Use of a novel anti-proliferative compound coated on a biopolymer to mitigate platelet-derived growth factor-induced proliferation in human aortic smooth muscle cells: comparison with sirolimus.
Drug eluting stents (DES) have become a common mode of treatment for stenosis in coronary arteries. However, currently, the use of sirolimus/paclitaxel-coated DES has come under scrutiny, because of their pro-thrombotic effects leading to potential adverse outcomes in the long run. We have previously documented that D: -threo-1-phenyl-2-decanoylamino-3-morholino propanol (D-PDMP); an inhibitor of glucosylceramide synthase and lactosylceramide (LacCer) synthase markedly inhibited platelet-derived growth factor (PDGF)-induced cell proliferation. We have fabricated DES wherein, D-PDMP or sirolimus was coated on to a double layer of poly (lactic-co-glycolic acid) on a bare metal stent. The in vitro release of D-PDMP from biopolymer and its consequent effect on PDGF induced proliferation and apoptosis was assessed in human aortic smooth muscle cells (ASMC). D-PDMP was released from biopolymers in a dose-dependent fashion and was accompanied with a decrease in PDGF-induced cell proliferation, but not apoptosis. In contrast, sirolimus markedly increased apoptosis in these cells in addition to inhibiting proliferation. Our mechanistic studies revealed that D-PDMP, but not sirolimus decreased the cellular level of glucosyl and lactosylceramide that accompanied inhibition of PDGF-induced cell proliferation. Our short-term (14 days) in vivo studies in rabbits also attested to the safety and biocompatibility of the D-PDMP coated stents. Our data reveal the superiority of D-PDMP coated biopolymers over sirolimus coated biopolymers in mitigating ASMC proliferation. Such D-PDMP coated stents may be useful for localized delivery of drug to mitigate neo-vascular hyperplasia and other proliferative disorders.
Tang
Yong-Dan
YD
Biomaterials Laboratory, School of Materials Science and Engineering, Nanyang Technological University, Singapore.
Pandey
Ambarish
A
Kolmakova
Antonina
A
Wang
Xin-Tong
XT
Venkatraman
Subbu S
SS
Chatterjee
Subroto
S
Boey
Freddy Y C
FY
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001011:Aorta / Q000166:cytology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D054855:Drug-Eluting Stents; D006801:Humans; D009025:Morpholines / Q000737:chemistry* / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011108:Polymers / Q000737:chemistry*; D011817:Rabbits; D020123:Sirolimus / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D009025:Morpholines; D010982:Platelet-Derived Growth Factor; D011108:Polymers; C033110:RV 538; D020123:Sirolimus