Skip to main content
SpringerLink
Log in

Fabrication and Characterization of Antibody-Loaded Cationic Porous PLGA Microparticles for Sustained Antibody Release

  • Research Article
  • Published:
The AAPS Journal Aims and scope Submit manuscript

Abstract

Poly lactic-co-glycolic acid (PLGA) microparticles have been formulated to allow the sustained release of numerous drugs, including antibodies. It is well-known that antibodies are susceptible to chemical and physical stress; therefore, it is necessary to be loaded on PLGA microparticles under mild conditions. In the present study, we constructed cationic porous PLGA microparticles that could be electrostatically adsorbed with infliximab as a model antibody. Cationic porous PLGA microparticles were prepared using the double emulsion method by adding polyethyleneimine and ammonium bicarbonate. After antibody loading, surface pores closure was achieved by mild heating. The size of the optimized formulation was approximately 5 μm, exhibiting a positive charge. The loaded antibody was gradually released from the formulation over 56 days. Based on a tumor necrosis factor (TNF)–α inhibition assay, the released infliximab maintained its pharmacological activity. Collectively, we successfully loaded antibodies into PLGA microparticles while maintaining activity and demonstrating long-acting properties.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Jin S, Sun Y, Liang X, Gu X, Ning J, Xu Y, et al. Emerging new therapeutic antibody derivatives for cancer treatment. Signal Transduct Target Ther. 2022;7(1):39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007;7(9):715–25.

    Article  CAS  PubMed  Google Scholar 

  3. Holliger P, Hudson PJ. Engineered antibody fragments and the rise of single domains. Nat Biotechnol. 2005;23(9):1126–36.

    Article  CAS  PubMed  Google Scholar 

  4. Okuyama T, Eto Y, Sakai N, Minami K, Yamamoto T, Sonoda H, et al. Iduronate-2-sulfatase with anti-human transferrin receptor antibody for neuropathic mucopolysaccharidosis II: a phase 1/2 trial. Mol Ther. 2019;27(2):456–64.

    Article  CAS  PubMed  Google Scholar 

  5. Rocha CV, Goncalves V, da Silva MC, Banobre-Lopez M, Gallo J. PLGA-based composites for various biomedical applications. Int J Mol Sci. 2022;23(4):2034.

  6. Alenezi A, Naito Y, Terukina T, Prananingrum W, Jinno Y, Tagami T, et al. Controlled release of clarithromycin from PLGA microspheres enhances bone regeneration in rabbit calvaria defects. J Biomed Mater Res B Appl Biomater. 2018;106(1):201–8.

    Article  CAS  PubMed  Google Scholar 

  7. Tanetsugu Y, Tagami T, Terukina T, Ogawa T, Ohta M, Ozeki T. Development of a sustainable release system for a ranibizumab biosimilar using poly(lactic-co-glycolic acid) biodegradable polymer-based microparticles as a platform. Biol Pharm Bull. 2017;40(2):145–50.

    Article  CAS  PubMed  Google Scholar 

  8. Naito Y, Terukina T, Galli S, Kozai Y, Vandeweghe S, Tagami T, et al. The effect of simvastatin-loaded polymeric microspheres in a critical size bone defect in the rabbit calvaria. Int J Pharm. 2014;461(1–2):157–62.

    Article  CAS  PubMed  Google Scholar 

  9. Colzani B, Pandolfi L, Hoti A, Iovene PA, Natalello A, Avvakumova S, et al. Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles. Int J Nanomedicine. 2018;13:957–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lee PW, Pokorski JK. Poly(lactic-co-glycolic acid) devices: production and applications for sustained protein delivery. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2018;10(5): e1516.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kim H, Park H, Lee J, Kim TH, Lee ES, Oh KT, et al. Highly porous large poly(lactic-co-glycolic acid) microspheres adsorbed with palmityl-acylated exendin-4 as a long-acting inhalation system for treating diabetes. Biomaterials. 2011;32(6):1685–93.

    Article  CAS  PubMed  Google Scholar 

  12. Zhang G-H, Hou R-X, Zhan D-X, Cong Y, Cheng Y-J, Fu J. Fabrication of hollow porous PLGA microspheres for controlled protein release and promotion of cell compatibility. Chin Chem Lett. 2013;24(8):710–4.

    Article  CAS  Google Scholar 

  13. Fang K, Yang F, Zhang Q, Zhang T, Gu N. Fabrication of nonporous and porous cationic PLGA microspheres. Mater Lett. 2014;117:86–9.

    Article  CAS  Google Scholar 

  14. Kim Y, Sah H. Protein loading into spongelike PLGA microspheres. Pharmaceutics. 2021;13(2):137.

  15. Tamazawa G, Ito A, Miyai T, Matsuno T, Kitahara K, Sogo Y, et al. Gatifloxacine-loaded PLGA and beta-tricalcium phosphate composite for treating osteomyelitis. Dent Mater J. 2011;30(3):264–73.

    Article  CAS  PubMed  Google Scholar 

  16. Meager A. A cytotoxicity assay for tumour necrosis using a human rhabdomyosarcoma cell line. J Immunol Methods. 1991;144(1):141–3.

    Article  CAS  PubMed  Google Scholar 

  17. Wang B, Friess W. Lipid-coated mannitol core microparticles for sustained release of protein. Eur J Pharm Biopharm. 2018;128:91–7.

    Article  CAS  PubMed  Google Scholar 

  18. Miller AC, Bershteyn A, Tan W, Hammond PT, Cohen RE, Irvine DJ. Block copolymer micelles as nanocontainers for controlled release of proteins from biocompatible oil phases. Biomacromolecules. 2009;10(4):732–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nakai T, Hirakura T, Sakurai Y, Shimoboji T, Ishigai M, Akiyoshi K. Injectable hydrogel for sustained protein release by salt-induced association of hyaluronic acid nanogel. Macromol Biosci. 2012;12(4):475–83.

    Article  CAS  PubMed  Google Scholar 

  20. Hong J, Lee Y, Lee C, Eo S, Kim S, Lee N, et al. Physicochemical and biological characterization of SB2, a biosimilar of Remicade(R) (infliximab). MAbs. 2017;9(2):364–82.

    Article  PubMed  Google Scholar 

  21. Terukina T, Naito Y, Tagami T, Morikawa Y, Henmi Y, Prananingrum W, et al. The effect of the release behavior of simvastatin from different PLGA particles on bone regeneration in vitro and in vivo: comparison of simvastatin-loaded PLGA microspheres and nanospheres. J Drug Deliv Sci Technol. 2016;33:136–42.

    Article  CAS  Google Scholar 

  22. Ozeki T, Kaneko D, Hashizawa K, Imai Y, Tagami T, Okada H. Improvement of survival in C6 rat glioma model by a sustained drug release from localized PLGA microspheres in a thermoreversible hydrogel. Int J Pharm. 2012;427(2):299–304.

    Article  CAS  PubMed  Google Scholar 

  23. Wang G, Pan L, Zhang Y, Wang Y, Zhang Z, Lu J, et al. Intranasal delivery of cationic PLGA nano/microparticles-loaded FMDV DNA vaccine encoding IL-6 elicited protective immunity against FMDV challenge. PLoS One. 2011;6(11): e27605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Elsaid N, Jackson TL, Elsaid Z, Alqathama A, Somavarapu S. PLGA microparticles entrapping chitosan-based nanoparticles for the ocular delivery of Ranibizumab. Mol Pharm. 2016;13(9):2923–40.

    Article  CAS  PubMed  Google Scholar 

  25. Wang C, Yang J, Han H, Chen J, Wang Y, Li Q, et al. Disulfiram-loaded porous PLGA microparticle for inhibiting the proliferation and migration of non-small-cell lung cancer. Int J Nanomedicine. 2017;12:827–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kim I, Byeon HJ, Kim TH, Lee ES, Oh KT, Shin BS, et al. Doxorubicin-loaded porous PLGA microparticles with surface attached TRAIL for the inhalation treatment of metastatic lung cancer. Biomaterials. 2013;34(27):6444–53.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was partly supported by JSPS KAKENHI Grant Number 20K07203 and the Eye Research Foundation for the Aged (EFRA).

Author information

Authors and Affiliations

  1. Drug Delivery and Nano Pharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi, 467-8603, Japan

    Ayaka Hanaki, Koki Ogawa, Tatsuaki Tagami & Tetsuya Ozeki

Authors
  1. Ayaka Hanaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Koki Ogawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tatsuaki Tagami
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tetsuya Ozeki
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Ayaka Hanaki: conceptualization, methodology, investigation, writing—original draft, visualization. Koki Ogawa: data curation, formal analysis, writing—original draft, supervision. Tatsuaki Tagami: conceptualization, writing—review and editing, supervision. Tetsuya Ozeki: resources, funding, writing—review and editing, supervision.

Corresponding author

Correspondence to Tetsuya Ozeki.

Ethics declarations

Conflict of Interest

The authors declare no conflicts of interest associated with this manuscript.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 358 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hanaki, A., Ogawa, K., Tagami, T. et al. Fabrication and Characterization of Antibody-Loaded Cationic Porous PLGA Microparticles for Sustained Antibody Release. AAPS J 25, 92 (2023). https://doi.org/10.1208/s12248-023-00859-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12248-023-00859-6

Keywords

Search

Navigation