Localized Cancer Treatment Using Thiol–Ene Hydrogels for Dual Drug Delivery

Combinatorial cancer therapy benefits from injectable hydrogels for localized, controlled drug delivery. This study presents a thiol-ene conjugated hydrogel formed by cross-linking thiol-modified hyaluronic acid (HASH) with vinyl sulfone-modified β-cyclodextrin (CDVS). Four formulations (23Gel-16, 23Gel-33, 99Gel-16, 99Gel-33) were synthesized by varying HASH molecular weight (23 or 99 kDa) and CDVS modification (16% or 33%). Rheological analysis confirmed enhanced viscoelasticity with increasing molecular weight and modification (99Gel-33 > 99Gel-16 > 23Gel-33 > 23Gel-16). The system enabled combinatorial delivery of doxorubicin (DOX) and carvacrol (CRV), exhibiting tumor-responsive degradation and tunable release. DOX release accelerated under tumor-mimicking conditions (100% in 46 h vs 58.7% in PBS), while CRV showed an initial burst followed by sustained release. The hydrogel promoted mesenchymal stem cell proliferation and effectively inhibited triple-negative breast cancer cells. This injectable, tumor-responsive hydrogel system offers a promising platform for minimally invasive, personalized cancer therapy.