An Injectable Click-Crosslinked Hydrogel that Prolongs Dexamethasone Release from Dexamethasone-Loaded Microspheres

Abstract

Our purpose was to test whether a preparation of injectable formulations of dexamethasone (Dex)-loaded microspheres (Dex-Ms) mixed with click-crosslinked hyaluronic acid (Cx-HA) (or Pluronic (PH) for comparison) prolongs therapeutic levels of released Dex. Dex-Ms were prepared using a monoaxial-nozzle ultrasonic atomizer with an 85% yield of the Dex-Ms preparation, encapsulation efficiency of 80%, and average particle size of 57 μm. Cx-HA was prepared via a click reaction between transcyclooctene (TCO)-modified HA (TCO-HA) and tetrazine (TET)-modified HA (TET-HA). The injectable formulations (Dex-Ms/PH and Dex-Ms/Cx-HA) were fabricated as suspensions and became a Dex-Ms-loaded hydrogel drug depot after injection into the subcutaneous tissue of Sprague Dawley rats. Dex-Ms alone also formed a drug depot after injection. The Cx-HA hydrogel persisted in vivo for 28 days, but the PH hydrogel disappeared within six days, as evidenced by in vivo near-infrared fluorescence imaging. The in vitro and in vivo cumulative release of Dex by Dex-Ms/Cx-HA was much slower in the early days, followed by sustained release for 28 days, compared with Dex-Ms alone and Dex-Ms/PH. The reason was that the Cx-HA hydrogel acted as an external gel matrix for Dex-Ms, resulting in the retarded release of Dex from Dex-Ms. Therefore, we achieved significantly extended duration of a Dex release from an in vivo Dex-Ms-loaded hydrogel drug depot formed by Dex-Ms wrapped in an injectable click-crosslinked HA hydrogel in a minimally invasive manner. In conclusion, the Dex-Ms/Cx-HA drug depot described in this work showed excellent performance on extended in vivo delivery of Dex.

Hyaluronic Acid Hydrogels Crosslinked in Physiological Conditions: Synthesis and Biomedical Applications

“…Biomedicines 2021, 9, x FOR PEER REVIEW 11 HA hydrogels are also formed by inverse electron demand Diels-Alder (IEDDA cloaddition reaction using tetrazine groups as the diene to react with alkenes or alky under physiological conditions (see Figure 8). The material formulations can be "in s injected into the area to be treated and rapidly form the crosslinked network, due to "click" properties of the reaction and do not require an external reagent [98][99][100][101][102]. H tetrazine (Tet) can react with PEG-norbornene to form DA hydrogels.…”

“…Furan + Maleimide [97,103] Amidation [97][98][99][100][101][102][103] Injectable [98][99][100]103]; tissue engineering [99,103]: bone [100]; rheumatoid arthritis [99]; cell encapsulation [97]; protein encapsulation [101]; drug release [98,99] Tetrazine + Trans-cyclooctene [98][99][100] Tetrazine + norbornene [101,102] 3. Thermoreversible Gelation of HA Hydrogels at Physiological Temperature Thermo-sensitive hydrogels, which undergo in situ sol-gel transition at physiological temperature, without chemical or enzymatic modification, are widely studied as biomaterials to be employed in tissue engineering and long-term controlled drug release [104] Among them, physical thermoreversible hydrogels obtained through noncovalent interactions (hydrogen bonding, ion crosslinking, or hydrophobic interactions, among others) have attracted considerable attention over the years because of the mild conditions required for the formation of crosslinking points [105].…”

“…Diels–Alder-based hyaluronic acid hydrogels do have an extensive sort of use in biomedicine due to their biocompatibility and injectability [ 98 , 99 , 100 , 103 ]. These systems have been applied in tissue engineering due to their ability to encapsulate cells.…”

“…In this regard, methotrexate-loaded hydrogels increased cartilage thickness, chondrocyte generation, and induced new bone formation in rheumatoid arthritis-affected body regions [ 99 ]. Dexamethasone (Dexa)-loaded microspheres mixed with cross-linked hyaluronic acid hydrogel displayed a retarded release of the Dexa in vitro and in vivo and represent a suitable method for the treatment of inflammatory and autoimmune disorders, such as rheumatoid arthritis [ 98 ]. Finally, bone morphogenetic protein-2 (BMP-2) mimetic peptide (BP) was loaded and released from an injectable hyaluronic acid hydrogel obtained through a Diels–Alder reaction between modified HA-tetrazine and HA- trans-cyclooctene (TCO).…”

Injectable Composite Systems Based on Microparticles in Hydrogels for Bioactive Cargo Controlled Delivery

“…When compared to the release patterns of microparticles alone, the microparticles in hydrogel systems will have a more controlled release. Heo et al [ 38 ] loaded dexamethasone (DEX) into PLGA microspheres and then combined them with Pluronic hydrogel and a hyaluronic acid (HA)-based hydrogel created via click reactions. The composite systems prolonged the delivery time and retarded the initial burst compared to the DEX loaded microspheres alone.…”