Key Laboratory of Colloid, Interface and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Bei Yi Jie 2, Zhong Guan Cun, Beijing 100190, China.
J Mater Chem B. 2020 Aug 12;8(31):6956-6963. doi: 10.1039/d0tb00893a.
MRI contrast agents such as paramagnetic Gd(iii)-chelates, can improve the ability of MRI in differentiating diseased and healthy tissues, and have been widely used in clinical diagnosis. However, the enhancement effect of small molecular MRI contrast agents is unsatisfied due to their relative high rotation rates. Furthermore, the small molecular contrast agents also suffer from the short blood half-life and nonspecific extracellular diffusion in tissues, which also restricts their applications. To address these issues, we developed a macromolecular MRI contrast agent based on a zwitterionic metal-chelating polymer. Poly(acrylic acid) (PAA) was chosen as the main chain, and diethylenetriamine pentaacetic acid (DTPA) as the metal-chelating group was coupled through the carboxyl groups of PAA using diethylenetriamine (DET) as a linker. The macromolecular MRI contrast agent constructed by chelating with Gd3+ (Gd-PAA) exhibited a much higher longitudinal relaxation rate (r1) than the clinical contrast agent Gd-DTPA. Importantly, due to the stealth ability of the zwitterionic structure, Gd-PAA can reside in the blood long enough without any microvascular leakage in the extracellular space of normal tissues, which allows it to be used for precise blood MR imaging, such as hepatorenal angiography, but also for tumor imaging because of the enhanced permeability and retention (EPR) effecta. Besides, the result of long-term toxicity tests highlights the safety feature of the current contrast agent. Hence, the current contrast agent overcomes the defect of traditional small molecular Gd(iii)-based T1-weighted contrast agents and shows great prospects for future clinical applications.
磁共振成像对比剂，如顺磁 Gd(iii)-螯合物，可以提高磁共振成像区分病变和健康组织的能力，已被广泛应用于临床诊断。然而，小分子磁共振成像对比剂由于其相对较高的旋转率，增强效果并不令人满意。此外，小分子对比剂还存在血液半衰期短和在组织中扩散非特异性的问题，这也限制了它们的应用。为了解决这些问题，我们开发了一种基于两性离子金属螯合聚合物的高分子磁共振成像对比剂。选择聚丙烯酸 (PAA) 作为主链，通过 PAA 的羧基与二亚乙基三胺五乙酸 (DTPA) 偶联，并使用二亚乙基三胺 (DET) 作为连接剂。通过与 Gd3+ 螯合构建的高分子磁共振成像对比剂 (Gd-PAA) 的纵向弛豫率 (r1) 明显高于临床对比剂 Gd-DTPA。重要的是，由于两性离子结构的隐身能力，Gd-PAA 可以在正常组织的细胞外空间没有任何微血管渗漏的情况下在血液中停留足够长的时间，这使其可用于精确的血液磁共振成像，如肝肾血管造影，也可用于肿瘤成像，因为其具有增强的通透性和保留（EPR）效应。此外，长期毒性试验的结果突出了当前对比剂的安全性特征。因此，当前的对比剂克服了传统小分子 Gd(iii)-基 T1 加权对比剂的缺陷，具有广阔的临床应用前景。
