Polymer chelate conjugates for diagnostic cancer imaging

本研究项目的目标是合成和开发新的靶向 纳米钆（III）螯合物作为安全、有效和肿瘤特异性造影剂 用磁共振成像（MRI）诊断癌症成像的试剂。FDA的 批准的临床MRI造影剂是非特异性试剂。经常使用高剂量 以实现准确的癌症诊断。然而，最近有报道称， 剂量的钆基造影剂可引起潜在致命的肾源性 某些肾功能不全患者的全身性纤维化。我们认为，有效的 肿瘤特异性造影剂可以显著减少注射剂量 癌症检测，因此，大大减少钆的毒副作用， 基于造影剂。我们建议设计，合成和评估肿瘤特异性 作为新型靶向MRI造影剂的肽靶向纳米Gd-DO 3A缀合物 用于诊断癌症成像的试剂。靶向造影剂将导致有效的 肿瘤特异性对比增强，剂量大大降低， 在核磁共振检查后从尸体上取下的他们将大大提高安全性 MRI增强扫描在肿瘤诊断中应用价值项目的具体目标 设计、合成和表征肿瘤特异性肽靶向纳米粒， 致密三维对称纳米晶中的Gd-DO 3A偶联物 作为靶向MRI造影剂的大分子;评价其理化性质 性质，包括transmetabolic稳定性和弛豫性，和生物学性质， 包括靶向纳米MRI的细胞毒性、血液毒性和肿瘤结合 造影剂;研究靶向纳米球造影剂对 在动物肿瘤模型中以降低的剂量进行肿瘤特异性对比增强MR成像; 评价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组织蓄积和肿瘤 靶向纳米MRI造影剂的靶向。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。新型肿瘤特异性MRI造影剂将被设计和开发， 准确和早期的癌症检测。准确的癌症诊断将通过 靶向造影剂的剂量大大降低，这将进一步改善 对比增强MRI的安全性。

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 relaxivity, 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. 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.