Injectable “cocktail” hydrogel with dual-stimuli-responsive drug release, photothermal ablation, and drug-antibody synergistic effect

Abstract

The combination of the first-line standard chemotherapeutic drug doxorubicin hydrochloride (DOX) and the molecular-targeted drug Herceptin (HCT) has emerged as a promising strategy for human epidermal growth receptor 2 (HER-2) overexpressing breast cancer treatment. However, insufficient drug accumulation and severe cardiotoxicity are two major challenges that limit its clinical application. Herein, an in situ forming gold nanorods (AuNRs)-sodium alginate (ALG) hybrid hydrogel encapsulating DOX and HCT was engineered for tumor synergistic therapy involving injectable, dual-stimuli-responsive drug release, photothermal ablation, and drug-antibody synergistic therapy. The photothermal agent AuNRs, anticancer drug DOX, and anticancer antibody HCT were mixed in ALG solution, and after injection, the soluble ALG was quickly transformed into a hydrogel in the presence of Ca²⁺ in the body. Significantly, the hybrid hydrogel exhibits an extremely high photothermal conversion efficiency of 70% under 808 nm laser irradiation. The thermal effect can also provide photothermal stimulation to trigger the drug release from the gel matrix. In addition, the drug release rate and the releasing degree are also sensitive to the pH. In vitro studies demonstrated that the PEI-AuNR/DOX/HCT/ALG hydrogel has facilitated the therapeutic efficiency of each payload and demonstrated a strong synergistic killing effect on SK-BR-3 cells. In vivo imaging results showed that the local drug delivery system can effectively reduce the nonspecific distribution in normal tissues and increase drug concentration at tumor sites. The proposed hydrogel system shows significant clinical implications by easily introducing a sustainable photothermal therapy and a potential universal carrier for the local delivery of multiple drugs to overcome the challenges faced in HER-2 overexpressing cancer therapy.

Keywords

dual-stimuli-responsive drug release / HER-2 overexpressing breast cancer / injectable hydrogel / photothermal therapy / synergistic effect

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