Injectable, self-healable, and pH-responsive hybrid hydrogels are highly promising biomaterials for controlled and long-term therapeutic agent release in cancer treatment. Herein, we fabricated an injectable, self-healable, and pH-responsive hybrid hydrogel through the formation of the hydrazone bond between hydrazide-functionalized gelatin (Gel-ADH) and aldehyde-functionalized PEG (diBA-PEG) polymers. During gelation, the resulting pregels were also integrated with laponite (LAP) nanodisks loaded with an anticancer drug, doxorubicin (DOX), yielding to hybrid Gel-ADH/diBA-PEG/LAP@DOX hydrogels. The gelation time of the hybrid hydrogel was observed to be 80 s and the resulting hybrid hydrogels demonstrated excellent injectability and rapid self-healing capability. The gel−sol transition behaviors of hybrid hydrogels indicated an outstanding gelation stability, which is a highly desirable feature in controlled drug delivery application. The injectable hybrid Gel-ADH/diBA-PEG/LAP@DOX hydrogels exhibited a very efficient pHdependent long-term drug release profile. Biocompatibility of the hydrogel components (Gel-ADH, diBA-PEG, and LAP) was also tested using the human breast cell line (SVCT) and endothelial cell line (HUVEC). All components of the hybrid hydrogel possess excellent biocompatibility and even support cell proliferation. Moreover, the cytotoxicity of the hydrogels was investigated on the human breast cancer cell line (MCF-7) and triple-negative breast cancer cell line (MDA-MB-231). Our results clearly suggested that this injectable, self-healable, and pH-responsive hybrid Gel-ADH/diBA-PEG/LAP@DOX hydrogel offers a promising potential as a drug carrier for long-term and controlled release application.

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Stimuli-sensitive and multifunctional nanoparticles are highly desirable biomedical materials for triggered and targeted drug delivery applications. Here, we have designed pH-and redox-triggered magnetic lipid−polymer hybrid nanoparticles (MHNPs) with a core− shell structure. This design is composed of a silica-/mesoporous silicacoated ellipsoidal magnetic nanoparticle with multifunctionality: carrying the anticancer drug (doxorubicin, DOX), the cancer cell targeting ligand (folic acid-conjugated poly(ethylene glycol), FA−PEG) polymer, and being coated with a biocompatible pH-/redox-responsive (poly-Lhistidine−poly(ethylene glycol)−lipoic acid; PLH−PEG−LA) polymer. The lipoic acid units of the PLH−PEG−LA shell of the FA-MHNPs were cross-linked using 1,4-dithiothreitol (DTT). When the FA-MHNPs-DOX were exposed to an endolysosomal pH of 5.5 and 10 mM glutathione (GSH), the particles exhibited a very efficient DOX release profile within 24 h. In addition, cytotoxicity, uptake, and apoptosis assays were performed against breast cancer cell lines. These results showed that FA-MHNPs-DOX promote an enhanced uptake and cell morbidity compared to the nontargeted MHNPs-DOX against tested cell lines. Moreover, the FA-MHNPs-DOX exhibited very effective cytotoxicity and also decreased the cell viability through apoptosis against breast cancer cell lines. In conclusion, it can be said that the pH and redox dual-responsive hybrid FA-MHNPs-DOX has a great potential for controlled drug release.