Hydrogel-based implantable system for local delivery of temozolomide in postsurgical brain cancer therapy

The innovative photocrosslinked/freeze-dried hydrogel-based flake-like systems for the local intraoperative temozolomide (TMZ) delivery in postsurgical glioblastoma (GBL) therapy are presented. Developed materials prepared utilizing an easy-to-scale-up methodology are composed of methacrylated gelatin, chitosan, and hyaluronic acid. To provide the drug release tuning, we have synthesized and tested two photocrosslinkable derivatives of TMZ, methacrylated TMZ and methacrylated chitosan-TMZ conjugate. Systems composed of biopolymers used in various weight ratios and containing different TMZ forms were fabricated and characterized for their physicochemical and biological properties. We have focused on the parameters that are especially important to rationally design biomaterials for local administration at the GBL resection site, including swellability, degradation profile, mechanical features, TMZ release, biocompatibility, biosafety, and therapeutic activity. It was found that by playing with polymeric matrix composition and using various TMZ derivatives, the physicochemical features of the presented systems might be modulated. We confirmed the materials’ anti-tumor activity, demonstrating their potential to inhibit cell cycle progression and induce apoptosis of human glioma cells. Simultaneously, the biocompatibility of the tested biomaterials was verified. The obtained materials were shown not to release toxic compounds that could affect normal cells. Depending on TMZ-biopolymeric matrix interaction, developed delivery systems exhibit differences in drug release and human glioma cell response, which is important for the potential clinical application. Faster release will be particularly considered for residual tumor mass, while slower release will be crucial to delay recurrence. Overall, the composites presented in this study possess qualities that render them a promising implantable system for oncological post-surgery glioma therapy.