期刊
JOURNAL OF NEUROSURGERY
卷 115, 期 4, 页码 720-727出版社
AMER ASSOC NEUROLOGICAL SURGEONS
DOI: 10.3171/2011.5.JNS10227
关键词
atherosclerosis; carotid artery; drug delivery; matrix metalloproteinase; liposome; vascular disorders
资金
- Japan Society for the Promotion of Science
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/PEG(2000)-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 mu m) compared with the other groups (no treatment 105.4 +/- 16.8 mu m; fasudil treatment 102.4 +/- 20.0 mu m; and liposomal fasudil treatment 102.8 +/- 22.2 mu m; 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. (DOI: 10.3171/2011.5.JN510227).
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