Development of a Synthetic, Injectable Hydrogel to Capture Residual Glioblastoma and Glioblastoma Stem‐Like Cells with CXCL12‐Mediated Chemotaxis

Abstract

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 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. A thiol‐Michael addition injectable hydrogel for compatibility with GBM therapy is previously characterized and optimized. This study aims to develop the hydrogel further to capture GBM/GSCs through CXCL12‐mediated chemotaxis. The release kinetics of hydrogel payloads are investigated, migration and invasion assays in response to chemoattractants are performed, and the GBM‐hydrogel interactions in vitro are studied. With a novel dual‐layer hydrogel platform, it is demonstrated 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. This synthetic hydrogel, therefore, demonstrates a promising method to attract and capture migratory GBM cells and GSCs responsive to CXCL12 chemotaxis.

Factors That Influence Base-Catalyzed Thiol-Ene Hydrogel Synthesis

“…Their composition can be tuned to mimic the hydrophilic nature of human tissues, making them particularly suitable for biomedical applications [2][3][4][5]. The biocompatibility of many hydrogels has positioned them as potentially useful materials for drug delivery, along with their degradation properties that can be finely tuned and their mechanical characteristics, which may closely resemble those of human tissues [6][7][8][9][10][11][12][13][14][15][16][17][18][19]. The ability to precisely target specific body areas and provide controlled release of therapeutic agents via these hydrogels significantly minimizes the potential for toxic or undesired systemic side effects, a common concern in more traditional drug delivery methods [20][21][22].…”