Polymer chelate conjugates for diagnostic cancer imaging

描述(申请人提供)：本研究项目的目标是合成和开发新型的靶向纳米球状Gd(III)络合物，作为安全、有效和肿瘤特异性的造影剂，用于磁共振成像(MRI)诊断癌症成像。FDA批准的临床MRI造影剂是非特异性药物。高剂量经常被用来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，大剂量的基于Gd的造影剂可能会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准确检测癌症所需的注射剂量，从而极大地减少基于Gd的造影剂的毒副作用。我们建议设计、合成和评价肿瘤特异性多肽纳米球Gd-DO3A偶联物作为新的靶向MRI造影剂用于癌症成像。靶向造影剂将以大大减少的剂量产生有效的肿瘤特异性对比剂增强，并在MRI检查后迅速从体内消除。它们将显著提高增强MRI在癌症诊断中的安全指数。该项目的具体目的是从致密的三维对称纳米球大分子中设计、合成和表征肿瘤特异性多肽Gd-DO3A结合物作为靶向MRI对比剂；评价靶向纳米球MRI对比剂的理化性质，包括跨金属稳定性和相关性，以及生物学特性，包括细胞毒性、血液毒性和肿瘤结合；研究靶向纳米球对比剂在动物肿瘤模型中用于肿瘤特异性对比剂增强成像的有效性；评价靶向纳米球MRI对比剂的体内毒理学和药学性质，包括急性和亚急性毒性、药动学、消除、Gd组织蓄积和肿瘤靶向性。长期目标是开发安全、有效和有针对性的核磁共振造影剂，用于特定的癌症成像。 与公众健康相关的新型肿瘤特异性核磁共振造影剂将被设计和开发，以更准确和更早地检测癌症。使用靶向造影剂将以大幅减少的剂量实现准确的癌症诊断，这将进一步提高对比剂增强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.