Development of hyaluronic acid/β-cyclodextrin semi-interpenetrating network hydrogels for prolonged delivery of water-soluble sunitinib malate

Sunitinib malate (SUM), widely used in cancer treatment for its anti-VEGF properties, has also been explored for ocular neovascular diseases. For ocular applications, sustained drug release is essential to reduce dosing frequency. Hyaluronic acid (HA)-based hydrogels are commonly used for controlled drug delivery, but their hydrophilicity leads to rapid drug diffusion, especially for water-soluble drugs like SUM. To address this, β-cyclodextrin (β-CD) polymers (2-300 kDa) were incorporated into tyramine-conjugated HA (HA-TA) (200-400 kDa) networks to extend drug release via the formation of host-guest inclusion complexes. SUM-CD intermolecular interactions were identified and characterised by ¹H NMR and FTIR spectroscopies, and NOESY spectra further confirmed a 1 SUM: 2 β-CD inclusion complex. β-CD polymers (10 % w/v) were integrated into HA-TA (0.25, 0.5, 1 % w/v) networks enzymatically crosslinked using horseradish peroxidase and hydrogen peroxide, forming semi-interpenetrating polymer network hydrogels. These gels exhibited faster gelation, enhanced swelling behaviour, higher drug loading capacity, a denser matrix, and a longer SUM release duration compared to HA-TA hydrogels. In an in vitro flow model, post-gelation loading of SUM led to a longer release duration than pre-loading, with release continuing over 20 days. The HA-CD semi-IPN hydrogel therefore warrants further exploration for its potential ocular applications.