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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1960.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Site-Specific Targeting of Nanoparticle Prednisolone Reduces In-Stent Restenosis in a Rabbit Model of Established Atheroma

Michael Joner; Katsumi Morimoto; Hiroaki Kasukawa; Kristin Steigerwald; Sabine Merl; Gaku Nakazawa; Michael C. John; Aloke V. Finn; Eduardo Acampado; Frank D. Kolodgie; Herman K. Gold; Renu Virmani

From Deutsches Herzzentrum Muenchen und 1. Medizinische Klinik, Klinikum rechts der Isar (M.L., K.S., S.M.), Muenchen, Germany; CVPath Insitute Inc (G.N., E.A., F.D.K., R.V.), Gaithersburg, Md; Cardiac Unit (M.C.J., A.V.F., H.K.G.), Department of Internal Medicine, Massachusetts General Hospital, Boston, Mass; Research and Development Center, Terumo Corporation (K.M., H.K.), Tokyo, Japan.

Correspondence to Renu Virmani, MD, Medical Director, CVPath, Institute Inc, 19 Firstfield Road, Gaithersburg, MD 20878. E-mail rvirmani{at}cvpath.org

Objective— TRM-484 is a novel drug consisting of nanoparticles of prednisolone with high affinity to chondroitin sulfate proteoglycans (CSPGs). This may allow for neointimal suppression via directed targeting to areas of injury at systemic concentrations low enough to avoid adverse side effects known to occur with oral delivery of steroids.

Methods and Results— Atherosclerotic New Zealand white Rabbits were implanted with bare metal stents and randomized to receive intravenous TRM-484 at doses of 1 mg/kg or 0.32 mg/kg starting at the day of stenting and continuing 3 times a week for the duration of the study. Control animals received empty liposomes (placebo) or saline infusion. Stented arterial segments were harvested at 42 days and processed for histomorphometry and immunohistochemistry. Tissue and plasma levels were determined along with confocal microscopic analysis to determine distribution of rhodamine-labeled TRM-484 at various time points. TRM-484 was exclusively observed at sites of stent-induced injury, with absence of drug in contralateral nonstented arteries. Tissue concentration of stented arteries exceeded that of contralateral nonstented arteries by 100-fold 24 hours after administration of 1 mg/kg TRM-484 and resulted in significant reduction of percent stenosis compared to saline and placebo treated rabbits (22.5±4.4 versus 31.0±8.4 and 29.5±8.1%, P<0.03).

Conclusion— TRM-484 at doses of 1 mg/kg resulted in significant suppression of in-stent neointimal growth in atherosclerotic rabbits. Site-specific targeting by this nanoparticle steroid in injured atherosclerotic areas might be a valuable and cost-effective approach for the prevention of in-stent restenosis.

Key Words: stent • inflammation • steroids • atherosclerosis • restenosis

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From Systemic Shotgun to Site-Specific Nanoparticle-Targeted Delivery: A New Paradigm for Drug Delivery

Ian J. Sarembock
Arterioscler Thromb Vasc Biol 2008 28: 1879-1881. [Extract] [Full Text] [PDF]

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