The use of antibody modified liposomes loaded with AMO-1 to deliver oligonucleotides to ischemic myocardium for arrhythmia therapy.
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 vivo imaging. The uptake and bio-distribution in vitro were observed by live cell station and flow cytometry, respectively. The anti-arrhythmic effects of cT-A-LIP in 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.
Department of Pharmaceutics, Daqing Campus of Harbin Medical University, Daqing 163319, China.
Meifang
M
Liu
Department of Pharmaceutics, Daqing Campus of Harbin Medical University, Daqing 163319, China.
Minghui
M
Li
Department of Pharmaceutics, Daqing Campus of Harbin Medical University, Daqing 163319, China.
Shouli
S
Sun
Department of Pharmaceutics, Harbin Medical University, Harbin 150086, China.
Baoxin
B
Li
Department of Pharmaceutics, Daqing Campus of Harbin Medical University, Daqing 163319, China.
Dan
D
Du
Department of Pharmaceutics, Harbin Medical University, Harbin 150086, China.
Jialiang
J
Sun
Department of Pharmaceutics, Daqing Campus of Harbin Medical University, Daqing 163319, China.
Fangyuan
F
Cao
Department of Pharmaceutics, Daqing Campus of Harbin Medical University, Daqing 163319, China.
Haichun
H
Li
Department of Chemical and Biological Engineering, Ames, IA 50011, USA.
Feng
F
Jia
Department of Chemical and Biological Engineering, Ames, IA 50011, USA.
Tianfu
T
Wang
Department of Pharmaceutics, Daqing Campus of Harbin Medical University, Daqing 163319, China.
Naidan
N
Chang
Department of Pharmaceutics, Daqing Campus of Harbin Medical University, Daqing 163319, China.
Hui
H
Yu
Department of Chemical and Biological Engineering, Ames, IA 50011, USA; Department of Civil, Construction and Environmental Engineering, Iowa State University, Ames, IA 50011, USA.
Qun
Q
Wang
Department of Pharmaceutics, Daqing Campus of Harbin Medical University, Daqing 163319, China; Department of Chemical and Biological Engineering, Ames, IA 50011, USA. Electronic address: fisher1688@163.com.
Haisheng
H
Peng
D000818:Animals; D000906:Antibodies / Q000378:metabolism*; D001145:Arrhythmias, Cardiac / Q000150:complications* / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D002470:Cell Survival / Q000187:drug effects; D005434:Flow Cytometry; D008081:Liposomes / Q000737:chemistry* / Q000648:ultrastructure; D035683:MicroRNAs / Q000378:metabolism; D017202:Myocardial Ischemia / Q000150:complications* / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010316:Particle Size; D051381:Rats; D017208:Rats, Wistar; D055672:Static Electricity; D013997:Time Factors; D059008:Time-Lapse Imaging; D019210:Troponin I / Q000378:metabolism; D014463:Ultrasonography
D000906:Antibodies; D008081:Liposomes; C542191:MIRN1 microRNA, rat; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D019210:Troponin I
Anti-cTnI antibody; Antisense oligonucleotide; In vivo imaging; Ischemic arrhythmias; Liposomes; MicroRNA-1