Enhancement in Anti-proliferative Effects of Paclitaxel in Aortic Smooth Muscle Cells upon Co-administration with Ceramide using Biodegradable Polymeric Nanoparticles
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Using a combination of paclitaxel (PTX), and the apoptotic signaling molecule, C6-ceramide (CER), the enhancement in anti-proliferative effect of human aortic smooth muscle cells (SMC) was examined by administering in polymeric nanoparticles.
PTX- and CER-loaded poly(ethylene oxide)-modified poly(epsilon caprolactone) (PEO-PCL) nanoparticles were formulated by solvent displacement and characterized. The uptake and intracellular localization of the nanoparticle in SMC was examined using Z-stack fluorescent confocal microscopy. Anti-proliferative and pro-apoptotic effects of SMC were determined upon administration of PTX and CER, either as single agent or in combination, in aqueous solution and in PEO-PCL nanoparticle formulations.
High encapsulation efficiencies (i.e., >95%) of PTX and CER at 10% (w/w) loading were attained in the PEO-PCL nanoparticles of around 270 nm in diameter. Fluorescence confocal analysis showed that nanoparticle delivery did facilitate cellular uptake and internalization. Additionally, combination of PTX and CER delivery in PEO-PCL nanoparticles was significantly more effective in decreasing the proliferation of SMC, probably by enhancing the apoptotic response.
The results of this study show that combination of PTX and CER when administered in PEO-PCL nanoparticles can significantly augment the anti-proliferative effect in SMC. This strategy may potentially be useful in the treatment of coronary restenosis.
KEY WORDSanti-proliferative effects aortic smooth muscle cells C6-ceramide coronary restenosis paclitaxel
- 7.J. Sharma, R. Kashyap, and A. Sharma. Restenosis following percutaneous transluminal coronary angioplasty among aircrew during intermediate and long term follow up. Ind. J. Aerospace Med. 47:17–22 (2003).Google Scholar
- 14.M. Pennati, A. J. Campbell, M. Curto, M. Binda, Y. Cheng, L. Z. Wang, N. Curtin, B. T. Golding, R. J. Griffin, I. R. Hardcastle, A. Henderson, N. Zaffaroni, and D. R. Newell. Potentiation of paclitaxel-induced apoptosis by the novel cyclin-dependent kinase inhibitor NU6140: a possible role for survivin down-regulation. Mol. Cancer. Ther. 4:1328–1337 (2005).PubMedCrossRefGoogle Scholar
- 15.S. J. Sollott, L. Cheng, R. R. Pauly, G. M. Jenkins, R. E. Monticone, M. Kuzuya, J. P. Froehlich, M. T. Crow, E. G. Lakatta, E. K. Rowinsky, et al. Taxol inhibits neointimal smooth muscle cell accumulation after angioplasty in the rat. J. Clin. Invest. 95:1869–1876 (1995).PubMedCrossRefGoogle Scholar
- 17.D. I. Axel, W. Kunert, C. Goggelmann, M. Oberhoff, C. Herdeg, A. Kuttner, D. H. Wild, B. R. Brehm, R. Riessen, G. Koveker, and K. R. Karsch. Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery. Circulation. 96:636–645 (1997).PubMedGoogle Scholar
- 21.C. E. Chalfant, B. Ogretmen, S. Galadari, B. J. Kroesen, B. J. Pettus, and Y. A. Hannun. FAS activation induces dephosphorylation of SR proteins; dependence on the de novo generation of ceramide and activation of protein phosphatase 1. J. Biol. Chem. 276:44848–44855 (2001).PubMedCrossRefGoogle Scholar
- 25.U. Westedt, L. Barbu-Tudoran, A. K. Schaper, M. Kalinowski, H. Alfke, and T. Kissel. Deposition of nanoparticles in the arterial vessel by porous balloon catheters: localization by confocal laser scanning microscopy and transmission electron microscopy. AAPS Pharm. Sci. 4:E41 (2002).CrossRefGoogle Scholar
- 29.S. B. Sieczkarskiand, and G. R. Whittaker. Dissecting virus entry via endocytosis. J. Gen. Virol. 83:1535–1545 (2002).Google Scholar
- 33.G. M. Lanza, X. Yu, P. M. Winter, D. R. Abendschein, K. K. Karukstis, M. J. Scott, L. K. Chinen, R. W. Fuhrhop, D. E. Scherrer, and S. A. Wickline. Targeted antiproliferative drug delivery to vascular smooth muscle cells with a magnetic resonance imaging nanoparticle contrast agent: implications for rational therapy of restenosis. Circulation. 106:2842–2847 (2002).PubMedCrossRefGoogle Scholar
- 38.D. Shenoy, S. Little, R. Langer, and M. Amiji. Poly(ethylene oxide)-modified poly(beta-amino ester) nanoparticles as a pH-sensitive system for tumor-targeted delivery of hydrophobic drugs: part 2. In vivo distribution and tumor localization studies. Pharm. Res. 22:2107–2114 (2005).PubMedCrossRefGoogle Scholar
- 42.M. Zaffaroni, R. Frapolli, T. Colombo, R. Fruscio, E. Bombardelli, P. Morazzoni, A. Riva, M. D’Incalci, and M. Zucchetti. High-performance liquid chromatographic assay for the determination of the novel C-Seco-taxane derivative (IDN 5390) in mouse plasma. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 780:93–98 (2002).PubMedCrossRefGoogle Scholar