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PRE-CLINICAL RESEARCH

Prolonged Targeting of Ischemic/Reperfused Myocardium by Liposomal Adenosine Augments Cardioprotection in Rats

Hiroyuki Takahama, MD^_*,,, Tetsuo Minamino, MD, PhD^,_*, Hiroshi Asanuma, MD, PhD, Masashi Fujita, MD, PhD, Tomohiro Asai, PhD^¶, Masakatsu Wakeno, MD, PhD^_*,,, Hideyuki Sasaki, MD^_*,,, Hiroshi Kikuchi, PhD^#, Kouichi Hashimoto^_**, Naoto Oku, PhD^¶, Masanori Asakura, MD, PhD, Jiyoong Kim, MD, Seiji Takashima, MD, PhD, Kazuo Komamura, MD, PhD^||, Masaru Sugimachi, MD, PhD^||, Naoki Mochizuki, MD, PhD^_*, and Masafumi Kitakaze, MD, PhD, FACC

^_* Department of Molecular Imaging in Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
Department of Cardiovascular Medicine, National Cardiovascular Center, Osaka, Japan
Department of Structural Analysis, Research Institute, National Cardiovascular Center, Osaka, Japan
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
^|| Department of Cardiovascular Dynamics, Research Institute, National Cardiovascular Center, Osaka, Japan
^¶ Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
^# Daiichi Pharmaceutical Co., Tokyo, Japan
^_** Daiichi-Sankyo Pharmaceutical Co., Tokyo, Japan

Manuscript received September 4, 2008; revised manuscript received October 21, 2008, accepted November 3, 2008.

^_* Reprint requests and correspondence: Dr. Tetsuo Minamino, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan (Email: minamino{at}medone.med.osaka-u.ac.jp).

Objectives: 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 µg/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 µg/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 A₁, A_2a, A_2b, or A₃ 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.

Key Words: myocardial infarction • liposome • drug delivery system • adenosine

Abbreviations and Acronyms   8-SPT = 8-(p-sulfophenyl) theophylline   EM = electron microscopy   MI = myocardial infarction   PEG = polyethylene glycol   RI = radioisotope   TTC = triphenyltetrazolium chloride

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