title: Targeting stents with local delivery of paclitaxel-loaded magnetic nanoparticles using uniform fields.
abstract: The use of stents for vascular disease has resulted in a paradigm shift with significant improvement in therapeutic outcomes. Polymer-coated drug-eluting stents (DES) have also significantly reduced the incidence of reobstruction post stenting, a disorder termed in-stent restenosis. However, the current DESs lack the capacity for adjustment of the drug dose and release kinetics to the disease status of the treated vessel. We hypothesized that these limitations can be addressed by a strategy combining magnetic targeting via a uniform field-induced magnetization effect and a biocompatible magnetic nanoparticle (MNP) formulation designed for efficient entrapment and delivery of paclitaxel (PTX). Magnetic treatment of cultured arterial smooth muscle cells with PTX-loaded MNPs caused significant cell growth inhibition, which was not observed under nonmagnetic conditions. In agreement with the results of mathematical modeling, significantly higher localization rates of locally delivered MNPs to stented arteries were achieved with uniform-field-controlled targeting compared to nonmagnetic controls in the rat carotid stenting model. The arterial tissue levels of stent-targeted MNPs remained 4- to 10-fold higher in magnetically treated animals vs. control over 5 days post delivery. The enhanced retention of MNPs at target sites due to the uniform field-induced magnetization effect resulted in a significant inhibition of in-stent restenosis with a relatively low dose of MNP-encapsulated PTX (7.5 microg PTX/stent). Thus, this study demonstrates the feasibility of site-specific drug delivery to implanted magnetizable stents by uniform field-controlled targeting of MNPs with efficacy for in-stent restenosis.
authors.affiliation: Division of Cardiology Research, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Chorny
authors.forename: Ilia
authors.initials: I
authors.lastname: Fishbein
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Yellen
authors.forename: Ivan S
authors.initials: IS
authors.lastname: Alferiev
authors.forename: Marina
authors.initials: M
authors.lastname: Bakay
authors.forename: Srinivas
authors.initials: S
authors.lastname: Ganta
authors.forename: Richard
authors.initials: R
authors.lastname: Adamo
authors.forename: Mansoor
authors.initials: M
authors.lastname: Amiji
authors.forename: Gary
authors.initials: G
authors.lastname: Friedman
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Levy
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems; D006083:Graft Occlusion, Vascular / Q000517:prevention & control; D008280:Magnetics; D008297:Male; D053768:Metal Nanoparticles / Q000008:administration & dosage* / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D017239:Paclitaxel / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015607:Stents
chemical_list: D017239:Paclitaxel
references.citation: J Vasc Interv Radiol. 2005 Mar;16(3):331-8
references.pmid: 15758128
references.citation: Cancer Chemother Pharmacol. 2007 Nov;60(6):907-14
references.pmid: 17375303
references.citation: Biochim Biophys Acta. 1993 Jul 11;1157(3):233-40
references.pmid: 8323953
references.citation: Circulation. 2003 Aug 19;108(7):788-94
references.pmid: 12900339
references.citation: J Control Release. 2002 Oct 30;83(3):401-14
references.pmid: 12387948
references.citation: Biochem Biophys Res Commun. 1991 Jun 14;177(2):861-6
references.pmid: 2049107
references.citation: J Pharm Sci. 1997 Dec;86(12):1458-63
references.pmid: 9423162
references.citation: Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):698-703
references.pmid: 18182491
references.citation: Biomed Chromatogr. 2007 Mar;21(3):310-7
references.pmid: 17221932
references.citation: Eur Heart J. 2009 Jan;30(1):16-24
references.pmid: 19033260
references.citation: Ann Pharmacother. 2004 Apr;38(4):661-9
references.pmid: 14766994
references.citation: J Endovasc Ther. 2006 Dec;13(6):701-10
references.pmid: 17154704
references.citation: J Control Release. 2001 May 14;72(1-3):191-202
references.pmid: 11389998
references.citation: N Engl J Med. 2007 Mar 8;356(10):1009-19
references.pmid: 17296822
references.citation: J Endovasc Ther. 2007 Aug;14(4):460-8
references.pmid: 17696619
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):159-64
references.pmid: 16371477
references.citation: Neth Heart J. 2007;15(11):395-6
references.pmid: 18612390
references.citation: Biomaterials. 1992;13(15):1093-102
references.pmid: 1493193
references.citation: J Biomed Mater Res. 1993 Aug;27(8):1019-28
references.pmid: 8408114
references.citation: Adv Protein Chem. 1985;37:161-245
references.pmid: 3904348