Ionic Liquid-Integrated Interpenetrating Polymer Hydrogel for Injectable, Self-Healing, and Stimuli-Responsive Co-Delivery of Protein and Chemotherapeutic Agents in Breast Cancer Therapy.
Jul 2026· ACS Applied Bio Materials· Vol 9, pp. 7428-7440· 0 citations· 53 references
Medicine
TL;DR
A stimuli-responsive, multifunctional polymeric hydrogel is developed by incorporating biocompatible choline-lineolate ionic liquid into a sodium alginate and polyvinyl alcohol and polyvinyl alcohol matrix for enhanced co-delivery of doxorubicin and zein in localized breast cancer treatment.
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.
Breast cancer treatment still faces challenges including local recurrence, systemic toxicity, tumor heterogeneity, drug resistance, and immunosuppression. Conventional systemic administration provides limited exposure at the tumor site and exhibits significant toxicity. Injectable hydrogels, combining the properties of minimally invasive administration, in situ gelation, local retention, and sustained release, have become a key platform for local precision drug delivery. Compared with nanomedicines or free drugs, hydrogels can both prolong drug retention time and achieve on-demand release through the modulation of crosslinking density, degradation rate, and responsive chemical bonds. This review is organized around the material logic of such systems. Injectable hydrogels are first classified into natural, synthetic, hybrid, supramolecular, nanocomposite, and self-healing systems, the in situ gelation chemistries available to each are compared, and network parameters such as crosslinking density, mesh size, swelling, porosity, modulus, and rheology are related to release kinetics and intratumoral retention. Current research is primarily advancing along two directions: one is the construction of pH-, enzyme-, redox/ROS-, hypoxia-, ATP-, glucose-or thermo-responsive hydrogels; the other is achieving active targeting by integrating functionalized hydrogels with targets such as CD44, folate receptor, integrins, EGFR, transferrin receptor, and HER2 or with biomimetic cell-membrane coatings. On this basis, hydrogels have been extended to cancer vaccines, immune checkpoint modulation, local delivery of CAR-T/CAR-NK, as well as combination therapies involving chemotherapy, photothermal therapy, photodynamic therapy, chemodynamic therapy, sonodynamic therapy, radiosensitization, gene therapy, and theranostics. The constraints imposed on hydrogel design by different payload classes, including small molecules, natural products, proteins and peptides, nucleic acids, antibodies, exosomes, and gene-editing machinery, are further examined, and imaging-integrated theranostic gels are discussed together with the emerging role of machine learning and digital fabrication in hydrogel optimization. Based on the biological foundations of breast cancer, this review summarizes advances in the material design, microenvironment-responsive release, targeting strategies, immunomodulation, and combination therapy of hydrogels, critically evaluates the limitations of each strategy, and aims to provide a reference for the design of mechanistically well-defined and translatable hydrogel delivery systems for breast cancer.
Results establish PDA-mediated non-covalent reinforcement as an effective crosslinker-free strategy for engineering thermoresponsive hydrogels with tunable network mechanics and controllable NIR-responsive drug transport for localized chemo-photothermal therapy.
Danielle Dalman, Quang Nhat Quynh Vo, Abdelrahman I. Rezk et al.· Journal of Colloid and Inter...· 0 citations
Chitosan/carbon nanotube (CS/CNT) nanocomposites have emerged as next-generation multifunctional drug delivery platforms by bridging the gap between material science and precision medicine. These systems combine the high surface area, tensile strength and photothermal conversion ability of carbon nanotubes with the biocompatibility, mucoadhesion and functional versatility of CS to provide a synergistic solution to long-standing limitations of conventional nanocarriers. Stimulus-responsive drug release, customized functionalization and scalable green synthesis are three important research areas that have advanced significantly in recent years. Novel covalent and non-covalent modifications with enhanced dispersion, prolonged circulation and enhanced therapeutic specificity include PEGylation, peptide targeting and metallic nanoparticle decoration. Creating multi-stimuli release systems that react to pH, enzymatic activity and near-infrared (NIR) radiation is a particularly exciting advancement that enables accurate spatiotemporal drug release profiles in infection and tumor microenvironments. We present a new Triple-Stimuli Release Model in this review that provides a computational experimental bridge to expedite preclinical validation while mathematically forecasting concurrent release kinetics. Applications of CS/CNT systems are highlighted in the fields of gene delivery, wound healing, oncology, antimicrobial therapy and regenerative medicine, with a focus on clinical bottlenecks and translational potential. We additionally assess how well molecular dynamics simulations and artificial intelligence (AI) combine to forecast toxicity, drug-carrier interactions and nanocomposite stability, suggesting that CS/CNT nanocomposites are promising candidates for AI-guided optimization pipelines. Finally, a progressive clinical translation roadmap is informed by a critical discussion of long term biosafety, GMP compliant manufacture, regulatory pathways and ethical considerations. This review emphasizes CS/CNT systems as key components for precision nanomedicine, theranostics and sustainable healthcare innovation that fuse experimental advances with computational vision.
H. Hashemi, Aref Zahiri Ghareh Mosa, Ketevan Tavamaishvili et al.· Discover Applied Sciences· 0 citations
Skin cancer, particularly melanoma, remains a major therapeutic challenge due to its high metastatic potential and limited efficacy of systemic chemotherapy. Localized and controlled delivery of chemotherapeutic agents such as doxorubicin (DOX) represents a promising alternative to systemic treatments and costly immunotherapies. Hybrid hydrogels that integrate polymeric scaffolds with embedded nanostructures (e.g., vesicles, micelles, or nanoparticles) have emerged as particularly effective platforms for enhancing therapeutic performance. Herein, we report the development of a thermosensitive hybrid hydrogel for potential melanoma drug delivery applications, obtained by dispersing DOX-loaded, pH-sensitive 12-2-12/SLSar catanionic vesicles within a poloxamer 237 (F87) scaffold. The system was comprehensively characterized in terms of rheological behavior, biocompatibility, drug-release kinetics, and in vitro anti-melanoma activity in 2D monolayer cell cultures and 3D spheroids. In parallel, molecular-level interactions between the F87 matrix and the surfactant-based vesicles were investigated. Strong polymer-surfactant interactions were observed, leading to the formation of mixed polymer/surfactant micelles and vesicles, and inducing significant modifications in aggregate physicochemical properties, particularly surface charge. These interactions were found to be thermally driven and strongly dependent on the polymer-to-surfactant ratio. The catanionic vesicles exhibited high DOX encapsulation efficiency and remained stably dispersed within the F87 scaffold. The resulting hybrid hydrogel demonstrated controlled release kinetics, offering potential advantages for localized drug delivery compared with vesicle-only formulations. Moreover, the hybrid system demonstrated excellent biocompatibility and significantly outperformed neat F87 hydrogels in enhancing DOX internalization and inducing melanoma cell death in vitro. Overall, this work presents a versatile and tunable strategy for integrating catanionic vesicles into thermosensitive polymeric scaffolds, providing a promising platform for localized melanoma drug delivery.
Rui L. Machado, Aitana Zoco, I. Oliveira et al.· ACS Applied Bio Materials· 0 citations
Cancer therapy demands smarter, more targeted strategies that minimize healthy tissue damage while maximizing therapeutic efficacy. This study introduces Hy-Si-IONC, a dual heat- and pH-responsive hydrogel-coated magnetic nanocluster, engineered to deliver chemotherapeutic drug within the tumor microenvironment. When combined with magnetic hyperthermia, it offers targeted, localized drug release, outperforming conventional single-stimulus carriers. The encapsulation efficiency and drug loading capacity of the Hy-Si-IONC were 47.3% and 4.6%, respectively. Hy-Si-IONC exhibited a lower critical solution temperature (LCST) of 43 °C with drug-release potential of 41.89% under tumor-mimicking conditions. A combinational therapy of doxorubicin-loaded Hy-Si-IONC and magnetic hyperthermia reduced the cell viability to 18% in MDA-MB-231 cells, confirming a strong therapeutic effect between thermal and chemotherapy. The nanosystem displayed good compatibility with human lymphocytes, MCF-7 and MDA-MB-231 cell lines. Hemolysis remained below 1%, and no genotoxicity was detected. Long-term in vivo safety was confirmed in a 25-week mice study, the nanoclusters predominantly accumulated in the liver and spleen. Transient changes in antioxidant markers - superoxide dismutase (SOD), catalase, glutathione S-transferase (GST), and glutathione (GSH) normalized by end of the study. No major histopathological abnormalities were observed in vital organs. Collectively, Hy-Si-IONC presents a biocompatible and potential dual-modal cancer therapy.
Regan Charles R, Subhasis Sarangi, A. V· Journal of drug targeting (P...· 0 citations
Osteosarcoma remains a clinical challenge due to its high invasiveness, early metastasis, and intrinsic radioresistance, which collectively limit the efficacy of conventional treatments and immunotherapy. Here, we developed a pH-responsive hydrogel reservoir, referred to as VP/CaNPs@Gel, by integrating verteporfin (VP)-loaded CaCO3 nanoparticles (CaNPs) into a β-cyclodextrin-crosslinked polysaccharide hydrogel to achieve precise radiosensitization and immunomodulation. The hydrogel undergoes rapid in-situ crosslinking to form a robust scaffold, ensuring the sustained and pH-triggered release of VP and Ca2+ within the tumor microenvironment. In vitro assays demonstrated that VP/CaNPs@Gel significantly amplifies radiation-induced reactive oxygen species (ROS) production and triggers robust pyroptotic cell death. In an in vivo orthotopic osteosarcoma model, VP/CaNPs@Gel effectively suppressed tumor growth and markedly enhanced the efficacy of immune checkpoint blockade under X-ray. Mechanistically, treatment induced PD-L1 upregulation, elevated systemic IL-1β, IL-18, and IFN-γ levels, promoted dendritic cell maturation and CD8+ T cell infiltration, increased M1 macrophage polarization, and reduced regulatory T cells and M2 macrophages. These shifts effectively converted the immunologically "cold" tumor into a "hot" state responsive to immune checkpoint inhibitors. This carrier-within-a-carrier strategy provides a multifunctional platform that couples potent radiosensitization with immunomodulation, offering a promising approach to overcoming radioresistance and improving therapeutic outcomes in osteosarcoma.