Biomaterials 25 (2004) 5333–5346 Molecular responses of vascular smooth muscle cells and phagocytes to curcumin-eluting bioresorbable stent materials Kytai T. Nguyen, Nishat Shaikh, Kajal P. Shukla, Shih-Horng Su, Robert C. Eberhart, Liping Tang* Department of Biomedical Engineering, University of Texas at Arlington, 214 Engineering Laboratory Building, 501 W 1st Street, Arlington, TX 76019, USA Received 20 June 2003; accepted 7 December 2003 Abstract A major complication of coronary stenting is restenosis, often accompanied by inflammatory reactions and smooth muscle cell proliferation. Curcumin has been shown to possess anti-inflammatory and anti-proliferative properties, thus we hypothesize that locally released curcumin by coronary stent would diminish in-stent restenosis. As a first test of this hypothesis, curcumin-eluting PLLA films (C-PLLA) were produced and the anti-inflammatory and anti-proliferative properties were then tested using peritoneal phagocytes and human coronary artery smooth muscle cell (hCASMCs) culture systems. We find that the addition of curcumin reduced phagocyte accumulation and activation on C-PLLA films. On the other hand, C-PLLA significantly reduced the proliferation, but not the adhesion, of hCASMCs. The molecular responses of hCASMCs to C-PLLA were further assessed by cDNA microarray analysis. Curcumin up-regulated genes related to apoptosis and enhanced the expression of anti-proliferative and anti-inflammatory factors, and of antioxidants. Equally important, C-PLLA inhibited the cell cycle progression of adherent hCASMCs. The results suggest that curcumin regulates gene expression and cell function through the protein kinase (PK) and mitogen-activated protein kinase (MAPK) pathways. These results support the use of curcumin to inhibit in-stent restenosis. r 2003 Elsevier Ltd. All rights reserved. Keywords: Polylactic acid; Inflammation; Drug delivery; Cell proliferation; Gene expression; Restenosis; Smooth muscle cells; Phagocytes 1. Introduction Coronary stents eliminate elastic recoil of target vessels, thereby reducing the restenosis rate in percuta- neous coronary interventions. Unfortunately, stents also induce restenosis. The pathogenesis of restenosis in- volves early inflammatory responses associated with the production of proinflammatory cytokines and growth factors, and subsequent fibrotic reactions related in part to vascular smooth muscle cell (VSMC) migration and proliferation [1]. Thus, intense efforts have been devoted to develop stent treatments that inhibit both cellular inflammation and proliferation, and those events for VSMC proliferation in particular. Thus, it is likely that local delivery of anti-inflammatory drugs could prevent stent restenosis. Curcumin (diferuloyl methane), a major chemical component of turmeric, has caught our attention, since it has low intrinsic toxicity [2] and possesses a wide range of pharmacological activities, including anti-thrombotic, anti-oxidant, anti-proliferative and anti-carcinogenic effects [3–5]. Curcumin is used in some countries to treat inflammatory disorders caused by its anti-inflammatory [6–8], anti-thrombosis [9,10], anti-proliferative [11,12], and anti-oxidant activities [4,13–15]. Curcumin was found to reduce the produc- tion of inflammatory cytokines, including interleukin-8 (IL-8), monocyte inflammatory protein-1a (MIP-1a), monocyte chemotactic protein-1 (MCP-1), interleukin- 1b (IL-1b) and tumor necrosis factor-a (TNF-a) from monocytes and macrophages [16]. Curcumin was shown to block TNF-a-induced expression of leukocyte adhesion molecules, including intracellular adhesion ARTICLE IN PRESS *Corresponding author. Tel.: +1-817-272-6075; fax: +1-817-272- 2251. E-mail address: ltang@uta.edu (L. Tang). 0142-9612/$-see front matter r 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.biomaterials.2003.12.033