Naturally-derived cellulose-chitosan soft-hydrogel for sustained local docetaxel micelles delivery: from in silico modeling to preclinical validation in ovarian and glioblastoma models

ABSTRACT Natural biopolymer-based hydrogels represent a promising strategy for localized drug delivery in cancer therapy, helping to overcome the systemic toxicity, limited specificity, and drug resistance associated with conventional treatments. However, sustained delivery of highly hydrophobic drugs using fully natural, physically crosslinked systems remains challenging. We report a fully natural, injectable cellulose-chitosan soft-hydrogel (HG) embedding docetaxel (DTX)-loaded Soluplus® micelles as a multifunctional depot for prolonged local chemotherapy. HG is formed without synthetic crosslinkers and rationally designed using in silico microspecies prediction and molecular dynamics simulations, providing insight into polymer-polymer and drug-carrier interactions, which were corroborated experimentally. Micelles with ∼72nm diameter efficiently encapsulated DTX (>95%) and homogeneously distributed within the HG matrix. The formulation exhibited shear-thinning and thixotropic behavior, enabling injectability with forces of 30-35 N followed by in situ depot formation. The HG retained structural integrity for over 21 days, showed gradual degradation (∼50% mass loss at 28 days), and enabled sustained DTX release (∼70% over 14 days) under physiological conditions. Biological evaluation demonstrated excellent cytocompatibility in healthy fibroblasts and significant antiproliferative activity in ovarian cancer and glioblastoma models, including 3D tumor spheroids. Overall, this work introduces a sustainable, fully biopolymeric platform for localized and prolonged chemotherapy with reduced systemic toxicity.