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Pharmaceutical Research

, Volume 25, Issue 8, pp 1936–1947 | Cite as

Enhancement in Anti-proliferative Effects of Paclitaxel in Aortic Smooth Muscle Cells upon Co-administration with Ceramide using Biodegradable Polymeric Nanoparticles

  • Dipti Deshpande
  • Harikrishna Devalapally
  • Mansoor Amiji
Research Paper

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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 WORDS

anti-proliferative effects aortic smooth muscle cells C6-ceramide coronary restenosis paclitaxel 

References

  1. 1.
    G. Dangas, and F. Kuepper. Cardiology patient page. Restenosis: repeat narrowing of a coronary artery: prevention and treatment. Circulation. 105:2586–2587 (2002).PubMedCrossRefGoogle Scholar
  2. 2.
    T. Uwatoku, H. Shimokawa, K. Abe, Y. Matsumoto, T. Hattori, K. Oi, T. Matsuda, K. Kataoka, and A. Takeshita. Application of nanoparticle technology for the prevention of restenosis after balloon injury in rats. Circ. Res. 92:e62–e69 (2003).PubMedCrossRefGoogle Scholar
  3. 3.
    K. Ganesan, and B. Balram. Prevention of restenosis after coronary angioplasty [Prevention]. Curr. Opin. Cardiol. 19:500–509 (2004).CrossRefGoogle Scholar
  4. 4.
    S. L. Goldberg, A. Loussararian, J. De Gregorio, C. Di Mario, R. Albiero, and A. Colombo. Predictors of diffuse and aggressive intra-stent restenosis. J. Am. Coll. Cardiol. 37:1019–1025 (2001).PubMedCrossRefGoogle Scholar
  5. 5.
    M. Bennett. In-stent stenosis: pathology and implications for the development of drug eluting stents. Heart (BMJ). 89:218–224 (2003).CrossRefGoogle Scholar
  6. 6.
    F. Airoldi, C. Di Mario, G. Stankovic, C. Briguori, E. Bramucci, B. Reimers, D. Ardissino, E. Aurier, D. Tavano, and A. Colombo. Effectiveness of treatment of in-stent restenosis with an 8-French compatible atherectomy catheter. Am. J. Cardiol. 92:725–728 (2003).PubMedCrossRefGoogle Scholar
  7. 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
  8. 8.
    H. J. Rapold, P. R. David, P. Guiteras Val, A. L. Mata, P. A. Crean, and M. G. Bourassa. Restenosis and its determinants in first and repeat coronary angioplasty. Eur. Heart J. 8:575–586 (1987).PubMedGoogle Scholar
  9. 9.
    M. A. Costa, and D. I. Simon. Molecular basis of restenosis and drug-eluting stents. Circulation. 111:2257–2273 (2005).PubMedCrossRefGoogle Scholar
  10. 10.
    F. G. Welt, and C. Rogers. Inflammation and restenosis in the stent era. Arterioscler. Thromb. Vasc. Biol. 22:1769–1776 (2002).PubMedCrossRefGoogle Scholar
  11. 11.
    C. P. Regan, P. J. Adam, C. S. Madsen, and G. K. Owens. Molecular mechanisms of decreased smooth muscle differentiation marker expression after vascular injury. J. Clin. Invest. 106:1139–1147 (2000).PubMedCrossRefGoogle Scholar
  12. 12.
    S. V. Ranade, K. M. Miller, R. E. Richard, A. K. Chan, M. J. Allen, and M. N. Helmus. Physical characterization of controlled release of paclitaxel from the TAXUS Express2 drug-eluting stent. J. Biomed. Mater. Res. A. 71:625–634 (2004).PubMedCrossRefGoogle Scholar
  13. 13.
    J. D. Adams, K. P. Flora, B. R. Goldspiel, J. W. Wilson, S. G. Arbuck, and R. Finley. Taxol: a history of pharmaceutical development and current pharmaceutical concerns. J. Natl. Cancer Inst. Monogr. 15:141–147 (1993).PubMedGoogle Scholar
  14. 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. 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
  16. 16.
    C. Herdeg, M. Oberhoff, A. Baumbach, A. Blattner, D. I. Axel, S. Schroder, H. Heinle, and K. R. Karsch. Local paclitaxel delivery for the prevention of restenosis: biological effects and efficacy in vivo. J. Am. Coll. Cardiol. 35:1969–1976 (2000).PubMedCrossRefGoogle Scholar
  17. 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
  18. 18.
    R. Kolesnick. The therapeutic potential of modulating the ceramide/sphingomyelin pathway. J. Clin. Invest. 110:3–8 (2002).PubMedGoogle Scholar
  19. 19.
    F. D. Kolodgie, A. Farb, and R. Virmani. Local delivery of ceramide for restenosis: is there a future for lipid therapy? Circ. Res. 87:264–267 (2000).PubMedGoogle Scholar
  20. 20.
    R. Charles, L. Sandirasegarane, J. Yun, N. Bourbon, R. Wilson, R. P. Rothstein, S. W. Levison, and M. Kester. Ceramide-coated balloon catheters limit neointimal hyperplasia after stretch injury in carotid arteries. Circ. Res. 87:282–288 (2000).PubMedGoogle Scholar
  21. 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
  22. 22.
    L. Brito, and M. Amiji. Nanoparticulate carriers for the treatment of coronary restenosis. Int. J. Nanomed. 2:143–161 (2007).CrossRefGoogle Scholar
  23. 23.
    V. Labhasetwar, C. Song, W. Humphrey, R. Shebuski, and R. J. Levy. Arterial uptake of biodegradable nanoparticles: effect of surface modifications. J. Pharm. Sci. 87:1229–1234 (1998).PubMedCrossRefGoogle Scholar
  24. 24.
    C. Song, V. Labhasetwar, X. Cui, T. Underwood, and R. J. Levy. Arterial uptake of biodegradable nanoparticles for intravascular local drug delivery: results with an acute dog model. J. Control Release. 54:201–211 (1998).PubMedCrossRefGoogle Scholar
  25. 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
  26. 26.
    S. Mukherjee, R. N. Ghosh, and F. R. Maxfield. Endocytosis. Physiol. Rev. 77:759–803 (1997).PubMedGoogle Scholar
  27. 27.
    J. Gruenberg. The endocytic pathway: a mosaic of domains. Nat. Rev. Mol. Cell. Biol. 2:721–730 (2001).PubMedCrossRefGoogle Scholar
  28. 28.
    L. Pelkmans, and A. Helenius. Endocytosis via caveolae. Traffic. 3:311–320 (2002).PubMedCrossRefGoogle Scholar
  29. 29.
    S. B. Sieczkarskiand, and G. R. Whittaker. Dissecting virus entry via endocytosis. J. Gen. Virol. 83:1535–1545 (2002).Google Scholar
  30. 30.
    S. A. Mousavi, L. Malerod, T. Berg, and R. Kjeken. Clathrin-dependent endocytosis. Biochem. J. 377:1–16 (2004).PubMedCrossRefGoogle Scholar
  31. 31.
    H. Cohen-Sacks, Y. Najajreh, V. Tchaikovski, G. Gao, V. Elazer, R. Dahan, I. Gati, M. Kanaan, J. Waltenberger, and G. Golomb. Novel PDGFbetaR antisense encapsulated in polymeric nanospheres for the treatment of restenosis. Gene. Ther. 9:1607–1616 (2002).PubMedCrossRefGoogle Scholar
  32. 32.
    H. Suh, B. Jeong, R. Rathi, and S. W. Kim. Regulation of smooth muscle cell proliferation using paclitaxel-loaded poly(ethylene oxide)–poly(lactide/glycolide) nanospheres. J. Biomed. Mater. Res. 42:331–338 (1998).PubMedCrossRefGoogle Scholar
  33. 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
  34. 34.
    L. E. van Vlerken, Z. Duan, M. V. Seiden, and M. M. Amiji. Modulation of intracellular ceramide using polymeric nanoparticles to overcome multidrug resistance in cancer. Cancer Res. 67:4843–4850 (2007).PubMedCrossRefGoogle Scholar
  35. 35.
    J. S. Chawla, and M. M. Amiji. Biodegradable poly(epsilon-caprolactone) nanoparticles for tumor-targeted delivery of tamoxifen. Int. J. Pharm. 249:127–138 (2002).PubMedCrossRefGoogle Scholar
  36. 36.
    J. S. Chawla, and M. M. Amiji. Cellular uptake and concentrations of tamoxifen upon administration in poly(epsilon-caprolactone) nanoparticles. AAPS Pharm. Sci. 5:E3 (2003).CrossRefGoogle Scholar
  37. 37.
    L. K. Shah, and M. M. Amiji. Intracellular delivery of saquinavir in biodegradable polymeric nanoparticles for HIV/AIDS. Pharm. Res. 23:2638–2645 (2006).PubMedCrossRefGoogle Scholar
  38. 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
  39. 39.
    M. S. Chun, S. Y. Lee, and S. M. Yang. Estimation of zeta potential by electrokinetic analysis of ionic fluid flows through a divergent microchannel. J. Colloid. Interface Sci. 266:120–126 (2003).PubMedCrossRefGoogle Scholar
  40. 40.
    S. Nsereko, and M. Amiji. Localized delivery of paclitaxel in solid tumors from biodegradable chitin microparticle formulations. Biomaterials. 23:2723–2731 (2002).PubMedCrossRefGoogle Scholar
  41. 41.
    R. T. Liggins, and H. M. Burt. Paclitaxel-loaded poly(L-lactic acid) microspheres 3: blending low and high molecular weight polymers to control morphology and drug release. Int. J. Pharm. 282:61–71 (2004).PubMedCrossRefGoogle Scholar
  42. 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
  43. 43.
    H. Devalapally, Z. Duan, M. V. Seiden, and M. M. Amiji. Paclitaxel and ceramide co-administration in biodegradable polymeric nanoparticulate delivery system to overcome drug resistance in ovarian cancer. Int. J. Cancer. 121:1830–1838 (2007).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Dipti Deshpande
    • 1
  • Harikrishna Devalapally
    • 1
  • Mansoor Amiji
    • 1
  1. 1.Department of Pharmaceutical Sciences, School of PharmacyNortheastern UniversityBostonUSA

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