Pre-Clinical Research
Prolonged Targeting of Ischemic/Reperfused Myocardium by Liposomal Adenosine Augments Cardioprotection in Rats

https://doi.org/10.1016/j.jacc.2008.11.014Get rights and content
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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, A2a, A2b, or A3subtype 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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Supported by a grant for Scientific Research and a grant for the Advancement of Medical Equipment from the Japanese Ministry of Health, Labor, and Welfare, as well as a grant from the Japan Cardiovascular Research Foundation.