Engineering GliaTrap: a biodegradable non-swelling hydrogel with tuned release of CXCL12 to attract migrating glioblastoma cells

Abstract

ABSTRACTGlioblastoma is the most aggressive type of brain cancer with an average overall survival of 15-21 months after first diagnosis. The relapse is mainly caused by migrating glioblastoma cells that diffuse away from the tumor mass into the brain parenchyma and retain cancer stem cell (GSC) properties. Current therapeutic options are ineffective and inevitably result in relapse, indicating a high unmet medical need for innovative therapies in the treatment of invasive glioblastoma. To address this challenge, we propose a new therapeutic modality: GliaTrap, a biodegradable non-swelling, injectable hydrogel with sustained release of a chemoattractant for GSCs that lures and traps the migrating cells back to the tumor resection cavity. We developed a biodegradable and injectable hyaluronan/collagen II-based (HA/Col) hydrogel that does not swell in vivo. The hydrogel is embedded with CXCL12 loaded liposomes and is tuned for sustained release of CXCL12. The safety profile of liposome-embedded HA/Col hydrogel was determined in-vivo after stereotactic implantation in the mouse brain. The efficacy of GliaTrap to attract GSCs was determined ex vivo using a 3D tumor spheroid model and in-vivo using 3D light-sheet microscopy in orthotopic human glioblastoma xenografts. Our findings suggest that GliaTrap could represent a safe and efficacious new therapeutic approach for glioblastoma and potentially serve as a drug delivery platform to locally deliver tumor-killing agents.One Sentence SummaryGliaTrap is a biodegradable non-swelling hydrogel with tuned release of a chemoattractant to attract invading glioma cells and serve as delivery platform for local therapeutics.