Amphiphilic branched polymer-nitroxides conjugate as a nanoscale agent for potential magnetic resonance imaging of multiple objects in vivo

Journal of Nanobiotechnology

Hu Zhang¹  Yun Ye²  Shiwei Guo³  Yan Dai³  Zhiqian Li⁴  Qiang Luo⁴  Xiaoming Wang⁵  Qiyong Gong⁶  Kui Luo⁶ 

[1] Amgen Bioprocessing Centre, Keck Graduate Institute Claremont, 91711, Claremont, CA, USA;Department of Pharmacy of the Affiliated Hospital of Southwest Medical University, Southwest Medical University, 646000, Luzhou, Sichuan Province, People’s Republic of China;Department of Pharmacy of the Affiliated Hospital of Southwest Medical University, Southwest Medical University, 646000, Luzhou, Sichuan Province, People’s Republic of China;Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, 646000, Luzhou, People’s Republic of China;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;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;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;Functional and Molecular Imaging Key Laboratory of Sichuan Province, Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, 610041, Chengdu, China;

关键词: Metal-free contrast agents;    Nitroxides;    Magnetic resonance imaging;    Polymers;   

DOI  :  10.1186/s12951-021-00951-z

来源: Springer

【 摘 要 】

BackgroundIn 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 Gd3+ 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 1H water relaxation by increasing the concentration of nitroxides and slowing the molecular rotation speed.ResultsBranched 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− 1 s− 1) is about three times that of 3-CP (0.17 mM− 1 s− 1); (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.ConclusionsAs 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.Graphical abstract

【 授权许可】

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