂将以大幅降低的剂量产生有效的肿瘤特异性造影增强，并在MRI检查后迅速从体内消除。它们将显著提高增强MRI在肿瘤诊断中的安全性指标。本项目的具体目标是从紧凑的三维对称纳米大分子中设计、合成和表征肿瘤特异性肽靶向纳米Gd-DO 3A缀合物作为靶向MRI造影剂;评价靶向纳米MRI造影剂的理化性质，包括transmetabolism稳定性和相关性，以及生物学性质，包括细胞毒性、血液毒性和肿瘤结合;研究靶向纳米造影剂在动物肿瘤模型中以降低剂量进行肿瘤特异性对比增强MR成像的有效性;评价体内毒理学和药物特性，包括靶向纳米MRI造影剂的急性和亚急性毒性、药代动力学、消除、Gd组织蓄积和肿瘤靶向。长期目标是开发安全、有效和靶向的MRI造影剂用于特定癌症成像。 将设计和开发新型肿瘤特异性MRI造影剂，以实现更准确和更早的癌症检测。准确的癌症诊断将实现与靶向造影剂在一个显着减少的剂量，这将进一步提高对比增强MRI的安全性。

DESCRIPTION (provided by applicant): The objectives of this research project are to synthesize and develop novel targeted nanoglobular gadolinium(III) chelates as safe, effective and tumor-specific contrast agents for diagnostic cancer imaging with magnetic resonance imaging (MRI). The FDA approved clinical MRI contrast agents are nonspecific agents. High doses are often used to achieve accurate cancer diagnosis. However, it has been recently reported that high doses of gadolinium-based contrast agents can cause potentially fatal nephrogenic systemic fibrosis in some patients with renal malfunctions. We believe that an effective tumor specific contrast agent can substantially reduce the injected dose for accurate cancer detection and, therefore, greatly minimize the toxic side effects of gadolinium- based contrast agents. We propose to design, synthesize and evaluate tumor-specific peptide targeted nanoglobular Gd-DO3A conjugates as novel targeted MRI contrast agents for diagnostic cancer imaging. The targeted contrast agents will result in effective tumor specific contrast enhancement at a substantially reduced dose and rapidly eliminate from the body after the MRI examinations. They will significantly improve the safety index of contrast enhanced MRI in cancer diagnosis. The specific aims of the projects are to design, synthesize and characterize tumor-specific peptide targeted nanoglobular Gd-DO3A conjugates from compact and three-dimensional symmetric nanoglobular macromolecules as targeted MRI contrast agents; to evaluate the physicochemical properties, including transmetallation stability and relativity, and biological properties, including cytotoxicity, hemotoxicity and tumor binding of the targeted nanoglobular MRI contrast agents; to investigate the efficacy of the targeted nanoglobular contrast agents for tumor-specific contrast enhanced MR imaging in animal tumor models at reduced doses; to evaluate in vivo toxicological and pharmaceutical properties, including acute and subacute toxicity, pharmacokinetics, elimination, Gd tissue accumulation and tumor targeting of the targeted nanoglobular MRI contrast agents. The long-term goal is to develop safe, effective and targeted MRI contrast agents for specific cancer imaging. PUBLIC HEALTH RELEVANCE Novel tumor-specific MRI contrast agents will be designed and developed for more accurate and earlier cancer detection. Accurate cancer diagnosis will be achieved with the targeted contrast agents at a substantially reduced dose, which will further improve the safety of contrast enhanced MRI.