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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

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Abstract

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.

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Abbreviations

DPDMP:

d-threo-1-phenyl-2-decanoylamino-3-morholino propanol

PDGF:

platelet-derived growth factor

LacCer:

lactosylceramide

GLcCer:

glucosylceramide

HPLC:

high performance liquid chromatography

PLGA:

polylactic-co-glycolic acid

TNF:

tissue necrosis factor

ASMC:

aortic smooth muscle cells

DES:

drug eluting stents

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Acknowledgements

We acknowledge Merlin Medical, Singapore for the assistance in the evaluation of crimped stents, as well as for the helpful discussions. This work was supported via funds from the Economic development board of Singapore, A*STAR and from the Johns Hopkins University, School of Medicine Institutional Funds.

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Authors and Affiliations

  1. Biomaterials Laboratory, School of Materials Science and Engineering, Nanyang Technological University, Singapore, Block N 4.1-B1-01, 639798, Singapore

    Yong-Dan Tang, Xin-Tong Wang, Subbu S. Venkatraman & Freddy Y. C. Boey

  2. Department of Pediatrics, Sphingolipid Signaling and Vascular Biology Laboratory, Johns Hopkins University, Suite 312, 550 North Broadway, Baltimore, MD, 21205, USA

    Ambarish Pandey, Antonina Kolmakova & Subroto Chatterjee

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  1. Yong-Dan Tang
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  2. Ambarish Pandey
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  3. Antonina Kolmakova
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  5. Subbu S. Venkatraman
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Correspondence to Subbu S. Venkatraman or Subroto Chatterjee.

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Yong-Dan Tang, Ambarish Pandey, Subbu S. Venkatraman, and Subroto Chatterjee contributed equally to this work.

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Tang, YD., Pandey, A., Kolmakova, A. et al. 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. Glycoconj J 26, 721–732 (2009). https://doi.org/10.1007/s10719-008-9192-y

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