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Characterization of nanochannel delivery membrane systems for the sustained release of resveratrol and atorvastatin: new perspectives on promoting heart health

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An Erratum to this article was published on 10 November 2012

Abstract

Novel drug delivery systems capable of continuous sustained release of therapeutics have been studied extensively for use in the prevention and management of chronic diseases. The use of these systems holds promise as a means to achieve higher patient compliance while improving therapeutic index and reducing systemic toxicity. In this work, an implantable nanochannel drug delivery system (nDS) is characterized and evaluated for the long-term sustained release of atorvastatin (ATS) and trans-resveratrol (t-RES), compounds with a proven role in managing atherogenic dyslipidemia and promoting cardioprotection. The primary mediators of drug release in the nDS are nanofluidic membranes with hundreds of thousands of nanochannels (up to 100,000/mm2) that attain zero-order release kinetics by exploiting nanoconfinement and molecule-to-surface interactions that dominate diffusive transport at the nanoscale. These membranes were characterized using gas flow analysis, acetone diffusion, and scanning and transmission electron microscopy (SEM, TEM). The surface properties of the dielectric materials lining the nanochannels, SiO2 and low-stress silicon nitride, were further investigated using surface charge analysis. Continuous, sustained in vitro release for both ATS and t-RES was established for durations exceeding 1 month. Finally, the influence of the membranes on cell viability was assessed using human microvascular endothelial cells. Morphology changes and adhesion to the surface were analyzed using SEM, while an MTT proliferation assay was used to determine the cell viability. The nanochannel delivery approach, here demonstrated in vitro, not only possesses all requirements for large-scale high-yield industrial fabrication, but also presents the key components for a rapid clinical translation as an implantable delivery system for the sustained administration of cardioprotectants.

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References

  1. Bansal SS, Goel M, Aqil F, Vadhanam MV, Gupta RC (2011) Advanced drug delivery systems of curcumin for cancer chemoprevention. Cancer Prev Res (Phila) 4(8):1158–1171. doi:10.1158/1940-6207.CAPR-10-0006

    Article  CAS  Google Scholar 

  2. Grattoni A, Shen H, Fine D, Ziemys A, Gill JS, Hudson L, Hosali S, Goodall R, Liu X, Ferrari M (2011) Nanochannel technology for constant delivery of chemotherapeutics: beyond metronomic administration. Pharm Res 28(2):292–300. doi:10.1007/s11095-010-0195-6

    Article  CAS  Google Scholar 

  3. Cohen JD, Brinton EA, Ito MK, Jacobson TA (2012) Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users. J Clin Lipidol 6(3):208–215. doi:10.1016/j.jacl.2012.03.003

    Article  Google Scholar 

  4. Penumathsa SV, Thirunavukkarasu M, Koneru S, Juhasz B, Zhan L, Pant R, Menon VP, Otani H, Maulik N (2007) Statin and resveratrol in combination induces cardioprotection against myocardial infarction in hypercholesterolemic rat. J Mol Cell Cardiol 42(3):508–516. doi:10.1016/j.yjmcc.2006.10.018

    Article  CAS  Google Scholar 

  5. Palem CR, Patel S, Pokharkar VB (2009) Solubility and stability enhancement of atorvastatin by cyclodextrin complexation. PDA j pharm sci technol/PDA 63(3):217–225

    CAS  Google Scholar 

  6. Toth PP, Thakker KM, Jiang P, Padley RJ (2012) Niacin extended-release/simvastatin combination therapy produces larger favorable changes in high-density lipoprotein particles than atorvastatin monotherapy. Vasc Health Risk Manag 8:39–44. doi:10.2147/VHRM.S22601

    Article  CAS  Google Scholar 

  7. Neves AR, Lucio M, Lima JL, Reis S (2012) Resveratrol in medicinal chemistry: a critical review of its pharmacokinetics, drug-delivery, and membrane interactions. Curr Med Chem 19(11):1663–1681

    Article  CAS  Google Scholar 

  8. Imamura G, Bertelli AA, Bertelli A, Otani H, Maulik N, Das DK (2002) Pharmacological preconditioning with resveratrol: an insight with iNOS knockout mice. Am J Physiol Heart Circ Physiol 282(6):H1996–H2003. doi:10.1152/ajpheart.01013.2001

    CAS  Google Scholar 

  9. Kaga S, Zhan L, Altaf E, Maulik N (2006) Glycogen synthase kinase-3beta/beta-catenin promotes angiogenic and anti-apoptotic signaling through the induction of VEGF, Bcl-2 and survivin expression in rat ischemic preconditioned myocardium. J Mol Cell Cardiol 40(1):138–147. doi:10.1016/j.yjmcc.2005.09.009

    Article  CAS  Google Scholar 

  10. Amri A, Chaumeil JC, Sfar S, Charrueau C (2012) Administration of resveratrol: what formulation solutions to bioavailability limitations? J Control Release 158(2):182–193. doi:10.1016/j.jconrel.2011.09.083

    Article  CAS  Google Scholar 

  11. Fine D, Grattoni A, Hosali S, Ziemys A, De Rosa E, Gill J, Medema R, Hudson L, Kojic M, Milosevic M, Brousseau Iii L, Goodall R, Ferrari M, Liu X (2010) A robust nanofluidic membrane with tunable zero-order release for implantable dose specific drug delivery. Lab Chip 10(22):3074–3083. doi:10.1039/c0lc00013b

    Article  CAS  Google Scholar 

  12. Grattoni A, Rosa ED, Ferrati S, Wang Z, Gianesini A, Liu X, Hussain F, Goodall R, Ferrari M (2009) Analysis of a nanochanneled membrane structure through convective gas flow. J Micromech Microeng 19(11):115018

    Article  Google Scholar 

  13. Laerme F, Schilp A, Funk K, Offenberg M (1999) Bosch deep silicon etching: improving uniformity and etch rate for advanced MEMS applications. In: Micro Electro Mechanical Systems, 1999. MEMS '99. Twelfth IEEE International Conference on, 17–21 Jan 1999. pp 211–216. doi:10.1109/memsys.1999.746812

  14. Grattoni A, Fine D, Zabre E, Ziemys A, Gill J, Mackeyev Y, Cheney MA, Danila DC, Hosali S, Wilson LJ, Hussain F, Ferrari M (2011) Gated and near-surface diffusion of charged fullerenes in nanochannels. ACS Nano 5(12):9382–9391. doi:10.1021/nn2037863

    Article  Google Scholar 

  15. Doppers LM, Sammon C, Breen C, Yarwood J (2006) FTIR-ATR studies of the sorption and diffusion of acetone/water mixtures in poly(vinyl alcohol). Polymer 47:2714–2722

    Article  Google Scholar 

  16. database g-c (2010) GSI Environment Inc, USA http://www.gsi-net.com/en/publications/gsi-chemical-database/single/4.html. Accessed June 12, 2012

  17. Karniadakis G, Beskok A, Aluru NR (2005) Microflows and nanoflows: fundamentals and simulation. Springer, New York

    Google Scholar 

  18. Hamblin MN, Edwards JM, Lee ML, Woolley AT, Hawkins AR (2007) Electroosmotic flow in vapor deposited silicon dioxide and nitride microchannels. Biomicrofluidics 1(3):34101. doi:10.1063/1.2752376

    Article  Google Scholar 

  19. Firnkes M, Pedone D, Knezevic J, Doblinger M, Rant U (2010) Electrically facilitated translocations of proteins through silicon nitride nanopores: conjoint and competitive action of diffusion, electrophoresis, and electroosmosis. Nano Lett 10(6):2162–2167. doi:10.1021/nl100861c

    Article  CAS  Google Scholar 

  20. Datta S, Conlisk AT, Kanani DM, Zydney AL, Fissell WH, Roy S (2010) Characterizing the surface charge of synthetic nanomembranes by the streaming potential method. J Colloid Interface Sci 348(1):85–95. doi:10.1016/j.jcis.2010.04.017

    Article  CAS  Google Scholar 

  21. Pitt CG, Gratzl MM, Jeffcoat AR, Zweidinger R, Schindler A (1979) Sustained drug delivery systems II: factors affecting release rates from poly(epsilon-caprolactone) and related biodegradable polyesters. J Pharm Sci 68(12):1534–1538

    Article  CAS  Google Scholar 

  22. Bansal SS, Kausar H, Vadhanam MV, Ravoori S, Gupta RC (2012) Controlled systemic delivery by polymeric implants enhances tissue and plasma curcumin levels compared with oral administration. Eur J Pharm Biopharm 80(3):571–577. doi:10.1016/j.ejpb.2011.12.009

    Article  CAS  Google Scholar 

  23. Tamada J, Langer R (1992) The development of polyanhydrides for drug delivery applications. J Biomater Sci Polym Ed 3(4):315–353

    Article  CAS  Google Scholar 

  24. Lemmouchi Y, Schacht E, Lootens C (1998) In vitro release of trypanocidal drugs from biodegradable implants based on poly([var epsilon]-caprolactone) and poly(−lactide). J Control Release 55(1):79–85. doi:10.1016/s0168-3659(98)00021-2

    Article  CAS  Google Scholar 

  25. Bansal SS, Vadhanam MV, Gupta RC (2011) Development and in vitro–in vivo evaluation of polymeric implants for continuous systemic delivery of curcumin. Pharm Res 28(5):1121–1130. doi:10.1007/s11095-011-0375-z

    Article  CAS  Google Scholar 

  26. Ron E, Turek T, Mathiowitz E, Chasin M, Hageman M, Langer R (1993) Controlled release of polypeptides from polyanhydrides. Proc Natl Acad Sci U S A 90(9):4176–4180

    Article  CAS  Google Scholar 

  27. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444(7117):337–342. doi:10.1038/nature05354

    Article  CAS  Google Scholar 

  28. Lennernas H (2003) Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet 42:1141–1160

    Article  Google Scholar 

  29. Walle T (2011) Bioavailability of resveratrol. Ann N Y Acad Sci 1215:9–15. doi:10.1111/j.1749-6632.2010.05842.x

    Article  CAS  Google Scholar 

  30. Hung CF, Chen JK, Liao MH, Lo HM, Fang JY (2007) The effect of oil components on the physicochemical properties and drug delivery of emulsions: tocol emulsion versus lipid emulsion. Int J Pharm 335:193–202

    Article  CAS  Google Scholar 

  31. Hung CF, Chen JK, Liao MH, Lo HM, Fang JY (2006) Development and evaluation of emulsion–liposome blends for resveratrol delivery. J Nanosci Nanotechnol 6:2950–2958

    Article  CAS  Google Scholar 

  32. Adah F, Benghuzzi H, Tucci M, Russell G, England B (2006) Effects of sustained release of statin by means of tricalcium phosphate lysine delivery system in defect and segmental femoral injuries on certain biochemical markers in vivo. Biomed Sci Instrum 42:126–135

    CAS  Google Scholar 

  33. Laurencin C, Domb A, Morris C, Brown V, Chasin M, McConnell R, Lange N, Langer R (1990) Poly(anhydride) administration in high doses in vivo: studies of biocompatibility and toxicology. J Biomed Mater Res 24(11):1463–1481. doi:10.1002/jbm.820241105

    Article  CAS  Google Scholar 

  34. Bansal SS, Kausar H, Aqil F, Jeyabalan J, Vadhanam MV, Gupta RC, Ravoori S (2011) Curcumin implants for continuous systemic delivery: safety and biocompatibility. Drug Deliv Trans Res 1:332–341

    Article  CAS  Google Scholar 

  35. Weisenberg BA, Mooradian DL (2002) Hemocompatibility of materials used in microelectromechanical systems: platelet adhesion and morphology in vitro. J Biomed Mater Res 60(2):283–291

    Article  CAS  Google Scholar 

  36. Baier RE, DePalma VA, Goupil DW, Cohen E (1985) Human platelet spreading on substrata of known surface chemistry. J Biomed Mater Res 19(9):1157–1167. doi:10.1002/jbm.820190922

    Article  CAS  Google Scholar 

  37. Bogner E, Dominizi K, Hagl P, Bertagnolli E, Wirth M, Gabor F, Brezna W, Wanzenboeck HD (2006) Bridging the gap—biocompatibility of microelectronic materials. Acta biomaterialia 2(2):229–237. doi:10.1016/j.actbio.2005.10.006

    Article  CAS  Google Scholar 

  38. Cappi B, Neuss S, Salber J, Telle R, Knuchel R, Fischer H (2010) Cytocompatibility of high strength non-oxide ceramics. J Biomed Mater Res A 93(1):67–76. doi:10.1002/jbm.a.32527

    Google Scholar 

  39. Kotzar G, Freas M, Abel P, Fleischman A, Roy S, Zorman C, Moran JM, Melzak J (2002) Evaluation of MEMS materials of construction for implantable medical devices. Biomaterials 23(13):2737–2750

    Article  CAS  Google Scholar 

  40. Neumann A, Reske T, Held M, Jahnke K, Ragoss C, Maier HR (2004) Comparative investigation of the biocompatibility of various silicon nitride ceramic qualities in vitro. J Mater Sci Mater Med 15(10):1135–1140. doi:10.1023/B:JMSM.0000046396.14073.92

    Article  CAS  Google Scholar 

  41. Voskerician G, Shive MS, Shawgo RS, von Recum H, Anderson JM, Cima MJ, Langer R (2003) Biocompatibility and biofouling of MEMS drug delivery devices. Biomaterials 24(11):1959–1967

    Article  CAS  Google Scholar 

  42. Chemical Database, Chemicalize (2012) ChemAxon http://www.chemicalize.org/structure/#!mol=lipitor. Accessed June 12, 2012

  43. Chemical Database, ChemSpider (2012) RSC, Cambridge, http://www.chemspider.com/Chemical-Structure.54810. Accessed June 12, 2012

  44. Filip V, Plocková M, Šmidrkal J, Špičková Z, Melzoch K, Schmidt Š (2003) Resveratrol and its antioxidant and antimicrobial effectiveness. Food Chem 83(4):585–593. doi:10.1016/s0308-8146(03)00157-2

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors express their heartfelt gratitude to Thomas Geninatti for his help in the preparation of the three-dimensional schematic of the membrane, to Lee Hudson for his support with the gas testing, and to Sharath Hosali for fabrication of the membranes. This work was supported with funds from NASA (NNJ06HEA and NNX08AW91G) and NanoMedical Systems (NMS). Authors D.F., M.F., and A.G disclose a financial interest in NanoMedical Systems, Inc. Authors J.S., S.B., S.F., S.F., K.R., E.Z., E.N., and G.P. declare no competing financial interest.

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Authors and Affiliations

  1. Department of Nanomedicine, The Methodist Hospital Research Institute, 6670 Bertner Ave., Room # R8-216, Houston, TX, 77030, USA

    Juliana Sih, Shyam S. Bansal, Stefano Filipini, Silvia Ferrati, Erika Zabre, Eugenia Nicolov, Daniel Fine, Mauro Ferrari & Alessandro Grattoni

  2. NanoMedical Systems, Inc, Austin, TX, 77030, USA

    Kunal Raghuwansi

  3. Department of Medicine, Weill Cornell Medical College, New York, NY, 10065, USA

    Mauro Ferrari

  4. Department of Bioengineering, Rice University, Houston, TX, 77005, USA

    Mauro Ferrari

  5. Alliance for NanoHealth, Houston, TX, 77030, USA

    Mauro Ferrari

  6. Department of Urology, University of Michigan, Ann Arbor, MI, USA

    Ganesh Palapattu

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  1. Juliana Sih
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Correspondence to Alessandro Grattoni.

Additional information

Published in the topical collection Characterization of Thin Films and Membranes with guest editors Daniel Mandler and Pankaj Vadgama.

Juliana Sih and Shyam S. Bansal contributed equally to this work.

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Sih, J., Bansal, S.S., Filipini, S. et al. Characterization of nanochannel delivery membrane systems for the sustained release of resveratrol and atorvastatin: new perspectives on promoting heart health. Anal Bioanal Chem 405, 1547–1557 (2013). https://doi.org/10.1007/s00216-012-6484-7

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