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Transdermal Immunization using Solid-in-oil Nanodispersion with CpG Oligodeoxynucleotide Adjuvants

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Abstract

Purpose

Simple and noninvasive vaccine administration alternatives to injections are desired. A solid-in-oil (S/O) nanodispersion system was able to overcome skin barriers and induce an immune response; however, antibody levels remained low. We applied an immune potentiator, CpG oligodeoxynucleotide (ODN), to enhance the immune response by controlling the T helper 1 (Th1)/T helper 2 (Th2) balance.

Methods

S/O nanodispersions containing ovalbumin (OVA) and CpG ODN (CpG-A or CpG-B) were characterized by size distribution analysis and a protein release test. The skin permeation of fluorescence-labeled OVA was observed by fluorescence microscopy. Antigen-specific IgG, IgG1, and IgG2a responses were measured by enzyme-linked immunosorbent assay.

Results

Co-encapsulation of CpG ODNs in S/O nanodispersions enhanced induction of OVA-specific IgG. S/O nanodispersion containing OVA and CpG-A had a smaller mean particle size and permeated the skin more efficiently. In contrast, CpG-B showed the highest protein release and induction of OVA-specific IgG. IgG subclass analysis revealed that OVA induced a Th2-dominant immune response, while the S/O nanodispersion containing CpG-A skewed the immune response toward a Th1-bias.

Conclusions

In combination with CpG ODN, the S/O nanodispersion system efficiently induced an antigen-specific antibody response. The Th1/Th2 immune balance could be controlled by the selection of CpG ODN type.

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Abbreviations

BCA:

Bicinchoninic acid

BSA:

Bovine serum albumin

DC:

Dendritic cell

ELISA:

Enzyme-linked immunosorbent assay

IFN:

Interferon

IPM:

Isopropyl myristate

L-195:

Sucrose laurate surfactant

LC:

Langerhans cell

OD:

Optical density

ODN:

Oligodeoxynucleotide

OVA:

Ovalbumin

PBS:

Phosphate-buffered saline

SC:

Stratum corneum

S/O:

Solid-in-oil

Th:

T helper

Th1:

T helper type 1

Th2:

T helper type 2

References

  1. Mishra DK, Dhote V, Mishra PK. Transdermal immunization: Biological framework and translational perspectives. Expert Opin Drug Deliv. 2013;10:183–200.

    Article  CAS  PubMed  Google Scholar 

  2. Combadiere B, Liard C. Transcutaneous and intradermal vaccination. Hum Vaccine. 2011;7(8):811–27.

    Article  CAS  Google Scholar 

  3. Radford KJ, Tullett KM, Lahoud MH. Dendritic cells and cancer immunotherapy. Curr Opin Immunol. 2014;27C:26–32.

    Article  Google Scholar 

  4. Mishra N, Gupta PN, Khatri K, Goyal AK, Vyas SP. Edible vaccines: A new approach to oral immunization. Indian J Biotechnol. 2008;7:283–94.

    CAS  Google Scholar 

  5. Jabbal-Gill I. Nasal vaccine innovation. J Drug Target. 2010;18(10):771–86.

    Article  CAS  PubMed  Google Scholar 

  6. Illum L. Nasal drug delivery: new developments and strategies. Drug Discov Today. 2002;7(23):1184–9.

    Article  CAS  PubMed  Google Scholar 

  7. Seid Jr RC, Look JL, Ruiz C, Frolov V, Flyer D, Schafer J, et al. Transcutaneous immunization with intercell’s vaccine delivery system. Vaccine. 2012;30(29):4349–54.

    Article  CAS  PubMed  Google Scholar 

  8. Li N, Peng LH, Chen X, Nakagawa S, Gao JQ. Transcutaneous vaccines: novel advances in technology and delivery for overcoming the barriers. Vaccine. 2011;29(37):6179–90.

    Article  CAS  PubMed  Google Scholar 

  9. Alexander A, Dwivedi S, Ajazuddin, Giri TK, Saraf S, Saraf S, et al. Approaches for breaking the barriers of drug permeation through transdermal drug delivery. J Control Release. 2012;164(1):26-40

  10. Lee MY, Shin MG, Yang VC. Transcutaneous antigen delivery system. BMB Rep. 2013;46(1):17–24.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Kitaoka M, Imamura K, Hirakawa Y, Tahara Y, Kamiya N, Goto M. Sucrose laurate-enhanced transcutaneous immunization with a solid-in-oil nanodispersion. Med Chem Commun. 2014;5(1):20–4.

    Article  CAS  Google Scholar 

  12. Tahara Y, Kamiya N, Goto M. Solid-in-oil dispersion: A novel core technology for drug delivery systems. Int J Pharm. 2012;438(1–2):249–57.

    Article  CAS  PubMed  Google Scholar 

  13. Kitaoka M, Imamura K, Hirakawa Y, Tahara Y, Kamiya N, Goto M. Needle-free immunization using a solid-in-oil nanodispersion enhanced by a skin-permeable oligoarginine peptide. Int J Pharm. 2013;458(2):334–9.

    Article  CAS  PubMed  Google Scholar 

  14. Tahara Y, Namatsu K, Kamiya N, Hagimori M, Kamiya S, Arakawa M, et al. Transcutaneous immunization by a solid-in-oil nanodispersion. Chem Commun. 2010;46(48):9200–2.

    Article  CAS  Google Scholar 

  15. Kidd P. Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Altern Med Rev. 2003;8(3):223–46.

    PubMed  Google Scholar 

  16. Roberts TL, Sweet MJ, Hume DA, Stacey KJ. Cutting Edge: Species-specific TLR9-mediated recognition of CpG and non-CpG phosphorothioate-modified oligonucleotides. J Immunol. 2005;174(2):605–8.

    Article  CAS  PubMed  Google Scholar 

  17. Sugita K, Kabashima K, Atarashi K, Shimauchi T, Kobayashi M, Tokura Y. Innate immunity mediated by epidermal keratinocytes promotes acquired immunity involving Langerhans cells and T cells in the skin. Clin Exp Immunol. 2007;147(1):176–83.

    PubMed Central  CAS  PubMed  Google Scholar 

  18. Klinman DM. Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat Rev Immunol. 2004;4(4):249–58.

    Article  CAS  PubMed  Google Scholar 

  19. Vabulas RM, Pircher H, Lipford GB, Häcker H, Wagner H. CpG-DNA activates in vivo T cell epitope presenting dendritic cells to trigger protective antiviral cytotoxic T cell responses. J Immunol. 2000;164(5):2372–8.

    Article  CAS  PubMed  Google Scholar 

  20. Ziegler A, Heidenreich R, Braumüller H, Wolburg H, Weidemann S, Mocikat R, et al. EpCAM, a human tumor-associated antigen promotes Th2 development and tumor immune evasion. Blood. 2009;113(15):3494–502.

    Article  CAS  PubMed  Google Scholar 

  21. Fonseca DE, Kline JN. Use of CpG oligonucleotides in treatment of asthma and allergic disease. Adv Drug Deliv Rev. 2009;61(3):256–62.

    Article  CAS  PubMed  Google Scholar 

  22. Mishra D, Mishra PK, Dubey V, Nahar M, Dabadghao S, Jain NK. Systemic and mucosal immune response induced by transcutaneous immunization using Hepatitis B surface antigen-loaded modified liposomes. Eur J Pharm Sci. 2008;33:424–33.

    Article  CAS  PubMed  Google Scholar 

  23. Chu RS, Targoni OS, Krieg AM, Lehmann PV, Harding CV. CpG oligodeoxynucleotides act as adjuvants that switch on T helper 1 (Th1) immunity. J Exp Med. 1997;186(10):1623–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Lin L, Gerth AJ, Peng SL. GpG DNA redirects class-switching towards “Th1-like” Ig isotype production via TLR9 and MyD88. Eur J Immunol. 2004;34(5):1483–7.

    Article  CAS  PubMed  Google Scholar 

  25. Diwan M, Tafaghodi M, Samuel J. Enhancement of immune responses by co-delivery of a CpG oligodeoxynucleotide and tetanus toxoid in biodegradable nanospheres. J Control Release. 2002;85(1–3):247–62.

    Article  CAS  PubMed  Google Scholar 

  26. Klinman DM, Barnhart KM, Conover J. CpG motifs as immune adjuvants. Vaccine. 1999;17(1):19–25.

    Article  CAS  PubMed  Google Scholar 

  27. Inoue J, Yotsumoto S, Sakamoto T, Tsuchiya S, Aramaki Y. Changes in immune responses to antigen applied to tape-stripped skin with CpG-oligodeoxynucleotide in NC/Nga mice. Pharm Res. 2005;22(10):1627–33.

    Article  CAS  PubMed  Google Scholar 

  28. Rothenfusser S, Hornung V, Ayyoub M, Britsch S, Towarowski A, Krug A, et al. CpG-A and CpG-B oligonucleotides differentially enhance human peptide-specific primary and memory CD8; T-cell responses in vitro. Blood. 2004;103(6):2162–9.

    Article  CAS  PubMed  Google Scholar 

  29. Schattenberg D, Schott M, Reindl G, Krueger T, Tschoepe D, Feldkamp J, et al. Response of human monocyte-derived dendritic cells to immunostimulatory DNA. Eur J Immunol. 2000;30(10):2824–31.

    Article  CAS  PubMed  Google Scholar 

  30. Slütter B, Bal SM, Ding Z, Jiskoot W, Bouwstra JA. Adjuvant effect of cationic liposomes and CpG depends on administration route. J Control Release. 2011;154(2):123–30.

    Article  PubMed  Google Scholar 

  31. Tahara Y, Honda S, Kamiya N, Piao H, Hirata A, Hayakawa E, et al. A solid-in-oil nanodispersion for transcutaneous protein delivery. J Control Release. 2008;131:14–8.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments and Disclosures

This work was financed by a Grant-in-Aid for Scientific Research (S) 24226019 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to M. G.). We thank Professor Yoshiki Katayama for animal experiments.

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Authors and Affiliations

  1. Department of Applied Chemistry, Graduate School of Engineering, Kyushu University, 744 Moto-oka, 819-0395, Fukuoka, Japan

    Momoko Kitaoka, Ayaka Naritomi, Yuya Hirakawa, Noriho Kamiya & Masahiro Goto

  2. Center for Future Chemistry, Kyushu University, 819-0395, Fukuoka, Japan

    Noriho Kamiya & Masahiro Goto

Authors
  1. Momoko Kitaoka
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  2. Ayaka Naritomi
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  3. Yuya Hirakawa
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  4. Noriho Kamiya
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  5. Masahiro Goto
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Correspondence to Masahiro Goto.

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Kitaoka, M., Naritomi, A., Hirakawa, Y. et al. Transdermal Immunization using Solid-in-oil Nanodispersion with CpG Oligodeoxynucleotide Adjuvants. Pharm Res 32, 1486–1492 (2015). https://doi.org/10.1007/s11095-014-1554-5

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  • DOI: https://doi.org/10.1007/s11095-014-1554-5

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