Background: In order to solve 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, nitroxides lower relaxivity and metabolizes rapidly in vivo are still challenge. Previous researches have proven that the construction of macromolecular nitroxides contrast agents (mORCAs) is a promising solution through the macromolecularization of nitroxides (ie, large molecules carry nitroxides). Macromolecular effects not only improve 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.
Results: Branched pDHPMA-mPEG-Ppa-PROXYL with high molecular weight (MW=160 kDa) and nitroxides content (0.059 mmol/g), it can form a nanoscale (~ 28 nm) self-assembled aggregate in a water environment and hydrophobic PROXYL can be protected by the hydrophilic outer layer to obtain the strong reduction resistance in vivo. Compared with the small molecular 3-Carboxy-PROXYL (3-CP), Branched pDHPMA-mPEG-Ppa-PROXYL displays there prominent performance: 1) its longitudinal relaxivity (0.50 mM-1 s-1) is about three times that of the 3-CP (0.17 mM-1 s-1); 2) the blood retention time of nitroxides is increased significantly from a few minutes of 3-CP to 6 h; 3) it could provide 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.
Conclusions: 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 tumor, liver and kidney imaging, but also in cardiovascular system imaging, which expands the application scope of this kind of CAs.