Covalent Cross-Linking Approaches for All-Trans Retinoic Acid-Loaded Thermo-Responsive Hydrogels

This study compared multiple covalent and non-covalent cross-linking strategies for thermo-responsive hydrogels designed for controlled delivery of all-trans retinoic acid (ATRA). Using PCLA–PEG–PCLA triblock copolymers, the team explored thiol-Michael, free-radical, and strain-promoted azide–alkyne cycloaddition (SPAAC) cross-linking mechanisms. SPAAC hydrogels achieved stable gelation and intermediate mechanical properties between non-covalent and free-radical gels. Free-radical gels reached the highest modulus (194 kPa) but ATRA loading disrupted radical cross-linking, reducing modulus to ~19 kPa. The SPAAC gel released ~80% of ATRA over 7 days in serum and inhibited proliferation of MDA‑MB‑468 breast cancer cells while maintaining hydrogel integrity.