Multifunctional and stimuli-responsive ionic liquid-polymeric hydrogel: a promising platform for co-drug delivery in cancer treatment

Abstract

Designing intelligent drug delivery systems that offer high drug loading, site-specific release, and improved therapeutic outcomes is crucial to overcome the limitations of conventional cancer treatments. This study presents a novel pH-responsive hydrogel developed by integrating a biocompatible ionic liquid (IL), [TMG][Ol], into a polymeric matrix to enable the co-delivery of the chemotherapeutic drug 5-fluorouracil (5-FU) and heparin (Hp), aimed at cancer treatment and metastasis inhibition. Structural and surface characterization studies were performed using XPS, FTIR, SANS and FE-SEM, confirming the successful formation of the composite network, while thermal stability was evaluated through DSC analysis. Rheological analysis demonstrated robust mechanical strength, while thixotropic studies validated its injectability, supporting minimally invasive delivery. The hydrogel also exhibited notable self-healing and adhesive properties. [TMG][Ol] incorporation enhanced drug loading capacity by ∼2.5-fold over the IL-free hydrogel. Drug release studies confirmed pH-responsive behaviour, with over 90.2% of 5-FU and 77.6% of Hp released at pH 5.2 within 48 hours, while release remained below 60% at physiological pH, minimizing off-target effects. Biocompatibility was validated using HaCaT cells, showing over 95% cell viability after 48 hours of exposure. In vitro cytotoxicity assays revealed a dose-dependent reduction in cancer cell viability, with significant inhibition observed in MCF-7 and HeLa cells, revealing significant therapeutic efficacy. Furthermore, anti-metastatic activity assessed via a scratch assay in HeLa cells showed a substantial reduction in cell migration compared to the control. These findings underscore the potential of the developed IL-based hydrogel as a promising dual-delivery platform with targeted, sustained release, strong therapeutic potential, and minimal toxicity to healthy cells, offering a new avenue for effective cancer therapy and metastasis suppression.