title: In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid-polymeric nanoparticles.
abstract: Following recent successes with percutaneous coronary intervention (PCI) for treating coronary artery disease (CAD), many challenges remain. In particular, mechanical injury from the procedure results in extensive endothelial denudation, exposing the underlying collagen IV-rich basal lamina, which promotes both intravascular thrombosis and smooth muscle proliferation. Previously, we reported the engineering of collagen IV-targeting nanoparticles (NPs) and demonstrated their preferential localization to sites of arterial injury. Here, we develop a systemically administered, targeted NP system to deliver an antiproliferative agent to injured vasculature. Approximately 60-nm lipid-polymeric NPs were surface functionalized with collagen IV-targeting peptides and loaded with paclitaxel. In safety studies, the targeted NPs showed no signs of toxicity and a ≥3.5-fold improved maximum tolerated dose versus paclitaxel. In efficacy studies using a rat carotid injury model, paclitaxel (0.3 mg/kg or 1 mg/kg) was i.v. administered postprocedure on days 0 and 5. The targeted NP group resulted in lower neointima-to-media (N/M) scores at 2 wk versus control groups of saline, paclitaxel, or nontargeted NPs. Compared with sham-injury groups, an ∼50% reduction in arterial stenosis was observed with targeted NP treatment. The combination of improved tolerability, sustained release, and vascular targeting could potentially provide a safe and efficacious option in the management of CAD.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Juliana M
authors.initials: JM
authors.lastname: Chan
authors.forename: June-Wha
authors.initials: JW
authors.lastname: Rhee
authors.forename: Chester L
authors.initials: CL
authors.lastname: Drum
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Gershon
authors.initials: G
authors.lastname: Golomb
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.forename: Omid C
authors.initials: OC
authors.lastname: Farokhzad
mesh_terms: D000818:Animals; D024141:Collagen Type IV / Q000378:metabolism; D023903:Coronary Restenosis / Q000517:prevention & control*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000627:therapeutic use*; D058426:Neointima / Q000517:prevention & control*; D017239:Paclitaxel / Q000378:metabolism / Q000627:therapeutic use*; D010455:Peptides / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D024141:Collagen Type IV; D010455:Peptides; D017239:Paclitaxel
references.citation: Circ Res. 1995 Sep;77(3):445-65
references.pmid: 7641318
references.citation: Circulation. 2005 Jun 28;111(25):3481-8
references.pmid: 15983262
references.citation: AAPS PharmSci. 2002;4(4):E41
references.pmid: 12646012
references.citation: Cardiovasc Pathol. 2002 Sep-Oct;11(5):272-6
references.pmid: 12361837
references.citation: N Engl J Med. 2006 Feb 2;354(5):483-95
references.pmid: 16452560
references.citation: Clin Pharmacol Ther. 2008 May;83(5):761-9
references.pmid: 17957183
references.citation: J Biol Chem. 1993 Dec 15;268(35):26033-6
references.pmid: 8253711
references.citation: J Control Release. 2006 Jun 12;113(1):23-30
references.pmid: 16697068
references.citation: Circulation. 2002 Sep 3;106(10):1195-8
references.pmid: 12208792
references.citation: Arterioscler Thromb Vasc Biol. 2001 Sep;21(9):1434-9
references.pmid: 11557668
references.citation: Biomaterials. 2009 Mar;30(8):1627-34
references.pmid: 19111339
references.citation: Methods Mol Med. 2007;139:1-30
references.pmid: 18287662
references.citation: Circulation. 1997 Aug 19;96(4):1291-8
references.pmid: 9286961
references.citation: Proc Natl Acad Sci U S A. 2010 May 4;107(18):8346-51
references.pmid: 20404175
references.citation: Int J Nanomedicine. 2007;2(2):143-61
references.pmid: 17722543
references.citation: ACS Nano. 2008 Aug;2(8):1696-702
references.pmid: 19206374
references.citation: Pharmacol Res. 2008 Mar;57(3):171-80
references.pmid: 18339557
references.citation: Circ Res. 2009 Apr 10;104(7):842-50
references.pmid: 19229058
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2213-8
references.pmid: 20133865
references.citation: J Control Release. 2001 May 14;72(1-3):191-202
references.pmid: 11389998
references.citation: Clin Cancer Res. 2002 Apr;8(4):1237-41
references.pmid: 11948138
references.citation: N Engl J Med. 2007 Mar 8;356(10):998-1008
references.pmid: 17296824
references.citation: Arterioscler Thromb Vasc Biol. 2007 Jul;27(7):1500-10
references.pmid: 17510464
references.citation: N Engl J Med. 1999 Jan 14;340(2):115-26
references.pmid: 9887164
references.citation: Expert Rev Cardiovasc Ther. 2007 Sep;5(5):939-53
references.pmid: 17867923
references.citation: Pharm Res. 2010 Mar;27(3):421-30
references.pmid: 20054705
references.citation: Circulation. 1997 Jul 15;96(2):636-45
references.pmid: 9244237
references.citation: N Engl J Med. 2009 May 7;360(19):1946-59
references.pmid: 19420364
references.citation: Trends Pharmacol Sci. 2010 May;31(5):199-205
references.pmid: 20172613
references.citation: J Pharm Sci. 1998 Oct;87(10):1229-34
references.pmid: 9758682
references.citation: Toxicol Lett. 2008 Apr 21;178(1):9-19
references.pmid: 18374523
references.citation: J Clin Invest. 1995 Apr;95(4):1869-76
references.pmid: 7706494
references.citation: Circulation. 2003 Dec 2;108(22):2798-804
references.pmid: 14610008
references.citation: Nat Clin Pract Cardiovasc Med. 2007 Nov;4(11):594-5
references.pmid: 17724479
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2586-91
references.pmid: 18272481
references.citation: Ann N Y Acad Sci. 2006 Oct;1080:451-65
references.pmid: 17132801
references.citation: Circulation. 2007 Oct 23;116(17):1952-65
references.pmid: 17965406
references.citation: Eur J Cancer. 2001 Sep;37(13):1590-8
references.pmid: 11527683
references.citation: Circulation. 1999 Jan 5-12;99(1):44-52
references.pmid: 9884378
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):3966-71
references.pmid: 20150514
references.citation: N Engl J Med. 2009 May 7;360(19):1933-45
references.pmid: 19420363
references.citation: Circ Res. 2003 Apr 18;92(7):e62-9
references.pmid: 12663484