The use of antibody modified liposomes loaded with AMO-1 to deliver oligonucleotides to ischemic myocardium for arrhythmia therapy

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• 作者：Meifang Liu ; Minghui Li ; Shouli Sun ; Baoxin Li ; Dan Du ; Jialiang Sun ; Fangyuan Cao ; Haichun Li ; Feng Jia ; Tianfu Wang ; Naidan Chang ; Hui Yu ; Qun Wang ; Haisheng Peng
• 关键词：Ischemic arrhythmias ; MicroRNA-1 ; Liposomes ; Antisense oligonucleotide ; Anti-cTnI antibody ; In vivo imaging
• 刊名：Biomaterials
• 出版年：April, 2014
• 年：2014
• 卷：35
• 期：11
• 页码：3697-3707
• 全文大小：4246 K

文摘

MicroRNA-1 (miR-1) has been found in cardiac and skeletal tissues. It is overexpressed in ischemic cardiac tissues. Down-regulation of miR-1 could relieve arrhythmogenesis by the anti-miR-1 antisense oligonucleotides (AMO-1). To increase the therapeutic efficiency and inhibit off-target effects of AMO-1, here we explored anti-cardiac troponin I (cTnI) antibody modified liposomes loading with AMO-1 (cT-A-LIP) to deliver the oligonucleotides to ischemic myocardium tissues. Liposomal cytotoxicity was assessed by MTT assay. The targeting abilities to foci were evaluated by in聽vivo imaging. The uptake and bio-distribution in聽vitro were observed by live cell station and flow cytometry, respectively. The anti-arrhythmic effects of cT-A-LIP in聽vivo were evaluated by electrocardiograms (ECG), immunohistochemistry, real-time PCR and patch-clamp recording. Immunohistochemistry showed that cTnI expression had a peak at the third day after myocardial infarction (MI). After cT-LIP administration via tail vein, accumulation of fluorescent trackers in the ischemic foci was significantly increased more than that of LIP. In addition, after cT-A-LIP administration, the ischemic arrhythmias were recovered and ST segment in ECG was elevated nearly back to normal. Compared with MI group, miR-1 expression was significantly down-regulated while Kir2.1 and CX43 protein expression were increased. Patch-clamp recordings showed that cT-A-LIP as well as AMO-1 incubation increased K⁺ current density in guinea pigs ventricular cardiomyocytes acting on repolarized membrane potential. In conclusion, the cT-A-LIP not only delivered AMO-1 to ischemic myocardium in MI rats, but validated AMO-1 on relieving ischemic arrhythmia by silencing of miR-1 in ischemic myocardium and restoring the depolarized resting membrane potential (RMP) in MI rats.