Simultaneous Release of a Hydroxy-Methylglutaryl Coenzyme A Reductase Inhibitor and a Glycoprotein IIb/IIIa Antagonist from a Thermoresponsive NiPAAm/NtBAAm Copolymer System

J. A. Hickey, I. Lynch, K. A. Dawson, D. Cox, A. K. Keenan

.

DOI: 10.4236/jbnb.2011.21003                

Abstract

While deployment of intracoronary stents has been shown to reduce restenosis, stenting can also damage the endothelial monolayer lining the vessel wall, leading to possible in-stent thrombosis. Local drug delivery from stent surfaces represents a means of delivering therapeutic doses of drug directly to the target site. The aim of this study was to elute fluvastatin, which can inhibit vascular smooth muscle cell proliferation, and xemilofiban, which prevents platelet adhesion and aggregation, together in bioactive concentrations from the same copolymer system. Combined elution from thermoresponsive N-isopropylacrylamide (NiPAAm)/N-tert-butylacrylamide (NtBAAm)-derived copolymer systems was achieved using microgels (NiPAAm/NtBAAm 65/35 wt/wt) randomly dispersed in 85/15 matrices. Fluvastatin elution from 5 mm films over a 14-day period showed initial burst release, which leveled off. Of the total incorporated (8.33 ± 0.21 nmol, n=4), 68.5 % was eluted during this period. Xemilofiban release was measured in terms of its ability to inhibit platelet adhesion, using a microfluidic system. To investigate the influence of location and hydrophobicity on elution of bioactivity, three separate systems were employed. While elution of anti-adhesive activity from the system containing xemilofiban-loaded matrices was more dramatic in the short term, a more sustained level of inhibition was achieved when xemilofiban had been incorporated into microgels. All samples investigated for anti-adhesive activity also decreased human coronary artery smooth muscle cell proliferation. Therefore xemilofiban has potential as an agent for preventing in-stent thrombosis. Our study has demonstrated the feasibility of using this novel matrix/microgel system to regulate simultaneous release of both agents in bioactive concentrations.

Keywords

Fluvastatin, Xemilofiban, Nipaam/Ntbaam, Microgels, Local Drug Delivery

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	U. Sigwart, J. Puel, V. Mirkovitch, F. Joffre and L. Kappenberger, “Intravascular Stents to Prevent Occlusion and Restenosis after Transluminal Angioplasty,” New England Journal of Medicine, Vol. 316, No. 12, 1987, pp. 701-706. doi:10.1056/NEJM198703193161201
[2]	V. A. Voudris, J. S. Skoularigis, Y. K. Dimitriou, G. N. Grapsa, J. S. Malakos, G. S. Pavlides, et al., “Diabetes Mellitus and Unstable Coronary Artery Disease: Improved Clinical Outcome of Coronary Artery Stenting in an Era of Glycoprotein IIb/IIIa Inhibitors and Lipid- Lowering Therapy,” Coronary Artery Disease, Vol. 15, No. 6, 2004, pp. 353-359. doi:10.1097/00019501-200409000-00009
[3]	A. T. Ong and P. W. Serruys, “Drug-Eluting Stents: Current Issues,” Texas Heart Institute Journal, Vol. 32, No. 3, 2005, pp. 372-377.
[4]	B. L. Hiatt, F. Ikeno, A. C. Yeung and A. J. Carter, “Drug-Eluting Stents for the Prevention of Restenosis: In Quest for the Holy Grail,” Catheterization and Cardiovascular Interventions, Vol. 55, No. 3, 2002, pp. 409-417. doi:10.1002/ccd.10161
[5]	S. Park and S. Lee, “Optimal Management of Platelet Function after Coronary Stenting,” Current Treatment Options in Cardiovascular Medicine, Vol. 9, No. 1, 2007, pp. 37-45. doi:10.1007/s11936-007-0049-7
[6]	R. M. da Silva, J. F. Mano and R. L. Reis, “Smart Thermoresponsive Coatings and Surfaces for Tissue Engineering: Switching Cell-Material Boundaries,” Trends in Biotechnology, Vol. 25, No. 12, 2007, pp. 577-583. doi:10.1016/j.tibtech.2007.08.014
[7]	E. S. Ron and L. E. Bromberg, “Temperature-Responsive Gels and Thermogelling Polymer Matrices for Protein and Peptide Delivery,” Advanced Drug Delivery Reviews, Vol. 31, No. 3, 1998, pp. 197-221. doi:10.1016/S0169-409X(97)00121-X
[8]	F. Eeckman, K. Amighi and A. J. Moes, “Effect of Some Physiological and Non-Physiological Compounds on the Phase Transition Temperature of Thermoresponsive Polymers Intended for Oral Controlled-Drug Delivery,” International Journal of Pharmaceutics, Vol. 222, No. 2, 2001, pp. 259-270.
[9]	K. B. Doorty, T. A. Golubeva, A. V. Gorelov, Y. A. Rochev, L. T. Allen, K. A. Dawson, W. M. Gallagher and A. K. Keenan, “Poly(N-isopropylacrylamide) Co-Polymer Films as Potential Vehicles for Delivery of an Antimitotic Agent to Vascular Smooth Muscle Cells,” Cardiovascular Pathology, Vol. 12, No. 2, pp. 105-110. doi:10.1016/S1054-8807(02)00165-5
[10]	S. J. Wilson, A. V. Gorelov, Y. A. Rochev, F. C. McGillicuddy, K. A. Dawson, W. M. Gallagher and A. K. Keenan, “Extended Delivery of the Antimitotic Agent Colchicine from Thermoresponsive N-isopropylacrylamide-Based Copolymer Films to Human Vascular Smooth Muscle Cells,” Journal of Biomedical Materials Research, Vol. 67, No. 2, 2003, pp. 667-673.
[11]	C. A. Kavanagh, T. A. Gorelova, I. I. Selezneva, Y. A. Rochev, K. A. Dawson, W. M. Gallagher, A. V. Gorelov and A. K. Keenan, “Poly(N-isopropylacrylamide) Copolymer Films as Vehicles for the Sustained Delivery of Proteins to Vascular Endothelial Cells,” Journal of Biomedical Materials Research, Vol. 72, No. 1, 2005, pp. 25-35. doi:10.1002/jbm.a.30192
[12]	I. Lynch and K. A. Dawson, “Synthesis and Characterization of an Extremely Versatile Structural Motif Called the “Plum-Pudding” Gel,” Journal of Physical Chemistry, Vol. 107, No. 36, 2003, pp. 9629-9637.
[13]	F. C. McGillicuddy, “Evaluation of N-isopropylacrylamide/N-tert-butylacrylamide Copolymer Microgel/Matrix Systems as Anti-Restenotic Drug Delivery Vehicles,” Ph.D. Thesis, 2006.
[14]	Y. Li and Y. Bae, “Volume Phase Transition of Submicron-Sized NIPAM/BAm Particles by Photon Correlation Spectroscopy,” Journal of Applied Polymer Science, Vol. 67, 1998, pp. 2088-2092.
[15]	B. R. Kwak, F. Mulhaupt and F. Mach, “Atherosclerosis: Anti-Inflammatory and Immunomodulatory Activities of Statins,” Autoimmunity Reviews, Vol. 2, No. 6, 2003, pp. 332-338. doi:10.1016/S1568-9972(03)00049-1
[16]	R. Riessen, D. I. Axel, M. Fenchel, U. U. Herzog, H. Rossmann and K. R. Karsch, “Effect of HMG-CoA Reductase Inhibitors on Extracellular Matrix Expression in Human Vascular Smooth Muscle Cells,” Basic Research in Cardiology, Vol. 94, No. 5, 1999, pp. 322-332.
[17]	B. Jaschke, C. Michaelis, S. Milz, M. Vogeser, T. Mund, L. Hengst, et al., “Local Statin Therapy Differentially Interferes with Smooth Muscle and Endothelial Cell Proliferation and Reduces Neointima on a Drug-Eluting Stent Platform,” Cardiovascular Research, Vol. 68, No. 3, 2005, pp. 483-492. doi:10.1016/j.cardiores.2005.06.029
[18]	N. Takeda, M. Kondo, S. Ito, Y. Ito, K. Shimokata and H. Kume, “Role of RhoA Inactivation in Reduced Cell Proliferation of Human Airway Smooth Muscle by Simvastatin,” American Journal of Respiratory Cell and Molecular Biology, Vol. 35, No. 6, 2006, pp. 722-729. doi:10.1165/rcmb.2006-0034OC
[19]	J. M. Corpataux, J. Naik, K. E. Porter and N. J. London, “The Effect of Six Different Statins on the Proliferation, Migration, and Invasion of Human Smooth Muscle Cells,” Journal of Surgery Research, Vol. 129, No. 1, 2005, pp. 52-56. doi:10.1016/j.jss.2005.05.016
[20]	F. C. McGillicuddy, I. Lynch, Y. A. Rochev, M. Burke, K. A. Dawson, W. M. Gallagher and A. K. Keenan, “Novel “Plum Pudding” Gels as Potential Drug-Eluting Stent Coatings: Controlled Release of Fluvastatin,” Journal of Biomedical Materials Research, Vol. 79, No. 4, 2006, pp. 923-933. doi:10.1002/jbm.a.30839
[21]	J. F. Granada and N. S. Kleiman, “Therapeutic Use of Intravenous Eptifibatide in Patients Undergoing Percutaneous Coronary Intervention: Acute Coronary Syndromes and Elective Stenting,” American Journal of Cardiovascular Drugs, Vol. 4, No. 1, 2004, pp. 31-41.
[22]	C. Patrono, F. Bachmann, C. Baigent, C. Bode, R. De Caterina, B. Charbonnier, et al., “Expert Consensus Document on the Use of Antiplatelet Agents. The Task Force on the Use of Antiplatelet Agents in Patients with Atherosclerotic Cardiovascular Disease of the European Society of Cardiology,” European Heart Journal, Vol. 25, No. 2, 2004, pp. 166-181. doi:10.1016/j.ehj.2003.10.013
[23]	W. W. O'Neill, P. Serruys, M. Knudtson, G. A. van Es, G. C. Timmis, C. van der Zwaan, et al., “Long-Term Treatment with a Platelet Glycoprotein-Receptor Antagonist after Percutaneous Coronary Revascularization. EXCITE Trial Investigators. Evaluation of Oral Xemilofiban in Controlling Thrombotic Events,” New England Journal of Medicine, Vol. 342, No. 18, 2000, pp. 1316-1324.
[24]	C. P. Cannon, C. H. McCabe, R. G. Wilcox, A. Langer, A. Caspi, P. Berink, et al., “Oral Glycoprotein IIb/IIIa Inhibition with Orbofiban in Patients With Unstable Coronary Syndromes (OPUS-TIMI 16) Trial,” Circulation, Vol. 102, No. 2, 2000, pp. 149-156.
[25]	L. K. Newby, “Long-Term Oral Platelet Glycoprotein IIb/IIIa Receptor Antagonism with Sibrafiban after Acute Coronary Syndromes: Study Design of the Sibrafiban Versus Aspirin to Yield Maximum Protection from Ischemic Heart Events Post-Acute Coronary Syndromes (SYMPHONY) Trial,” Symphony Steering Committee, American Heart Journal, Vol. 138, 1999, pp. 210-218. doi:10.1016/S0002-8703(99)70104-3
[26]	SYMPHONY, “Comparison of Sibrafiban with Aspirin for Prevention of Cardiovascular Events after Acute Coronary Syndromes: A Randomised Trial. The SYMPHONY Investigators. Sibrafiban Versus Aspirin to Yield Maximum Protection from Ischemic Heart Events Post- acute Coronary Syndromes,” Lancet, Vol. 355, 2000, pp. 337-345. doi:10.1016/S0140-6736(99)11179-6
[27]	E. J. Topol, J. D. Easton, P. Amarenco, R. Califf, R. Harrington, C. Graffagnino, et al., “Design of the Blockade of The Glycoprotein IIb/IIa Receptor to Avoid Vascular Occlusion (BRAVO) Trial,” American Heart Journal, Vol. 139, 2000, pp. 927-933.
[28]	V. S. Srinivas, B. Skeif, A. Negassa, J. Y. Bang, H. Shaqra and E. S. Monrad, “Effectiveness of Glycoprotein IIb/IIa Inhibitor Use during Primary Coronary Angioplasty: Results of Propensity Analysis Using the New York State Percutaneous Coronary Intervention Reporting System,” American Journal of Cardiology, Vol. 99, 2007, pp. 482-485. doi:10.1016/j.amjcard.2006.08.061
[29]	T. Heer, U. Zeymer, C. Juenger, A. K. Gitt, H. Wienbergen, R. Zahn, et al., “Beneficial Effects of Abciximab in Patients with Primary Percutaneous Intervention for Acute ST Segment Elevation Myocardial Infarction in Clinical Practice,” Heart, Vol. 92, 2006, pp. 484-489.
[30]	T. Yin, G. Wang, C. Ruan, R. Guzman and R. Guidoin, “In-Vitro Assays of Polymer-Coated Stents Eluting Platelet Glycoprotein IIb/IIIa Receptor Monoclonal Antibody,” Journal of Biomedical Materials Research, Vol. 83, 2007, pp. 861-867. doi:10.1002/jbm.a.31369
[31]	R. K. Aggarwal, D. C. Ireland, M. A. Azrin, M. D. Ezekowitz, D. P. de Bono and A. H. Gershlick, “Antithrombotic Potential of Polymer-Coated Stents Eluting Platelet Glycoprotein IIb/IIIa Receptor Antibody,” Circulation, Vol. 94, No. 12, 1996, pp. 3311-3317.