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Sahar Awwad, Peng Tee Khaw, Steve Brocchini; A collapsable hyaluronic acid hydrogel to prolong protein release in the vitreous. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3363.
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Intraocular delivery systems designed to prolong the release of a drug while maintaining a therapeutic concentration for a long period are needed to treat patients with chronic blinding conditions. In situ-forming thermoresponsive injectable hydrogels can encapsulate drugs to prolong local intraocular release times. To increase mixing of an antibody to better increase the release period, a thermoresponsive hydrogel derived from N-isopropylyacrylamide (NIPAAM) and acrylated hyaluronic acid (Ac-HA) as the biodegradable crosslinker was prepared in the presence of antibody.
Ac-HA was synthesised through the reaction between the primary hydroxyl group of hyaluronic acid and acryloyl chloride (Ac-Cl). NIPAAM (0.35 mmol) was dissolved in deionised water (0.5 mL). Ac-HA (2.0 or 4.0 mg/mL, 40 to 200 nmol), APS (0.018 mmol) and infliximab (0.5 mL of 10.0 mg/mL) or bevacizumab (0.5 mL of 25.0 mg/mL) were added to NIPAAM. The entire content was gently mixed for 1 hour at 25°C to ensure protein entanglement within the hydrogel. TEMED (0.1 mmol) was added and vortexed for 10 seconds. The mixture was incubated at 4°C (24 hours). The gels were washed every 10 minutes with PBS (v: 20.0 mL) and the fractions were analysed using UV-spectroscopy (280 nm). The reaction mixture was either stored in the fridge (4-8°C) or freeze-dried prior to analysis.
A range of hydrogels were prepared by crosslinking Ac-HA (2.0-10.0 mg/mL, 40 to 200 nmol) with NIPAAM by redox polymerisation in the presence of protein. The prepared hydrogels with lower amounts of Ac-HA (2.0 and 4.0 mg/mL, 40 and 80 nmol respectively) showed more favourable properties in terms of thermoresponsiveness, rheological properties, injectability, swelling and water retention than the hydrogels with higher amounts of crosslinker (7.0 and 10.0 mg/mL). The hydrogels were seen to be degradable with hyaluronidase (5-50 U/mL) suggesting the hydrogel will be degradable over a longer period of time. Release studies of bevacizumab-loaded hydrogels were investigated in an in vitro model of the human eye called the PK-Eye™ at 37°C. Prolonged and continuous release was observed with bevacizumab for at least 50 days in PBS (pH 7.4), while maintaining binding to human vascular endothelial growth factor (VEGF).
These encouraging results suggest that extended release of proteins in the vitreous can be achieved using injectable hydrogels.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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