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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1434.)
© 2001 American Heart Association, Inc.

Vascular Biology

Formulation and Delivery Mode Affect Disposition and Activity of Tyrphostin-Loaded Nanoparticles in the Rat Carotid Model

Ilia Fishbein; Michael Chorny; Shmuel Banai; Alexander Levitzki; Haim D. Danenberg; Jianchuan Gao; Xing Chen; Evgeny Moerman; Irith Gati; Victoria Goldwasser; Gershon Golomb

From the Department of Pharmaceutics (I.F., M.C., J.G., X.C., E.M., I.G., V.G., G.G.), School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem; the Department of Cardiology (S.B.), Bikur Holim Hospital; the Department of Biological Chemistry (A.L.), Silverman Institute of Life Sciences, Hebrew University of Jerusalem; and the Department of Cardiology (H.D.D.), Hadassah-Hebrew University Hospital, Jerusalem, Israel. G.G. is a member of the David R. Bloom Center of Pharmacy at the Hebrew University of Jerusalem.

Correspondence to Dr Gershon Golomb, Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, POB 12065, Jerusalem 91120, Israel. E-mail golomb{at}md.huji.ac.il

Abstract—— Poor drug residence in the arterial wall hinders clinical implementation of local drug delivery strategies for the treatment of restenosis. A rat carotid model of vascular injury and intraluminal delivery of tyrphostin-containing polylactic acid (PLA) nanoparticles (NPs) were used to determine the relationship between residence properties and biological activity of different formulations and administration modes. The effects of delivery modes (denudation and delivery time) and formulation variables (adsorbed vs encapsulated drug, and NP size) on arterial drug/NP retention were examined. Antirestenotic effects of large (160 nm) and small (90 nm) tyrphostin-containing NPs, surface-absorbed tyrphostin, and systemic treatment were compared. Fluorescent NPs were used to study the spatial distribution of the carrier in the arterial wall. The decrease in arterial tyrphostin level over time fitted a biexponential model. Delivery time and pressure, endothelium integrity, particle size, and drug-polymer association affected local pharmacokinetics and the antirestenotic results after 14 days. The PLA-based tyrphostin NP formulation ensured a prolonged drug residence at the angioplasty site after single intraluminal application. Several readily adjustable formulation and procedural factors considerably modified arterial ingress of the drug-loaded NPs and governed their subsequent redistribution, tissue binding, elimination, and ensuing antirestenotic effect.

Key Words: restenosis • nanoparticles • local delivery • tyrphostins • controlled release

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