Ionic Liquid-Integrated Interpenetrating Polymer Hydrogel for Injectable, Self-Healing, and Stimuli-Responsive Co-Delivery of Protein and Chemotherapeutic Agents in Breast Cancer Therapy.

Abstract

Due to poor drug solubility, protein instability, and inefficient carrier systems, the co-delivery of chemotherapeutics and proteins remains a critical challenge in cancer therapy. To address these limitations, we developed a stimuli-responsive, multifunctional polymeric hydrogel by incorporating biocompatible choline-lineolate ([Cho][Lin]) ionic liquid into a sodium alginate (SA) and polyvinyl alcohol (PVA) matrix for enhanced co-delivery of doxorubicin (DOX) and zein in localized breast cancer treatment. Small-angle neutron scattering suggested the aggregation behavior of [Cho][Lin] and confirmed the solubility and stability of the drug and protein within the hydrogel. Fourier-transform infrared spectroscopy and circular dichroism demonstrated noncovalent interactions between the ionic liquid and polymers, alongside preserved protein structural integrity. Field-emission scanning electron microscopy revealed a well-defined, porous three-dimensional network with elongated fibers, while rheological analysis confirmed mechanical stability (γc = 100% strain), viscoelasticity, and shear-thinning behavior. The hydrogel exhibited self-healing, injectability, and strong adhesion, with in vitro biocompatibility assays on HaCaT cells showing >92% viability after 48 h. Drug and protein release studies demonstrated pH-responsive behavior, with significantly higher release under acidic conditions (89% DOX, 80% zein) than neutral pH. In vitro cytotoxicity assays on MCF-7 breast cancer cells revealed an IC50 of ∼2 μM for the drug-loaded hydrogel. These results highlight the potential of ionic liquid-based hydrogels as a versatile and practical platform for the co-delivery of therapeutic agents, offering a targeted and efficient strategy for localized breast cancer therapy.