Development of a Synthetic, Injectable Hydrogel to Capture Residual Glioblastoma and Glioblastoma Stem-like Cells with CXCL12-mediated Chemotaxis.

Glioblastoma (GBM), characterized by high infiltrative capacity, is the most common and deadly type of primary brain tumor in adults. GBM cells, including therapy-resistant glioblastoma stem-like cells (GSCs), invade into the healthy brain parenchyma to form secondary tumors even after patients undergo surgical resection and chemoradiotherapy. New techniques are therefore urgently needed to eradicate these residual tumor cells. We previously characterized and optimized a thiol-Michael addition injectable hydrogel for compatibility toward GBM therapy. In this study, we aimed to develop the hydrogel further to capture GBM/GSCs through CXCL12-mediated chemotaxis. We investigate the release kinetics of hydrogel payloads, perform migration and invasion assays in response to chemoattractants, and study the GBM-hydrogel interactions in vitro. We demonstrate with a novel dual layer hydrogel platform that CXCL12 released from the synthetic hydrogel can induce the migration of U251 GBM cells and GSCs from the extracellular matrix microenvironment and promote invasion into the synthetic hydrogel via amoeboid migration. The survival of GBM cells entrapped deep into the synthetic hydrogel is limited, while live cells near the surface reinforce the hydrogel through fibronectin deposition. Our synthetic hydrogel therefore demonstrates a promising method to attract and capture migratory GBM cells and GSCs responsive to CXCL12 chemotaxis. This article is protected by copyright. All rights reserved.