Title : New potential nanotechnology-based therapy with novel Gal-3 inhibitor for the treatment of rheumatoid arthritis
Abstract:
Intra-articular (IA) administration of drugs is an appealing therapy for the effective treatment of joint diseases; however, challenging due to premature elimination of injected drugs and drug delivery systems (DDSs) from the synovial cavity.
Aiming at increased retention and prolonged drugs release in the joints, a novel DDS composed of an in situ hydrogel combined with hyaluronic acid (HA) nanocapsules (NCs) is developed upon this study. NCs, consisting of an olive oil core surrounded by a HA shell, exhibit a particle size of 135 ± 9 nm, a negative surface charge (−31 ± 5 mV) and a capacity to encapsulate model drugs. Subsequently, two injectable in situ hydrogel compositions of HA-fibrin and fortified HA-fibrin (with crosslinker factor XIII and α2-antiplasmin) loaded with up to 30% (v/v) of NCs are developed. The morphology and porosity of the hydrogels show a regular structure with a mean pore diameter of 4.88 ± 1.12 μm. They display adjustable gelation time, the moderate initial viscosity that allows good syringeability, while rheological properties of the assembled DDS enable resistance to high deformations, displaying the hydrogel suitable for IA application. In this regard, to validate the new delivery system, dexamethasone is used as a model drug. The non-fortified HA-fibrin hydrogels with 30% NCs show the capacity to control the dexamethasone release in simulated synovial fluid during 72 h. Besides, a novel and potential lead compound for immunotherapeutic anti-rheumatic drug candidate – galectin-3 antagonist – is synthesized, characterized and evaluated in this study. The preliminary in vivo results demonstrated remarkable suppression of acute joint inflammation in rats by galectin-3 inhibitor encapsulated within this DDS and administrated IA at microgram scale doses compared to the non-treated control.
Overall, these findings highlight the potential of the DDS with encapsulated synthetic galectin-3 inhibitor as a capable in situ nanotechnology-based platform for rheumatoid arthritis treatment, intended to contribute to efficient joints therapies.
Audience take away:
- A new approach in the treatment of non-curable autoimmune diseases such as rheumatoid arthritis is based on the inhibition of a novel immune target galectin-3, a primer trigger of inflammation, by the developed highly specific and selective antagonists of this protein.
- Challenges of IA drug delivery - premature elimination of the DDS from the synovial cavity along with fast synovial fluid (SF) turnover could be overcome by the development of advanced formulations involving a combination of nano-/microcarriers and hydrogels. Such DDSs allow increased retention and prolonged release and improve the efficacy/toxicity balance of the drug.
- Additionally, articular cartilage has a limited ability for self-regeneration and synovial fluid greatly loses its intrinsic functions at pathological joints conditions. Having this in mind, multifunctional drug delivery carriers should contribute to diarthrosis healing. They should not only provide a controlled and prolonged drug release, but also be composed of deformation-resistant materials that may have a prolonged retention in the articulation. Simultaneously, such a nanotechnology-based platform should ideally work as a viscosupplementation agent for improving the knee homeostasis, and as an in situ cell scaffold for cartilage tissue regeneration.
- Sharing the results of my interdisciplinary project will extend the scientific horizons, elucidate the state-of-the-art in the field of joint diseases treatment, contribute to the understanding of the etiology of the rheumatoid arthritis and its treatment, and stimulate new collaborations and new efforts towards the development of the efficient therapies for the treatment of arthropathies.
