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Enzymatically crosslinked tyramine-gellan gum hydrogels as drug delivery system for rheumatoid arthritis treatment

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Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint synovial inflammation, as well as cartilage and bone tissue destruction. Current strategies for the treatment of RA can reduce joint inflammation, but the treatment options still represent stability concerns since they are not sufficient and present a fast clearing. Thus, several drug delivery systems (DDS) have been advanced to tackle this limitation. Injectable gellan gum (GG) hydrogels, reduced by physical crosslinking methods, also being proposed as DDS, but this kind of crosslinking can produce hydrogels that become weaker in physiological conditions. Nevertheless, enzymatic crosslinking emerged as an alternative to increase mechanical strength, which can be adjusted by the degree of enzymatic crosslinking. In this study, tyramine-modified gellan gum (Ty-GG) hydrogels were developed via horseradish peroxidase (HRP) crosslinking; and betamethasone was encapsulated within, to increase the specificity and safety in the treatment of patients with RA. Physicochemical results showed that it was possible to modify GG with tyramine, with a degree of substitution of approximately 30%. They showed high mechanical strength and resistance, presenting a controlled betamethasone release profile over time. Ty-GG hydrogels also exhibited no cytotoxic effects and do not negatively affected the metabolic activity and proliferation of chondrogenic primary cells. Furthermore, the main goal was achieved since betamethasone-loaded Ty-GG hydrogels demonstrated to have a more effective therapeutic effect when compared with the administration of betamethasone alone. Therefore, the developed Ty-GG hydrogels represent a promising DDS and a reliable alternative to traditional treatments in patients with RA.

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Acknowledgments

I. Oliveira thanks the financial support under the Norte2020 project (“NORTE-08-5369-FSE-000044”), REMIX project (G.A. 778078 — REMIX — H2020-MSCA-RISE-2017), and Gilson Lab, Chonbuk National University, Republic of Korea. The FCT distinction attributed to J. Miguel Oliveira under the Investigator FCT program (IF/01285/2015) is also greatly acknowledged. C. Gonçalves also wish to acknowledge FCT for supporting her research (No. SFRH/BPD/94277/2013).

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Authors and Affiliations

  1. 3B’s Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics of University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal

    Isabel Matos Oliveira, Cristiana Gonçalves, Rui L. Reis & Joaquim Miguel Oliveira

  2. ICVS/3B’s - PT Government Associate Laboratory, /Guimarães, Braga, Portugal

    Isabel Matos Oliveira, Cristiana Gonçalves, Rui L. Reis & Joaquim Miguel Oliveira

  3. Department of BIN Fusion Technology, Department of Polymer Nanoscience and Polymer BIN Research Centre, Chonbuk National University, 567 Baekje-daero, Deokjin-gu, Jeonju, 561-756, Republic of Korea

    Myeong Eun Shin, Sumi Lee & Gilson Khang

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  1. Isabel Matos Oliveira
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  2. Cristiana Gonçalves
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Correspondence to Joaquim Miguel Oliveira.

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The national and institutional guidelines and certification for the animal experimentation were followed as approved by the Direcção Geral de Alimentação e Veterinária (DGAV) and following the local ethical committee recommendations.

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Oliveira, I.M., Gonçalves, C., Shin, M.E. et al. Enzymatically crosslinked tyramine-gellan gum hydrogels as drug delivery system for rheumatoid arthritis treatment. Drug Deliv. and Transl. Res. 11, 1288–1300 (2021). https://doi.org/10.1007/s13346-020-00855-9

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