ABSTRACT
Purpose
Coating coronary stents with antirestenotic drugs revolutionized interventional cardiology. We developed a system for post-hoc drug delivery to uncoated stents.
Methods
We coupled rapamycin or a chemically similar fluorescent dye to superparamagnetic nanoparticles. The antiproliferative activity of rapamycin coupled to nanoparticles was confirmed in vitro in primary porcine vascular cells. The particles were then incorporated into lipid based microbubbles. Commercially available stents were made magnetizable by nickel plating and used to induce strong field gradients in order to capture magnetic microbubbles from flowing liquids when placed in an external magnetic field.
Results
Nanoparticle bound Rapamycin dose dependently inhibited cell proliferation in vitro. Magnetic microcbubbles carrying coated nanoparticles were caught by magnets placed external to a flow-through tube. Plating commercial stents with nickel resulted in increased deposition at stent struts and allowed for widely increased distance of external magnets. Deposition depended on circulation time and velocity and distance of magnets. Deposited microbubbles were destroyed by ultrasound and delivered their cargo to targeted sites.
Conclusions
Drugs can be incorporated into nanoparticle loaded microbubbles and thus be delivered to magnetizable stents from circulating fluids by applying external magnetic fields. This technology could allow for post-hoc drug coating of already implanted vascular stents.
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REFERENCES
Fischman DL, Leon MB, Baim DS, Schatz RA, Savage MP, Penn I, Detre K, Veltri L, Ricci D, Nobuyoshi M. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med. 1994;331:496–501.
Serruys PW, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, Emanuelsson H, Marco J, Legrand V, Materne P. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med. 1994;331:489–95.
Daemen J, Serruys PW. Drug-eluting stent update 2007: part I. A survey of current and future generation drug-eluting stents: meaningful advances or more of the same? Circulation. 2007;116:316–28.
Dangas GD, Claessen BE, Caixeta A, Sanidas EA, Mintz GS, Mehran R. In-stent restenosis in the drug-eluting stent era. J Am Coll Cardiol. 2010;56:1897–907.
Grewe PH, Deneke T, Machraoui A, Barmeyer J, Muller KM. Acute and chronic tissue response to coronary stent implantation: pathologic findings in human specimen. J Am Coll Cardiol. 2000;35:157–63.
Joner M, Finn AV, Farb A, Mont EK, Kolodgie FD, Ladich E, Kutys R, Skorija K, Gold HK, Virmani R. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol. 2006;48:193–202.
Finn AV, Nakazawa G, Joner M, Kolodgie FD, Mont EK, Gold HK, Virmani R. Vascular responses to drug eluting stents: importance of delayed healing. Arterioscler Thromb Vasc Biol. 2007;27:1500–10.
Scheller B, Hehrlein C, Bocksch W, Rutsch W, Haghi D, Dietz U, Bohm M, Speck U. Treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. N Engl J Med. 2006;355:2113–24.
Unverdorben M, Vallbracht C, Cremers B, Heuer H, Hengstenberg C, Maikowski C, Werner GS, Antoni D, Kleber FX, Bocksch W, Leschke M, Ackermann H, Boxberger M, Speck U, Degenhardt R, Scheller B. Paclitaxel-coated balloon catheter versus paclitaxel-coated stent for the treatment of coronary in-stent restenosis. Circulation. 2009;119:2986–94.
Pislaru SV, Harbuzariu A, Gulati R, Witt T, Sandhu NP, Simari RD, Sandhu GS. Magnetically targeted endothelial cell localization in stented vessels. J Am Coll Cardiol. 2006;48:1839–45.
Chorny M, Fishbein I, Yellen BB, Alferiev IS, Bakay M, Ganta S, Adamo R, Amiji M, Friedman G, Levy RJ. Targeting stents with local delivery of paclitaxel-loaded magnetic nanoparticles using uniform fields. Proc Natl Acad Sci U S A. 2010;107:8346–51.
Mannell H, Hammitzsch A, Mettler R, Pohl U, Krotz F. Suppression of DNA-PKcs enhances FGF-2 dependent human endothelial cell proliferation via negative regulation of Akt. Cell Signal. 2010;22:88–96.
Slevin M, Badimon L, Grau-Olivares M, Ramis M, Sendra J, Morrison M, Krupinski J. Combining nanotechnology with current biomedical knowledge for the vascular imaging and treatment of atherosclerosis. Mol Biosyst. 2010;6:444–50.
Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med. 1999;340:115–26.
Peng ZG, Hidajat K, Uddin MS. Adsorption of bovine serum albumin on nanosized magnetic particles. J Colloid Interface Sci. 2004;271:277–83.
Lindner JR, Song J, Jayaweera AR, Sklenar J, Kaul S. Microvascular rheology of Definity microbubbles after intra-arterial and intravenous administration. J Am Soc Echocardiogr. 2002;15:396–403.
Ferns GA, Avades TY. The mechanisms of coronary restenosis: insights from experimental models. Int J Exp Pathol. 2000;81:63–88.
Schiele TM, Krotz F, Klauss V. Vascular restenosis - striving for therapy. Expert Opin Pharmacother. 2004;5:2221–32.
Unger EC, Porter T, Culp W, Labell R, Matsunaga T, Zutshi R. Therapeutic applications of lipid-coated microbubbles. Adv Drug Deliv Rev. 2004;56:1291–314.
Braide M, Rasmussen H, Albrektsson A, Bagge U. Microvascular behavior and effects of sonazoid microbubbles in the cremaster muscle of rats after local administration. J Ultrasound Med. 2006;25:883–90.
Grishenkov D, Kari L, Brodin LK, Brismar TB, Paradossi G. In vitro contrast-enhanced ultrasound measurements of capillary microcirculation: comparison between polymer- and phospholipid-shelled microbubbles. Ultrasonics. 2011;51:40–8.
Chertok B, Moffat BA, David AE, Yu F, Bergemann C, Ross BD, Yang VC. Iron oxide nanoparticles as a drug delivery vehicle for MRI monitored magnetic targeting of brain tumors. Biomaterials. 2008;29:487–96.
Polyak B, Fishbein I, Chorny M, Alferiev I, Williams D, Yellen B, Friedman G, Levy RJ. High field gradient targeting of magnetic nanoparticle-loaded endothelial cells to the surfaces of steel stents. Proc Natl Acad Sci U S A. 2008;105:698–703.
Holton A, Walsh E, Anayiotos A, Pohost G, Venugopalan R. Comparative MRI compatibility of 316 L stainless steel alloy and nickel-titanium alloy stents. J Cardiovasc Magn Reson. 2002;4:423–30.
Hug J, Nagel E, Bornstedt A, Schnackenburg B, Oswald H, Fleck E. Coronary arterial stents: safety and artifacts during MR imaging. Radiology. 2000;216:781–7.
Uppal R, Caravan P. Targeted probes for cardiovascular MR imaging. Future Med Chem. 2010;2(3):451–70.
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Räthel, T., Mannell, H., Pircher, J. et al. Magnetic Stents Retain Nanoparticle-Bound Antirestenotic Drugs Transported by Lipid Microbubbles. Pharm Res 29, 1295–1307 (2012). https://doi.org/10.1007/s11095-011-0643-y
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DOI: https://doi.org/10.1007/s11095-011-0643-y