Visible Light Photo-Cross-Linked Thermogel─A Single-Component Hybrid Supramolecular-Covalent Hydrogel for Sustained Drug Release

Temperature-responsive supramolecular thermogels, advanced biomaterials that exhibit sol-to-gel phase transitions when warmed, show great promise as next-generation in vivo drug delivery depots for their excellent biocompatibility and ease of formulation and administration. However, the lack of permanent covalent cross-links within the gel framework often results in short in vivo persistence and rapid gel swelling, in turn limiting duration of sustained drug release attainable. Herein, we developed a general strategy that retains the thermogels’ intrinsic ease of injectability, yet allowing significantly enhanced sustained drug release durations. By incorporating a visible light-cross-linkable chromophore into the thermogel polymer structure, in situ cross-linking can be achieved after depot administration with facile external control. As compared to conventional photo-cross-linking strategies utilizing ionizing and hazardous UV light, our thermogels can be covalently cured using blue light or even under ambient indoor lighting conditions, making them potentially suitable for sensitive applications such as ophthalmic drug release. We show that these thermogels can be applied as an in situ cross-linked depot that allows the release of the antivascular endothelial growth factor biologic, Aflibercept, to be prolonged for more than 3 months, achieving a marked improvement over existing treatment regimens for diseases such as neovascular age-related macular degeneration that necessitate monthly injections. Additionally, these photo-cross-linked thermogels can also prolong the release of small proteins (e.g., bovine serum albumin) from membrane-based delivery systems by more than 3 times compared to nonirradiated controls. These visible light-photo-cross-linkable gels offer new versatile platforms for achieving long-duration drug release suitable for different biological applications and delivery modalities.