Immunoliposomal drug-delivery system targeting lectin-like oxidized low-density lipoprotein receptor–1 for carotid plaque lesions in rats

Laboratory investigation

Atsushi Saito Tohoku University Hospital, Emergency Center, and

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 M.D., Ph.D.
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Hiroaki Shimizu Department of Neuroendovascular Therapy, Tohoku University Graduate School of Medicine, Sendai;

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Yusuke Doi Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, University of Tokushima, Tokushima;

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Tatsuhiro Ishida Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, University of Tokushima, Tokushima;

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Miki Fujimura Department of Neurosurgery, Konan Hospital, Sendai; and

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Takashi Inoue Department of Neurosurgery, Konan Hospital, Sendai; and

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Hiroshi Kiwada Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, University of Tokushima, Tokushima;

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Teiji Tominaga Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan

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 M.D., Ph.D.
Page Range:
720–727
Volume/Issue:
Volume 115: Issue 4
DOI link:
https://doi.org/10.3171/2011.5.JNS10227
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Object

Targeted drug delivery with immunoliposomes has been applied to various in vivo animal models and is newly focused as a novel therapeutic target. Lectin-like oxidized low-density lipoprotein receptor–1 (LOX1) is a potent regulator of systemic atherosclerosis, and the authors focused on its effect on carotid plaques. The authors developed a LOX1-targeted liposomal rho-kinase inhibitor and examined the therapeutic effect on carotid intimal hypertrophy in rats.

Methods

LOX1-targeted rho-kinase inhibitor fasudil-containing liposomes, composed of hydrogenated soy phosphatidylcholine/cholesterol/PEG2000-DSPE, were prepared by conjugating anti-LOX1 antibodies on the surface and by remote loading of fasudil. Carotid intimal hypertrophy was induced by balloon injury, and the drugs were intravenously administered on Day 3 postinjury. The rats were divided into 4 groups: nontreatment, treatment with intravenous fasudil (2 mg), treatment with liposomal fasudil (2 mg), and treatment with LOX1-targeted liposomal fasudil (2 mg). The authors compared intimal hypertrophy, atherosclerotic factor, and matrix metalloproteinase-9 expression among groups.

Results

DiI–labeled LOX1-targeted liposomes were prominently observed in the lesions on Day 7 after the surgery. The intimal thickness was significantly reduced in the LOX1-targeted liposomal fasudil–treated group (mean 81.6 ± 13.9 μm) compared with the other groups (no treatment 105.4 ± 16.8 μm; fasudil treatment 102.4 ± 20.0 μm; and liposomal fasudil treatment 102.8 ± 22.2 μm; p = 0.046). Matrix metalloproteinase-9 expression was also significantly reduced in the LOX1-targeted liposomal fasudil group.

Conclusions

Liposomes conjugated with anti-LOX1 antibody effectively reached carotid artery lesions, and liposomal rho-kinase significantly inhibited intimal hypertrophy. The new liposomal drug delivery system targeting LOX1 may become a therapeutic strategy for atherosclerotic diseases.

Abbreviations used in this paper:

HSPC = high-purity hydrogenated soy phosphatidylcholine cholesterol; LOX1 = lectin-like oxidized low-density lipoprotein receptor–1; MMP = matrix metalloproteinase; oxLDL = oxidized low-density lipoprotein.
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Contributor Notes

Address correspondence to: Atsushi Saito, M.D., Ph.D., Department of Neurosurgery, Tohoku University, 1-1 Seiryomachi, Aoba, Sendai, Miyagi, 980-8574 Japan. email: satsushi2002@yahoo.co.jp.

Please include this information when citing this paper: published online June 17, 2011; DOI: 10.3171/2011.5.JNS10227.

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