Targeting JAK/STAT3 in glioblastoma cells using an alginate-PNIPAm molecularly imprinted hydrogel for the sustained release of ruxolitinib.

Abstract

Glioblastoma (GBM) is a notoriously aggressive primary brain tumor characterized by elevated recurrence rates and poor overall survival despite multimodal treatment. Local treatment strategies for GBM are safer and more effective alternatives to systemic chemotherapy, directly tackling residual cancer cells in the resection cavity by circumventing the blood-brain barrier. Molecularly imprinted polymers (MIPs) are promising drug delivery systems due to their high-affinity binding cavities that enable tailored release kinetics. This study reports the development of a semi-synthetic polysaccharide MIP-based hydrogel intended for the post-surgical management of GBM. The biodegradable implant, made of calcium-crosslinked alginate-poly(N-isopropylacrylamide) graft copolymer, was designed for the sustained release of ruxolitinib (RUX) in the resection cavity, targeting the Janus kinase/Signal Transducer and Activator of Transcription-3 signaling pathway. The molecularly imprinted hydrogel demonstrated thermo-thickening and shear-thinning behavior, high entrapment efficiency of RUX (84.59 ± 0.73 %), and sustained release over 14 days, underscoring the advantages that molecular imprinting of the alginate matrix provides compared to conventional MIPs. The dose-dependent inhibitory effects of the imprinted hydrogel against U251 and A172 GBM cells were demonstrated by increased apoptosis, reduced confluence, colony formation, and delayed wound healing, whereas the non-imprinted hydrogel was biocompatible. The MIP hydrogel could be a safe and effective GBM treatment.