Polymer chelate conjugates for diagnostic cancer imaging

描述（由申请人提供）：本研究项目的目标是合成和开发新型靶向纳米球状钆（III）螯合剂，作为安全、有效和肿瘤特异性的对比剂，用于磁共振成像（MRI）诊断癌症成像。FDA批准的临床MRI造影剂是非特异性的。高剂量通常用于实现准确的癌症诊断。然而，最近有报道称，在一些肾功能不全的患者中，高剂量的钆造影剂可能导致潜在的致命性肾源性系统性纤维化。我们相信，一种有效的肿瘤特异性造影剂可以大大减少注射剂量，以准确检测癌症，因此，大大减少钆基造影剂的毒副作用。我们建议设计，合成和评估肿瘤特异性肽靶向纳米球形Gd-DO3A偶联物作为诊断癌症成像的新型靶向MRI造影剂。靶向造影剂将在大幅降低的剂量下产生有效的肿瘤特异性造影剂增强，并在MRI检查后迅速从体内消除。它们将显著提高对比增强MRI在癌症诊断中的安全指标。该项目的具体目标是设计，合成和表征肿瘤特异性肽靶向纳米红蛋白Gd-DO3A缀合物，这些纳米红蛋白是紧凑的和三维对称的纳米红蛋白大分子，作为靶向MRI造影剂；评估靶向纳米球状MRI造影剂的物理化学特性，包括变性稳定性和相关性，以及生物特性，包括细胞毒性、血液毒性和肿瘤结合；研究靶向纳米球造影剂在减少剂量的动物肿瘤模型中用于肿瘤特异性造影剂增强磁共振成像的效果；评估靶向纳米球状MRI造影剂的体内毒理学和药物特性，包括急性和亚急性毒性、药代动力学、消除、Gd组织积累和肿瘤靶向性。长期目标是开发安全、有效和有针对性的MRI造影剂，用于特定的癌症成像。

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.