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Research Article

In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid–polymeric nanoparticles

Juliana M. Chan, June-Wha Rhee, Chester L. Drum, Roderick T. Bronson, Gershon Golomb, Robert Langer, and Omid C. Farokhzad
  1. aDepartment of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139;
  2. bLaboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
  3. cDepartment of Chemical Engineering and Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139;
  4. dRodent Histopathology Core, Harvard Medical School, Boston, MA 02115; and
  5. eSchool of Pharmacy, Hebrew University of Jerusalem, Jerusalem 91120, Israel

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PNAS November 29, 2011 108 (48) 19347-19352; https://doi.org/10.1073/pnas.1115945108
Juliana M. Chan
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June-Wha Rhee
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Chester L. Drum
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Roderick T. Bronson
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Gershon Golomb
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Robert Langer
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  • For correspondence: rlanger@mit.edu ofarokhzad@zeus.bwh.harvard.edu
Omid C. Farokhzad
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  • For correspondence: rlanger@mit.edu ofarokhzad@zeus.bwh.harvard.edu
  1. Contributed by Robert Langer, October 2, 2011 (sent for review March 28, 2011)

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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.

Footnotes

  • ↵1J.M.C. and J.-W.R. contributed equally to this work.

  • ↵2To whom correspondence may be addressed. E-mail: rlanger{at}mit.edu or ofarokhzad{at}zeus.bwh.harvard.edu.
  • Author contributions: J.M.C., J.-W.R., G.G., R.L., and O.C.F. designed research; J.M.C. and J.-W.R. performed research; J.M.C., J.-W.R., C.L.D., R.T.B., R.L., and O.C.F. analyzed data; and J.M.C., J.-W.R., R.L., and O.C.F. wrote the paper.

  • Conflict of interest statement: In compliance with the Brigham and Women's Hospital and Harvard Medical School institutional guidelines, O.C.F. discloses his financial interest in BIND Biosciences and Selecta Biosciences, two biotechnology companies developing nanoparticle technologies for medical applications. BIND and Selecta did not support the aforementioned research, and currently these companies have no rights to any technology or intellectual property developed as part of this research.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1115945108/-/DCSupplemental.

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In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid–polymeric nanoparticles
Juliana M. Chan, June-Wha Rhee, Chester L. Drum, Roderick T. Bronson, Gershon Golomb, Robert Langer, Omid C. Farokhzad
Proceedings of the National Academy of Sciences Nov 2011, 108 (48) 19347-19352; DOI: 10.1073/pnas.1115945108

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In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid–polymeric nanoparticles
Juliana M. Chan, June-Wha Rhee, Chester L. Drum, Roderick T. Bronson, Gershon Golomb, Robert Langer, Omid C. Farokhzad
Proceedings of the National Academy of Sciences Nov 2011, 108 (48) 19347-19352; DOI: 10.1073/pnas.1115945108
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