Drug-eluting stent for delivery of signal pathway-specific 1,3-dipropyl-8-cyclopentyl xanthine.
1,3-Dipropyl-8-cyclopentyl xanthine (DPCPX) is a highly selective antagonist of the adenosine A(1) receptor (A(1)R). The A(1)R mediates mitogenic effects of adenosine in coronary artery smooth muscle cells (CASMC). DPCPX plays a role as an antimitogen and reduces CASMC proliferation by the blockage of A(1)R. A drug-eluting stent (DES) loaded with DPCPX was prepared. The water solubility of DPCPX is 1.6 microg/mL at pH 3-9, and 38.1 +/- 2.3 microg/mL at pH 11. A series of DPCPX-eluting stents were formulated in polyurethane (PU) films with different dose densities and film thicknesses. The release of DPCPX from the PU-coated stents was nearly linear. The release rate and duration were effectively controlled by adjusting the film thickness with the same drug concentration. The eluted DPCPX from the PU films was effective in preventing CASMC proliferation, regardless of stimulation by 2-chloro-N-6-cyclopentyladenosine (CCPA), a highly selective A(1)R agonist. A(1)R specific antagonist DPCPX was effective in preventing CASMC proliferation and holds great promise for intracoronary delivery from DESs to test the role of the A(1)R signaling pathway for prevention of in-stent restenosis.
Weldon School of Biomedical Engineering & Department of Pharmaceutics, Purdue University, West Lafayette, Indiana, USA.
Eunah
E
Kang
Kumar
K
Vedantham
Xin
X
Long
Maria
M
Dadarlat
Maria
M
Dadara
Il-Keun
IK
Kwon
Michael
M
Sturek
Kinam
K
Park
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016503:Drug Delivery Systems; D054855:Drug-Eluting Stents; D008934:Mitogens; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011140:Polyurethanes / Q000737:chemistry; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D015398:Signal Transduction; D013552:Swine; D014970:Xanthines / Q000008:administration & dosage*
D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D008934:Mitogens; D011140:Polyurethanes; D043682:Receptor, Adenosine A1; D014970:Xanthines; C058394:2-chloro-N(6)cyclopentyladenosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine