Huaxi MR Research Center (HMRRC), Department of Radiology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041, Chengdu, China.
Department of Radiology, Chongqing General Hospital, University of Chinese Academy of Sciences (UCAS), No. 104 Pipashan Main Street, Yuzhong District, 400014, Chongqing, China.
J Nanobiotechnology. 2021 Jul 9;19(1):205. doi: 10.1186/s12951-021-00951-z.
In order to address the potential toxicity of metal-based magnetic resonance imaging (MRI) contrast agents (CAs), a concept of non-metallic MRI CAs has emerged. Currently, paramagnetic nitroxides (such as (2,2,5,5-tetramethylpyrrolidine-1-oxyl, PROXYL), (2,2,6,6-tetramethylpiperidine-1-oxide, TEMPO), etc.) are being extensively studied because their good stability and imaging mechanism are similar to metal-based contrast agents (such as Gd chelate-based clinical CAs). However, a lower relaxivity and rapid in vivo metabolism of nitroxides remain to be addressed. Previous studies have demonstrated that the construction of macromolecular nitroxides contrast agents (mORCAs) is a promising solution through macromolecularization of nitroxides (i.e., use of large molecules to carry nitroxides). Macromolecular effects not only increase the stability of nitroxides by limiting their exposure to reductive substances in the body, but also improve the overall H water relaxation by increasing the concentration of nitroxides and slowing the molecular rotation speed.
Branched pDHPMA-mPEG-Ppa-PROXYL with a high molecular weight (MW = 160 kDa) and a nitroxides content (0.059 mmol/g) can form a nanoscale (~ 28 nm) self-assembled aggregate in a water environment and hydrophobic PROXYL can be protected by a hydrophilic outer layer to obtain strong reduction resistance in vivo. Compared with a small molecular CA (3-Carboxy-PROXYL (3-CP)), Branched pDHPMA-mPEG-Ppa-PROXYL displays three prominent features: (1) its longitudinal relaxivity (0.50 mM s) is about three times that of 3-CP (0.17 mM s); (2) the blood retention time of nitroxides is significantly increased from a few minutes of 3-CP to 6 h; (3) it provides long-term and significant enhancement in MR imaging of the tumor, liver, kidney and cardiovascular system (heart and aortaventralis), and this is the first report on nitroxides-based MRI CAs for imaging the cardiovascular system.
As a safe and efficient candidate metal-free magnetic resonance contrast agent, Branched pDHPMA-mPEG-Ppa-PROXYL is expected to be used not only in imaging the tumor, liver and kidney, but also the cardiovascular system, which expands the application scope of these CAs.
为了解决基于金属的磁共振成像（MRI）对比剂（CA）的潜在毒性问题，出现了一种非金属 MRI CA 的概念。目前，顺磁氮氧自由基（如（2,2,5,5-四甲基吡咯烷-1-氧自由基，PROXYL）、（2,2,6,6-四甲基哌啶-1-氧化物，TEMPO）等）正在被广泛研究，因为它们的稳定性好，成像机制类似于基于金属的对比剂（如 Gd 螯合物的临床 CA）。然而，氮氧自由基的弛豫率较低和体内代谢较快仍然是需要解决的问题。先前的研究表明，通过氮氧自由基的大分子化（即使用大分子携带氮氧自由基）构建大分子氮氧自由基对比剂（mORCA）是一种很有前途的解决方案。大分子效应不仅通过限制其与体内还原物质的接触来增加氮氧自由基的稳定性，而且通过增加氮氧自由基的浓度和减慢分子旋转速度来提高整体 H 水弛豫率。
具有高分子量（MW=160 kDa）和氮氧自由基含量（0.059 mmol/g）的支化 pDHPMA-mPEG-Ppa-PROXYL 在水环境中可以形成纳米级（约 28 nm）自组装聚集体，疏水性的 PROXYL 可以被亲水性外壳保护，从而在体内获得很强的抗还原能力。与小分子 CA（3-羧基-PROXYL（3-CP）相比，支化 pDHPMA-mPEG-Ppa-PROXYL 具有三个显著特点：（1）其纵向弛豫率（0.50 mM s）约为 3-CP（0.17 mM s）的三倍；（2）氮氧自由基的血液保留时间从 3-CP 的几分钟显著延长至 6 小时；（3）它可以在肿瘤、肝脏、肾脏和心血管系统（心脏和腹主动脉）的磁共振成像中提供长期和显著的增强效果，这是首次报道用于心血管系统成像的基于氮氧自由基的 MRI CA。
作为一种安全有效的无金属磁共振对比剂候选物，支化 pDHPMA-mPEG-Ppa-PROXYL 有望不仅用于肿瘤、肝脏和肾脏成像，还用于心血管系统成像，从而扩展了这些 CA 的应用范围。
