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AAPS PharmSciTech

, Volume 19, Issue 1, pp 192–200 | Cite as

Topical Delivery of Coumestrol from Lipid Nanoemulsions Thickened with Hydroxyethylcellulose for Antiherpes Treatment

  • Débora Fretes Argenta
  • Juliana Bidone
  • Letícia Scherer Koester
  • Valquíria Link Bassani
  • Cláudia Maria Oliveira Simões
  • Helder Ferreira TeixeiraEmail author
Research Article

Abstract

We have recently shown that coumestrol, an isoflavonoid-like compound naturally occurring in soybeans, alfafa, and red clover, inhibited Herpes Simplex Virus types 1 (HSV-1) and 2 (HSV-2) replication. In this study, we designed coumestrol formulations in an attempt to enable its topical delivery to mucosa tissues. Physicochemical and microscopic examinations suggested that coumestrol was efficiently incorporated in positively-charged nanoemulsions dispersed in a hydroxyethylcellulose gel. The higher coumestrol flux through excised porcine esophageal mucosa was detected from nanoemulsions composed by a fluid phospholipid (dioleylphosphocholine, DOPC) in comparison with that of a rigid one (distearoylphosphocholine, DSPC) in two mucosa conditions (intact and injured). Such results were supported by confocal fluorescence images. Furthermore, the low IC50 values demonstrated an increasement in the antiviral inhibition against HSV-1 and HSV-2 after incorporation of coumestrol into nanoemulsions containing DOPC. Overall, coumestrol-loaded nanoemulsions proved to be beneficial for herpes simplex treatment.

KEY WORDS

coumestrol nanoemulsion hydroxylethylcellulose mucosa permeation herpes 

Notes

ACKNOWLEDGEMENTS

The authors wish to thank the financial support of the National Council for Scientific and Technological Development (CNPq, grant number 459619/2014-4) and the Brazilian Federal Agency for Support and Evaluation of Graduate Education (CAPES, Nanobiotec Network, grant number 902/2009). L.K., V.B., C.M.O.S., and H.T are recipients of CNPq research fellowships.

REFERENCES

  1. 1.
    Stopper H, Schmitt E, Kobras K. Genotoxicity of phytoestrogens. Mutat Res. 2005;574:139–55.CrossRefPubMedGoogle Scholar
  2. 2.
    Argenta DF, Silva IT, Bassani VL, Koester LS, Teixeira HF, Simões CM. Antiherpes evaluation of soybean isoflavonoids. Arch Virol. 2015a;160:2335–42.CrossRefPubMedGoogle Scholar
  3. 3.
    Brady RC, Bernstein DI. Treatment of herpes simplex virus infections. Antivir Res. 2004;61:73–81.CrossRefPubMedGoogle Scholar
  4. 4.
    Colgrove RC, Liu X, Griffiths A, Raja P, Deluca NA, Newman RM, et al. History and genomic sequence analysis of the herpes simplex virus 1 KOS and KOS1.1 sub-strains. Virology. 2015;487:215–22.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Goodyear H. Infections and infestations of the skin. Paediatr Child Health. 2015;25:72–7.CrossRefGoogle Scholar
  6. 6.
    Hassan ST, Masarčíková R, Berchová K. Bioactive natural products with anti-herpes simplex virus properties. J Pharm Pharmacol. 2015;67:1325–36.CrossRefPubMedGoogle Scholar
  7. 7.
    Chentoufi AA, Benmohamed L. Mucosal herpes immunity and immunopathology to ocular and genital herpes simplex virus infections. Clin Dev Immunol. 2012;2012:01–22.Google Scholar
  8. 8.
    Hodge VRA, Field HJ. Antiviral agents for herpes simplex virus. Adv Pharmacol. 2013;67:1–38.CrossRefGoogle Scholar
  9. 9.
    Sandri G, Rossi S, Ferrari F, Bonferoni MC, Muzzarelli C, Caramella C. Assessment of chitosan derivatives as buccal and vaginal penetration enhancers. Eur J Pharm Sci. 2004;21:351–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Franz-Montan M, Serpe L, Martinelli CC, Silva CB, Santos CP, Novaes PD, et al. Evaluation of different pig oral mucosa sites as permeability barrier models for drug permeation studies. Eur J Pharm Sci. 2016;81:52–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Neves J, Bahia MF. Gels as vaginal drug delivery systems. Int J Pharm. 2006;318:1–14.CrossRefPubMedGoogle Scholar
  12. 12.
    Vanić Ž, Škalko-Basnet N. Nanopharmaceuticals for improved topical vaginal therapy: can they deliver? Eur J Pharm Sci. 2013;50:29–41.CrossRefPubMedGoogle Scholar
  13. 13.
    Issa MM, Köping-Höggård M, Artursson P. Chitosan and the mucosal delivery of biotechnology drugs. Drug Discov Today Technol. 2005;2:1–6.CrossRefPubMedGoogle Scholar
  14. 14.
    McGill SL, Smyth HD. Disruption of the mucus barrier by topically applied exogenous particles. Mol Pharm. 2010;7:2280–8.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Martirosyan A, Olesen MJ, Howard KA. Chitosan-based nanoparticles for mucosal delivery of RNAi therapeutics. Adv Genet. 2014;88:325–52.PubMedGoogle Scholar
  16. 16.
    Wong TW, Dhanawat M, Rathbone MJ. Vaginal drug delivery: strategies and concerns in polymeric nanoparticle development. Expert OpinDrug Deliv. 2014;11:1419–34.CrossRefGoogle Scholar
  17. 17.
    Singh Y, Meher JG, Raval K, Khan FA, Chaurasia M, Jain NK, et al. Nanoemulsion: concepts, development and applications in drug delivery. J Control Release. 2017;252:28–49.CrossRefPubMedGoogle Scholar
  18. 18.
    Caon T, Simões CM. Effect of freezing and type of mucosa on ex vivo drug permeability parameters. AAPS PharmSciTech. 2011;12:587–92.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Argenta DF, Franco C, Koester LS, Bassani VL, Teixeira HF. LC analysis of coumestrol incorporated into topical lipid nanoemulsions. Pharmazie. 2011;66:929–32.PubMedGoogle Scholar
  20. 20.
    Argenta DF, Mattos CB, Misturini FD, Koester LS, Bassani VL, Simões CM, et al. Factorial design applied to the optimization of lipid composition of topical antiherpetic nanoemulsions containing isoflavone genistein. Int J Nanomedicine. 2014;9:4737–47.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Vichai V, Kirtikara K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc. 2006;1:1112–6.CrossRefPubMedGoogle Scholar
  22. 22.
    Argenta DF, Bidone J, Misturini FD, Bassani VL, Koester LS, Teixeira HF, et al. In vitro evaluation of mucosa permeation/retention and antiherpes activity of genistein from cationic nanoemulsions. J Nanosci Nanotechnol. 2015b;15:1–9.CrossRefGoogle Scholar
  23. 23.
    Hoeller S, Sperger A, Valenta C. Lecithin based nanoemulsions: a comparative study of the influence of non-ionic surfactants and the cationic phytosphingosine on physicochemical behaviour and skin permeation. Int J Pharm. 2009;370(1–2):181–6.CrossRefPubMedGoogle Scholar
  24. 24.
    Hull CM, Levin MJ, Tyring SK, Spruance SL. Novel composite efficacy measure to demonstrate the rationale and efficacy of combination antiviral-anti-inflammatory treatment for recurrent herpes simplex labialis. Antimicrob Agents Chemother. 2014;58:1273–8.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Barbosa-Barros L, Rodríguez G, Barba C, Cócera M, Rubio L, Estelrich J, et al. Bicelles: lipid nanostructured platforms with potential dermal applications. Small. 2012;8:807–17.CrossRefPubMedGoogle Scholar
  26. 26.
    Greenspan P, Mayer EP, Fowler SD. Nile red: a selective fluorescent stain for intracellular lipid droplets. J Cell Biol. 1985;100:965–73.CrossRefPubMedGoogle Scholar
  27. 27.
    Gabal YM, Kamel AO, Sammour OA, Elshafeey AH. Effect of surface charge on the brain delivery of nanostructured lipid carriers in situ gels via the nasal route. Int J Pharm. 2014;473:442–57.CrossRefPubMedGoogle Scholar
  28. 28.
    Uyangaa E, Patil AM, Eo SK. Prophylactic and therapeutic modulation of innate and adaptive immunity against mucosal infection of herpes simplex virus. Immune Netw. 2014;14:187–200.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Schwarz KB. Oxidative stress during viral infection: a review. FreeRadic Biol Med. 1996;21:641–9.CrossRefGoogle Scholar
  30. 30.
    Reiter RJ, Rosales-Corral SA, Liu XY, Acuna-Castroviejo D, Escames G, Tan DX. Melatonin in the oral cavity: physiological and pathological implications. J Periodontal Res. 2015;50:9–17.CrossRefPubMedGoogle Scholar
  31. 31.
    Mitchell JH, Gardner PT, McPhail DB, Morrice PC, Collins AR, Duthie GG. Antioxidant efficacy of phytoestrogens in chemical and biological model systems. Arch Biochem Biophys. 1998;360:142–8.CrossRefPubMedGoogle Scholar
  32. 32.
    Castro CC, Pagnussat AS, Moura N, Da Cunha MJ, Machado FR, Wyse AT, et al. Coumestrol treatment prevents Na+, K+ −ATPase inhibition and affords histological neuroprotection to male rats receiving cerebral global ischemia. Neurol Res. 2014;36:198–206.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  • Débora Fretes Argenta
    • 1
  • Juliana Bidone
    • 1
  • Letícia Scherer Koester
    • 1
  • Valquíria Link Bassani
    • 1
  • Cláudia Maria Oliveira Simões
    • 2
  • Helder Ferreira Teixeira
    • 1
    Email author
  1. 1.Programa de Pós-graduação em Ciências FarmacêuticasUniversidade Federal do Rio Grande do Sul (UFRGS)Porto AlegreBrazil
  2. 2.Programa de Pós-graduação em FarmáciaUniversidade Federal de Santa Catarina (UFSC)FlorianópolisBrazil

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