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

Abstract

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 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.

• Authors: Atsushi Saito, Hiroaki Shimizu, Yusuke Doi, Tatsuhiro Ishida, Miki Fujimura, Takashi Inoue, Hiroshi Kiwada, Teiji Tominaga
• Journal: Journal of neurosurgery (J Neurosurg) Vol. 115 Issue 4 Pg. 720-7 (Oct 2011) ISSN: 1933-0693 [Electronic] United States
• PMID: 21682565 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Liposomes
• Scavenger Receptors, Class E
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
• fasudil

Topics

• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (administration & dosage, analogs & derivatives, therapeutic use)
• Animals
• Carotid Artery Diseases (immunology, metabolism, therapy)
• Carotid Artery, Common (immunology, metabolism)
• Drug Delivery Systems (methods)
• Liposomes (immunology)
• Male
• Plaque, Atherosclerotic (immunology, metabolism, therapy)
• Rats
• Rats, Sprague-Dawley
• Scavenger Receptors, Class E (metabolism)