Prolonged targeting of ischemic/reperfused myocardium by liposomal adenosine augments cardioprotection in rats.
OBJECTIVE
The purpose of this study was to investigate whether liposomal adenosine has stronger cardioprotective effects and fewer side effects than free adenosine.


BACKGROUND
Liposomes are nanoparticles that can deliver various agents to target tissues and delay degradation of these agents. Liposomes coated with polyethylene glycol (PEG) prolong the residence time of drugs in the blood. Although adenosine reduces the myocardial infarct (MI) size in clinical trials, it also causes hypotension and bradycardia.


METHODS
We prepared PEGylated liposomal adenosine (mean diameter 134 +/- 21 nm) by the hydration method. In rats, we evaluated the myocardial accumulation of liposomes and MI size at 3 h after 30 min of ischemia followed by reperfusion.


RESULTS
The electron microscopy and ex vivo bioluminescence imaging showed the specific accumulation of liposomes in ischemic/reperfused myocardium. Investigation of radioisotope-labeled adenosine encapsulated in PEGylated liposomes revealed a prolonged blood residence time. An intravenous infusion of PEGylated liposomal adenosine (450 microg/kg/min) had a weaker effect on blood pressure and heart rate than the corresponding dose of free adenosine. An intravenous infusion of PEGylated liposomal adenosine (450 microg/kg/min) for 10 min from 5 min before the onset of reperfusion significantly reduced MI size (29.5 +/- 6.5%) compared with an infusion of saline (53.2 +/- 3.5%, p < 0.05). The antagonist of adenosine A(1), A(2a), A(2b), or A(3) subtype receptor blocked cardioprotection observed in the PEGylated liposomal adenosine-treated group.


CONCLUSIONS
An infusion as PEGylated liposomes augmented the cardioprotective effects of adenosine against ischemia/reperfusion injury and reduced its unfavorable hemodynamic effects. Liposomes are promising for developing new treatments for acute MI.
Takahama
Hiroyuki
H
Department of Molecular Imaging in Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan.
Minamino
Tetsuo
T
Asanuma
Hiroshi
H
Fujita
Masashi
M
Asai
Tomohiro
T
Wakeno
Masakatsu
M
Sasaki
Hideyuki
H
Kikuchi
Hiroshi
H
Hashimoto
Kouichi
K
Oku
Naoto
N
Asakura
Masanori
M
Kim
Jiyoong
J
Takashima
Seiji
S
Komamura
Kazuo
K
Sugimachi
Masaru
M
Mochizuki
Naoki
N
Kitakaze
Masafumi
M
D000241:Adenosine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D005453:Fluorescence; D007262:Infusions, Intravenous; D008081:Liposomes / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D011092:Polyethylene Glycols; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology
D002316:Cardiotonic Agents; D004337:Drug Carriers; D008081:Liposomes; D014665:Vasodilator Agents; D011092:Polyethylene Glycols; D000241:Adenosine