Application of nanoparticle technology for the prevention of restenosis after balloon injury in rats.
Restenosis after percutaneous coronary intervention continues to be a serious problem in clinical cardiology. Recent advances in nanoparticle technology have enabled us to deliver an antiproliferative drug selectively to the balloon-injured artery for a longer time. NK911, which is a core-shell nanoparticle of polyethyleneglycol-based block copolymer encapsulating doxorubicin, accumulates in vascular lesions with increased permeability. We first confirmed that balloon injury caused a marked and sustained increase in vascular permeability (as evaluated by Evans blue staining) for a week in the rat carotid artery. We then observed that intravenous administration of just 3 times of NK911, but not doxorubicin alone, significantly inhibited the neointimal formation of the rat carotid artery at 4 weeks after the injury in both a single- and double-injury model. Immunostaining demonstrated that the effect of NK911 was due to inhibition of vascular smooth muscle proliferation but not to enhancement of apoptosis or inhibition of inflammatory cell recruitment. Measurement of vascular concentrations of doxorubicin confirmed the effective delivery of the agent to the balloon-injured artery by NK911 in both a single- and double-injury model. RNA protection assay demonstrated that NK911 inhibited expression of several cytokines but not that of apoptosis-related molecules. NK911 was well tolerated without any adverse systemic effects. These results suggest that nanoparticle technology to target vascular lesions with increased permeability is a promising and safe approach for the prevention of restenosis after balloon injury. The full text of this article is available at http://www.circresaha.org.
Uwatoku
Toyokazu
T
Department of Cardiovascular Medicine, Kyushu University Graduate, School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Shimokawa
Hiroaki
H
Abe
Kohtaro
K
Matsumoto
Yasuharu
Y
Hattori
Tsuyoshi
T
Oi
Keiji
K
Matsuda
Takehisa
T
Kataoka
Kazunori
K
Takeshita
Akira
A
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020212:Carotid Artery Injuries / Q000503:physiopathology / Q000517:prevention & control; D002404:Catheterization / Q000009:adverse effects; D023903:Coronary Restenosis / Q000209:etiology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D006439:Hemodynamics / Q000187:drug effects; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008297:Male; D008823:Micelles; D036103:Nanotechnology; D010455:Peptides / Q000493:pharmacokinetics / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000493:pharmacokinetics / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D011921:Rats, Inbred WKY; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000903:Antibiotics, Antineoplastic; D008823:Micelles; C438847:NK911; D010455:Peptides; D018809:Proliferating Cell Nuclear Antigen; D011092:Polyethylene Glycols; D004317:Doxorubicin