Strategy to prevent cardiac toxicity induced by polyacrylic acid decorated iron MRI contrast agent and investigation of its mechanism
Strategy to prevent cardiac toxicity induced by polyacrylic acid decorated iron MRI contrast agent and investigation of its mechanism
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聚丙烯酸修饰铁MRI造影剂心脏毒性的预防策略及机制研究
DOI：
10.1016/j.biomaterials.2019.119442
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发表时间：
2019
期刊：
影响因子：
14
通讯作者：
Duan Yourong
中科院分区：
文献类型：
--
作者：
Fu Hao;Miao Chongchong;Rui Yuanpeng;Hu Fenglin;Shen Ming;Xu Hong;Zhang Chunfu;Dong Yi;Wang Wenping;Gu Hongchen;Duan Yourong
聚电解质修饰的氧化铁纳米颗粒在临床磁共振成像和贫血治疗方面具有巨大的应用潜力，但其可能的心脏毒性却鲜有报道。本文合成了聚丙烯酸（PAA）包覆的Fe_3O_4纳米粒子（PION），并将其应用于体内，观察到了致死性反应。彩色多普勒超声和动态矢量血流技术观察表明，PION可破坏电解质平衡，导致严重心力衰竭。结果表明，PION对二价离子有较强的吸收倾向，最大耐受剂量（MTD）低于100 mg/kg。心电图（ECG）显示PION对CaV1.2离子通道有明显影响，导致致命性心律失常。预防这种致命作用的适当解决方案是将Ca 2+（n（Ca）：n（COOH）= 3：8）预螯合到PION（PION-Ca），当封闭二价阳离子与PAA的结合点时，其显示出更高的心脏和电生理安全性。Beagle犬注射进一步证实了PION-Ca的安全性。本研究探讨了PAA修饰纳米粒的心脏毒性机制，为提高PAA修饰纳米粒的安全性提供了指导，为临床应用提供了保障。
Polyelectrolyte modified iron oxide nanoparticles have great potential applications for clinical magnetic resonance imaging (MRI) and anemia treatments, however, possible associated heart toxicity is rarely reported. Here, polyacrylic acid (PAA)-coated Fe3O4nanoparticles (PION) were synthesized and lethal reactions appeared when it was appliedin vivo. The investigation of underlying mechanism showed that PION could break electrolyte balance and further resulted in serious heart failure, which was observed under color doppler ultrasound and dynamic vector blood flow technique. The results demonstrated that PION had a strong absorption tendency for divalent ions and the maximum tolerated dose (MTD) was lower than 100 mg/kg. From electrocardiography (ECG), PION presented an obvious impact on CaV1.2ion channel, which leading to fatal arrhythmia. An appropriate solution for preventing this deadly effect was pre-chelation Ca2+(n(Ca): n(COOH)= 3: 8) to PION (PION-Ca), which displayed much higher cardiac and electrophysiological safety when sealing the binding point of divalent cation ions with PAA. The injection in Beagle dogs further confirmed the safety of PION-Ca. This study explored the mechanism and offered a solution for cardiac toxicity induced by PAA-coated nanoparticles, which guides for enhancing the safety of such polyelectrolyte decorated nanoparticles and provides assurance for clinical applications.