Heparin-functionalized polymer graft surface eluting MK2 inhibitory peptide to improve hemocompatibility and anti-neointimal activity

Yunki Lee, Phuong Le Thi, Gyeung Mi Seon, Seung Bae Ryu, Colleen M. Brophy, Yong Tae Kim, Jongchul Park, Ki Dong Park, Joyce Cheung-Flynn, Hak Joon Sung

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The leading cause of synthetic graft failure includes thrombotic occlusion and intimal hyperplasia at the site of vascular anastomosis. Herein, we report a co-immobilization strategy of heparin and potent anti-neointimal drug (Mitogen Activated Protein Kinase II inhibitory peptide; MK2i) by using a tyrosinase-catalyzed oxidative reaction for preventing thrombotic occlusion and neointimal formation of synthetic vascular grafts. The binding of heparin–tyramine polymer (HT) onto the polycarprolactone (PCL) surface enhanced blood compatibility with significantly reduced protein absorption (64.7% decrease) and platelet adhesion (85.6% decrease) compared to bare PCL surface. When loading MK2i, 1) the HT depot surface gained high MK2i-loading efficiency through charge-charge interaction, and 2) this depot platform enabled long-term, controlled release over 4 weeks (92–272 μg/mL of MK2i). The released MK2i showed significant inhibitory effects on VSMC migration through down-regulated phosphorylation of target proteins (HSP27 and CREB) associated with intimal hyperplasia. In addition, it was found that the released MK2i infiltrated into the tissue with a cumulative manner in ex vivo human saphenous vein (HSV) model. This present study demonstrates that enzymatically HT-coated surface modification is an effective strategy to induce long-term MK2i release as well as hemocompatibility, thereby improving anti-neointimal activity of synthetic vascular grafts.

Original languageEnglish
Pages (from-to)321-330
Number of pages10
JournalJournal of Controlled Release
Volume266
DOIs
Publication statusPublished - 2017 Nov 28

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Tunica Intima
Blood Vessels
Heparin
Polymers
Transplants
Peptides
Hyperplasia
HSP27 Heat-Shock Proteins
Cyclic AMP Response Element-Binding Protein
Monophenol Monooxygenase
Saphenous Vein
Mitogen-Activated Protein Kinases
Immobilization
Blood Platelets
Phosphorylation
Pharmaceutical Preparations
Proteins

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Cite this

Lee, Yunki ; Le Thi, Phuong ; Seon, Gyeung Mi ; Ryu, Seung Bae ; Brophy, Colleen M. ; Kim, Yong Tae ; Park, Jongchul ; Park, Ki Dong ; Cheung-Flynn, Joyce ; Sung, Hak Joon. / Heparin-functionalized polymer graft surface eluting MK2 inhibitory peptide to improve hemocompatibility and anti-neointimal activity. In: Journal of Controlled Release. 2017 ; Vol. 266. pp. 321-330.
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abstract = "The leading cause of synthetic graft failure includes thrombotic occlusion and intimal hyperplasia at the site of vascular anastomosis. Herein, we report a co-immobilization strategy of heparin and potent anti-neointimal drug (Mitogen Activated Protein Kinase II inhibitory peptide; MK2i) by using a tyrosinase-catalyzed oxidative reaction for preventing thrombotic occlusion and neointimal formation of synthetic vascular grafts. The binding of heparin–tyramine polymer (HT) onto the polycarprolactone (PCL) surface enhanced blood compatibility with significantly reduced protein absorption (64.7{\%} decrease) and platelet adhesion (85.6{\%} decrease) compared to bare PCL surface. When loading MK2i, 1) the HT depot surface gained high MK2i-loading efficiency through charge-charge interaction, and 2) this depot platform enabled long-term, controlled release over 4 weeks (92–272 μg/mL of MK2i). The released MK2i showed significant inhibitory effects on VSMC migration through down-regulated phosphorylation of target proteins (HSP27 and CREB) associated with intimal hyperplasia. In addition, it was found that the released MK2i infiltrated into the tissue with a cumulative manner in ex vivo human saphenous vein (HSV) model. This present study demonstrates that enzymatically HT-coated surface modification is an effective strategy to induce long-term MK2i release as well as hemocompatibility, thereby improving anti-neointimal activity of synthetic vascular grafts.",
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Heparin-functionalized polymer graft surface eluting MK2 inhibitory peptide to improve hemocompatibility and anti-neointimal activity. / Lee, Yunki; Le Thi, Phuong; Seon, Gyeung Mi; Ryu, Seung Bae; Brophy, Colleen M.; Kim, Yong Tae; Park, Jongchul; Park, Ki Dong; Cheung-Flynn, Joyce; Sung, Hak Joon.

In: Journal of Controlled Release, Vol. 266, 28.11.2017, p. 321-330.

Research output: Contribution to journalArticle

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AU - Lee, Yunki

AU - Le Thi, Phuong

AU - Seon, Gyeung Mi

AU - Ryu, Seung Bae

AU - Brophy, Colleen M.

AU - Kim, Yong Tae

AU - Park, Jongchul

AU - Park, Ki Dong

AU - Cheung-Flynn, Joyce

AU - Sung, Hak Joon

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N2 - The leading cause of synthetic graft failure includes thrombotic occlusion and intimal hyperplasia at the site of vascular anastomosis. Herein, we report a co-immobilization strategy of heparin and potent anti-neointimal drug (Mitogen Activated Protein Kinase II inhibitory peptide; MK2i) by using a tyrosinase-catalyzed oxidative reaction for preventing thrombotic occlusion and neointimal formation of synthetic vascular grafts. The binding of heparin–tyramine polymer (HT) onto the polycarprolactone (PCL) surface enhanced blood compatibility with significantly reduced protein absorption (64.7% decrease) and platelet adhesion (85.6% decrease) compared to bare PCL surface. When loading MK2i, 1) the HT depot surface gained high MK2i-loading efficiency through charge-charge interaction, and 2) this depot platform enabled long-term, controlled release over 4 weeks (92–272 μg/mL of MK2i). The released MK2i showed significant inhibitory effects on VSMC migration through down-regulated phosphorylation of target proteins (HSP27 and CREB) associated with intimal hyperplasia. In addition, it was found that the released MK2i infiltrated into the tissue with a cumulative manner in ex vivo human saphenous vein (HSV) model. This present study demonstrates that enzymatically HT-coated surface modification is an effective strategy to induce long-term MK2i release as well as hemocompatibility, thereby improving anti-neointimal activity of synthetic vascular grafts.

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