Gonçalves, JoaquimMelo, Bruna Daniela LopesPouso, Manuel António do RosárioCorreia, Ilídio Joaquim Sobreirade Melo-Diogo, Duarte2025-10-022025-10-022025-09-11Gonçalves, J. J., Melo, B. L., Pouso, M. R., Correia, I. J., & de Melo-Diogo, D. (2025). Dual-crosslinked injectable in situ forming Alginate/CaCl2/Pluronic F127/α-Cyclodextrin hydrogels incorporating Doxorubicin and Graphene-based nanomaterials for cancer chemo-photothermal therapy. Journal of Drug Delivery Science and Technology, 1075201773-2247http://hdl.handle.net/10400.6/18944Injectable in situ forming hydrogels have been emerging due to their capacity to perform the direct delivery of therapeutics into the tumor site with minimal off-target leakage. Particularly, physical crosslinked injectable in situ forming hydrogels are appealing due to their straightforward preparation that exploits the native jointing capabilities of specific polymers/materials. However, the features of these hydrogels (e.g., injectability, degradation, swelling) are strongly pre-determined by the physical interactions available on the selected polymers/ materials, occasionally yielding undesired outcomes. Thus, the combination of multiple physical crosslinking cues may allow the preparation of hydrogels with enhanced properties. In this work, a dual-crosslinked injectable in situ forming hydrogel was engineered by combining Pluronic F127/α-Cyclodextrin and Alginate/CaCl2 (i.e., combination of host-guest and electrostatic interactions), being loaded with Doxorubicin (chemotherapeutic drug) and Dopamine-reduced Graphene Oxide (photothermal nano-agent) for application in cancer chemophotothermal therapy. When compared to the single-crosslinked hydrogels, the dual-crosslinking contributed to the assembly of formulations with suitable injectability and improved degradation and water absorption behaviors. Moreover, the dual-crosslinked hydrogels presented a good photothermal capacity (ΔT ≈ 14 ◦C), leading to a 1.18-times enhanced Doxorubicin release. In in vitro cell-based studies, the dual-crosslinked hydrogels exhibited an excellent cytocompatibility towards healthy (normal human dermal fibroblasts) and breast cancer (MCF-7) cells. As importantly, the dual-crosslinked hydrogels were able to mediate a chemophotothermal effect that diminished the cancer cells’ viability to just 23 %. Overall, the developed dualcrosslinked injectable in situ forming hydrogels incorporating Doxorubicin and Dopamine-reduced Graphene Oxide are a promising macroscale system for breast cancer chemo-photothermal therapy.engCancerChemo-photothermal therapyGraphene family nanomaterialsInjectable hydrogelsLocal deliveryMacroscale delivery systemsresearch articlehttps://doi.org/10.1016/j.jddst.2025.107520