Erlotinib and curcumin-loaded nanoparticles embedded in thermosensitive chitosan hydrogels for enhanced treatment of head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) remain a major oncological challenge with significant morbidity and mortality rates. Erlotinib (Er) and Curcumin (Cm) are potential therapeutic agents for HNSCC, yet they are hindered by poor solubility and bioavailability. This study explored the optimization of poly(lactic-co-glycolic acid) nanoparticles co-loaded with Er and Cm (Er/Cm-NP), prepared via a D-optimal response surface design-guided nanoprecipitation process. The optimized formulation, optEr/Cm-NP, was then incorporated into chitosan/β-glycerophosphate hydrogels (optEr/Cm-NP-HG) to create an injectable intratumoral (IT) nanocomposite hydrogel (HG) delivery system. Physicochemical properties of the formulations, including gelation time, injectability, mechanical strength and drug release profiles were assessed alongside hemolytic activity. Compared to optEr/Cm-NP alone, the NP-loaded HG formulation exhibited a more pronounced modulation effect, enabling sustained and controlled drug release. The cytotoxicity of the developed formulations was evaluated using the FaDu HNSCC cancer cell line. Both optEr/Cm-NP and optEr/Cm-NP-HG21 displayed enhanced cytotoxicity compared to free drugs. Confocal laser microscopy and flow cytometry confirmed superior cellular uptake of Er and Cm when delivered via NPs or NP-loaded HG. Furthermore, a significant increase in apoptotic cell death upon treatment with optEr/Cm-NP was observed, highlighting its potential for HNSCC therapy. In vivo studies conducted on a xenograft HNSCC mouse model revealed the significant capacity of the intratumorally-injected optEr/Cm-NP-HG21 formulation to retard the tumor growth. Conclusively, the results presented herein report the successful development of a nanocomposite HG system incorporating NPs co-loaded with Er and Cm that could be efficiently utilized in the treatment of HNSCC.