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An In Situ Hyaluronic Acid-Fibrin Hydrogel Containing Drug-Loaded Nanocapsules for Intra-Articular Treatment of Inflammatory Joint Diseases

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Abstract

Intra-articular (IA) administration of drugs is an appealing route for the effective treatment of large-joint diseases. However, a key limitation of this route is the premature elimination of the injected drugs from the synovial cavity. The objective of this work was to develop an easily injectable controlled release system intended to prolong the activity of anti-inflammatory drugs in the articular cavity. The system was an in situ forming hydrogel, made of fibrin and hyaluronic acid (HA), loaded with nanocapsules (NCs). The NCs, consisting of an olive oil core surrounded by a HA shell, were loaded with two different drugs, dexamethasone (DMX) and a galectin-3 inhibitor. They presented a particle size in the range of 122–135 nm and a surface charge of − 29/− 31 mV. The gelation time, rheological properties and porosity of the system could be adjusted by different parameters, such as addition of fibrin crosslinkers factor XIII and α2-antiplasmin. The non-crosslinked HA-fibrin hydrogels containing 30% (v/v) NCs showed the capacity to control the release of the encapsulated drug, DMX, for 72 h in simulated synovial fluid. The preliminary in vivo evaluation of the system containing a galectin-3 inhibitor in an acute synovitis rat model showed a suppression of inflammation after IA administration compared with the non-treated control. In brief, this work shows the possibility to combine an in situ forming hydrogel and NCs as a drug delivery strategy for IA administration and suggests its potential for the treatment of arthropathies.

Lay Summary

This work describes the development and characterization of a new in situ forming hydrogel adapted for intra-articular administration of anti-inflammatory drugs. The prolonged local delivery of these drugs is expected to improve the treatment of large-joint arthropathies. To achieve this objective, the hydrogel, made of biodegradable materials, was loaded with nanodeposits of drugs, named nanocapsules. The efficacy of the system, containing a new galectin-3 inhibitor as a drug candidate, was tested in a rat model of acute synovial inflammation. These results represent the first insights on the in vivo activity of a new galectin-3 inhibitor on a potential galectin-3 immunotherapeutic target for inflammatory joints diseases.

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Acknowledgements

The authors express gratitude for financial support from EM NanoFar Doctoral Fellowship (Project 2013-05-C2-EM), Xunta de Galicia (Competitive Reference Groups-FEDER Funds Ref: ED431C 2017/09, ENE2017-86425-C2-1-R Project), Xunta de Galicia and the Laboratoires Servier for post-doctoral fellowships, and Fundação para a Ciência e a Tecnologia (Program UID/DTP/04138/2013).

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Authors and Affiliations

  1. Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Department of Pharmacology, Pharmacy and Pharmaceutical Technology, Universidade de Santiago de Compostela, Campus Vida, 15782, Santiago de Compostela, Spain

    Nataliya Storozhylova, José Crecente-Campo & María J. Alonso

  2. Department of Applied Physics, Faculty of Science, University of Vigo, 36310, Vigo, Spain

    David Cabaleiro & Luis Lugo

  3. Université de Nantes, CNRS, UFIP, UMR 6286, F-40000, Nantes, France

    Nataliya Storozhylova, Christophe Dussouy & Cyrille Grandjean

  4. Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, 1649-003, Lisbon, Portugal

    Sandra Simões

  5. Laboratório de Patologia, Instituto Nacional de Investigação Agrária e Veterinária, 2780-157, Oeiras, Portugal

    Madalena Monteiro

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  1. Nataliya Storozhylova
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Storozhylova, N., Crecente-Campo, J., Cabaleiro, D. et al. An In Situ Hyaluronic Acid-Fibrin Hydrogel Containing Drug-Loaded Nanocapsules for Intra-Articular Treatment of Inflammatory Joint Diseases. Regen. Eng. Transl. Med. 6, 201–216 (2020). https://doi.org/10.1007/s40883-020-00154-2

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