Journal of Electronic Materials

, Volume 48, Issue 10, pp 6570–6582 | Cite as

An Agarose–Curdlan Nanogel that Carries Etanercept to Target and Neutralises TNF-α Produced by Dectin-1-Expressing Immune Cells

  • Dung H. T. Nguyen
  • Ngoc B. Nguyen
  • Linh T. P. Nguyen
  • Ly T. Do
  • Tung T. Nguyen
  • Nam H. Nguyen
  • Sakurai Kazuo
  • Mochizuki Shinichi
  • Kihara Takanori
  • Thang D. Nguyen
  • Anh T. V. Nguyen
  • Huong T. T. PhamEmail author


Etanercept (ETA) has been used as a drug to neutralise tumour necrotic factor alpha (TNF-α) for treatment of rheumatoid arthritis (RA), yet there are limitations concerning its low specific drug targeting and side effects. In this study, agarose–curdlan encapsulating etanercept (ACE) gel was successfully formulated and evenly distributed as nano-particles of 30–100 nm diameter, exhibiting an ETA encapsulation efficiency of 73.8% and an ETA-releasing efficiency of 50% after 52 h. The number of dectin-1-overexpressing macrophage cells, RAW264.7, exposed to ACE that migrated in the Boyden chamber assay was equal to that exposed to either agarose–curdlan or curdlan nanogels, but substantially higher than those exposed to agarose gel and water-soluble ETA by 67 and 141 fold, respectively (p < 0.05), suggesting the targeting effect of curdlan on dectin-1. Enzyme-linked immunosorbent assay revealed that the ETA released from the ACE nanogel could neutralise TNF-α secreted by lipopolysaccharide (LPS)-induced RAW264.7. Moreover, at 24 h and 72 h, the released ETA showed 1.3- to 4.4-fold greater effectiveness, respectively, than water-soluble ETA. This study demonstrates that the ACE nanogel can attract immune cells and slowly release ETA to efficiently neutralise the TNF-α produced by these cells and, thus, could be a promising ETA carrier for targeted RA treatment.


Agarose–curdlan nanogel targeted drug delivery TNF-α neutralization etanercept treatment dectin-1-expressing cell rheumatoid arthritis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.



This work was supported by a grant from Vietnam National University, Hanoi to Huong T. T.Pham Under project number KLEPT.16.01. We thank Msc. Phan Thi Kieu Trang from the Faculty of Environmental Engineering, University of Kitakyushu for her kind guidance on setting the drug targeting experiment, and Dr. Pham Bao Yen from the Key Laboratory of Enzyme and Protein Technology, VNU University of Science, Vietnam National University-Hanoi for English correction

Conflict of interest

The authors report no conflict of interest.


  1. 1.
    D.S. Dimitrov, Therapeutic Proteins (Berlin: Springer, 2012), pp. 1–26.CrossRefGoogle Scholar
  2. 2.
    T.S. Plantinga, J. Fransen, N. Takahashi, R. Stienstra, P.L. van Riel, W.B. van den Berg, M.G. Netea, and L.A. Joosten, Arthritis Res. Ther. 12, R26 (2010).CrossRefGoogle Scholar
  3. 3.
    L.M. van den Berg, E.M. Zijlstra-Willems, C.D. Richters, M.M. Ulrich, and T.B. Geijtenbeek, Cell. Immunol. 289, 49 (2014).CrossRefGoogle Scholar
  4. 4.
    E.H. Choy and G.S. Panayi, N. Engl. J. Med. 344, 907 (2001).CrossRefGoogle Scholar
  5. 5.
    C. Tetta, G. Camussi, V. Modena, C. Di Vittorio, and C. Baglioni, Ann. Rheum. Dis. 49, 665 (1990).CrossRefGoogle Scholar
  6. 6.
    H. Matsuno, K. Yudoh, R. Katayama, F. Nakazawa, M. Uzuki, T. Sawai, T. Yonezawa, Y. Saeki, G.S. Panayi, and C. Pitzalis, Rheumatology 41, 329 (2002).CrossRefGoogle Scholar
  7. 7.
    Y.-F. Chen, P. Jobanputra, P. Barton, S. Jowett, S. Bryan, W. Clark, A. Fry-Smith, and A. Burls, Health Technol. Assess. 10, 1 (2006).CrossRefGoogle Scholar
  8. 8.
    Z. Kaymakcalan, P. Sakorafas, S. Bose, S. Scesney, L. Xiong, D.K. Hanzatian, J. Salfeld, and E.H. Sasso, Clin. Immunol. 131, 308 (2009).CrossRefGoogle Scholar
  9. 9.
    K. Malottki, P. Barton, A. Tsourapas, A.O. Uthman, Z. Liu, K. Routh, M. Connock, P. Jobanputra, D. Moore, A. Fry-Smith, and Y.-F. Chen, Health Technol. Assess. 15, 1 (2011).CrossRefGoogle Scholar
  10. 10.
    U.G. Longo, S. Petrillo, and V. Denaro, Int. J. Rheumatol. 2015, 648073 (2015).CrossRefGoogle Scholar
  11. 11.
    J. Panyam and V. Labhasetwar, Adv. Drug Deliv. Rev. 55, 329 (2003).CrossRefGoogle Scholar
  12. 12.
    N. Wang and X.S. Wu, Int. J. Pharm. 166, 1 (1998).CrossRefGoogle Scholar
  13. 13.
    N. Wang and X.S. Wu, Pharm. Dev. Technol. 2, 135 (1997).CrossRefGoogle Scholar
  14. 14.
    P. Serwer, Agarose gels: properties and use for electrophoresis. Electrophoresis 4, 375 (1983).CrossRefGoogle Scholar
  15. 15.
    P. Zarrintaj, S. Manouchehri, Z. Ahmadi, M.R. Saeb, A.M. Urbanska, D.L. Kaplan, and M. Mozafari, Carbohydr. Polym. 187, 66 (2018).CrossRefGoogle Scholar
  16. 16.
    J. Liu, S. Lin, L. Li, and E. Liu, Int. J. Pharm. 298, 117 (2005).CrossRefGoogle Scholar
  17. 17.
    O. Erdemli, S. Ozen, D. Keskin, A. Usanmaz, E.D. Batu, B. Atilla, and A. Tezcaner, J. Biomater. Appl. 29, 524 (2014).CrossRefGoogle Scholar
  18. 18.
    M. Giulbudagian, G. Yealland, S. Hönzke, A. Edlich, B. Geisendörfer, B. Kleuser, S. Hedtrich, and M. Calderón, Theranostics 8, 450 (2018).CrossRefGoogle Scholar
  19. 19.
    K.B. Soo, J.I. Duck, K.J. Sik, L. Jung-heon, L.I. Young, and L.K. Bok, Biotechnol. Lett. 22, 1127 (2000).CrossRefGoogle Scholar
  20. 20.
    M. Kanke, K. Koda, Y. Koda, and H. Katayama, Pharm. Res. 9, 414 (1992).CrossRefGoogle Scholar
  21. 21.
    Z. Cai and H. Zhang, Food Hydrocoll. 68, 128 (2017).CrossRefGoogle Scholar
  22. 22.
    Y. Matsumura and H. Maeda, Cancer Res. 46, 6387 (1986).Google Scholar
  23. 23.
    X. Ma, Y. Xia, L. Ni, L. Song, and Z. Wang, Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 121, 657 (2014).CrossRefGoogle Scholar
  24. 24.
    E.J. Lee, J.K. Park, S.A. Khan, and K.H. Lim, J. Chem. Eng. Jpn 44, 502 (2011).CrossRefGoogle Scholar
  25. 25.
    B.G. Zanetti-Ramos, E. Lemos-Senna, V. Soldi, R. Borsali, E. Cloutet, and H. Cramail, Polymer 47, 8080 (2006).CrossRefGoogle Scholar
  26. 26.
    D. Lu and A.J. Hickey, AAPS PharmSciTech 6, E641 (2005).CrossRefGoogle Scholar
  27. 27.
    H.C. Chen, Cell Migration (Berlin: Springer, 2005), pp. 15–22.Google Scholar
  28. 28.
    W. Hergert, Chapter 2. Springer Series in Optical Sciences, Vol. 169 (Berlin: Springer, 2012).Google Scholar
  29. 29.
    E. Al-Emam, A.G. Motawea, K. Janssens, and J. Caen, Herit. Sci. 7, 22 (2019).CrossRefGoogle Scholar
  30. 30.
    Y. Adachi, T. Ishii, Y. Ikeda, A. Hoshino, H. Tamura, J. Aketagawa, S. Tanaka, and N. Ohno, Infect. Immun. 72, 4159 (2004).CrossRefGoogle Scholar
  31. 31.
    A.S. Palma, T. Feizi, Y. Zhang, M.S. Stoll, A.M. Lawson, E. Díaz-Rodríguez, M.A. Campanero-Rhodes, J. Costa, S. Gordon, and G.D. Brown, J. Biol. Chem. 281, 5771 (2006).CrossRefGoogle Scholar
  32. 32.
    D.A. Salvatore, P. Carlo, C. Fabrizio, L. Ennio, M. Antonio, M. Alessandro, S. Carlo, S. Raffaele, S. Antonio, and O. Ignazio, Clin. Exp. Rheumatol. 29, 865 (2011).Google Scholar
  33. 33.
    X. Chen, D.C. DuBois, R.R. Almon, and W.J. Jusko, Drug Metab. Dispos. 43, 898 (2015).CrossRefGoogle Scholar
  34. 34.
    O.C. Farokhzad and R. Langer, ACS Nano 3, 16 (2009).CrossRefGoogle Scholar
  35. 35.
    M. Moscovici, C. Hlevca, C. Angela, and R.D. Pavaloiu, Nanocellulose and Nanohydrogel Matrices: Biotechnological and Biomedical Applications (Colorado: Wiley, 2017), pp. 209–269.CrossRefGoogle Scholar
  36. 36.
    H. Schierbeck, H. Wähämaa, U. Andersson, and H.E. Harris, Mol. Med. 16, 343 (2010).CrossRefGoogle Scholar
  37. 37.
    J.H. Egberts, V. Cloosters, A. Noack, B. Schniewind, L. Thon, S. Klose, B. Kettler, C. von Forstner, C. Kneitz, and J. Tepel, Can. Res. 68, 1443 (2008).CrossRefGoogle Scholar
  38. 38.
    S.H. Zhao, X.T. Wu, W.C. Guo, Y.M. Du, L. Yu, and J. Tang, Int. J. Pharm. 393, 269 (2010).CrossRefGoogle Scholar
  39. 39.
    J. Varshosaz, M.R. Zaki, M. Minaiyan, and J. Banoozadeh, Biomed. Res. Int. 2015, 571816 (2015).Google Scholar
  40. 40.
    Z. Hu, S. Li, and L. Yang, Polímeros 22, 422 (2012).CrossRefGoogle Scholar
  41. 41.
    Y. Xu, Y. Du, R. Huang, and L. Gao, Biomaterials 24, 5015 (2003).CrossRefGoogle Scholar
  42. 42.
    J. Han, J. Cai, W. Borjihan, T. Ganbold, T.M. Rana, and H. Baigude, Carbohydr. Polym. 117, 324 (2015).CrossRefGoogle Scholar
  43. 43.
    S. Mochizuki and K. Sakurai, J. Control. Release 151, 155 (2011).CrossRefGoogle Scholar

Copyright information

© The Minerals, Metals & Materials Society 2019

Authors and Affiliations

  • Dung H. T. Nguyen
    • 1
  • Ngoc B. Nguyen
    • 1
  • Linh T. P. Nguyen
    • 1
  • Ly T. Do
    • 1
  • Tung T. Nguyen
    • 1
  • Nam H. Nguyen
    • 2
  • Sakurai Kazuo
    • 3
  • Mochizuki Shinichi
    • 3
  • Kihara Takanori
    • 4
  • Thang D. Nguyen
    • 1
  • Anh T. V. Nguyen
    • 1
  • Huong T. T. Pham
    • 1
    Email author
  1. 1.Key Laboratory of Enzyme and Protein TechnologyVNU University of Science, Vietnam National UniversityThanh XuanVietnam
  2. 2.Nano and Energy Research Center, Faculty of PhysicsVNU University of Science, Vietnam National UniversityThanh XuanVietnam
  3. 3.Department of Chemistry and BiochemistryUniversity of KitakyushuKitakyushuJapan
  4. 4.Department of Life and Environment Engineering, Faculty of Environmental EngineeringUniversity of KitakyushuKitakyushuJapan

Personalised recommendations