Virginia Tech - Wake Forest University School of Biomedical Engineering and Sciences, Virginia Tech, Blacksburg, VA, 24061, USA.
Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University, Winston-Salem, NC, 27157, USA.
Adv Healthc Mater. 2023 Jun;12(14):e2300671. doi: 10.1002/adhm.202300671. Epub 2023 Apr 20.
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.
胶质母细胞瘤（GBM）具有高浸润性，是成年人中最常见且致命的原发性脑肿瘤。GBM 细胞，包括对治疗有抗性的胶质母细胞瘤干细胞样细胞（GSCs），即使在患者接受手术切除和放化疗后，也会侵入健康的脑实质，形成继发性肿瘤。因此，迫切需要新技术来消灭这些残留的肿瘤细胞。先前已经对一种用于 GBM 治疗的巯基-迈克尔加成可注射水凝胶进行了表征和优化。本研究旨在进一步开发该水凝胶，通过 CXCL12 介导的趋化作用捕获 GBM/GSCs。研究了水凝胶有效载荷的释放动力学，进行了对趋化剂的迁移和侵袭测定，并研究了 GBM 与水凝胶的体外相互作用。通过一种新型双层水凝胶平台，证明了合成水凝胶中释放的 CXCL12 可以诱导 U251 GBM 细胞和 GSCs 从细胞外基质微环境中迁移，并通过变形虫样迁移促进其侵入合成水凝胶。被困在合成水凝胶深部的 GBM 细胞的存活受到限制，而靠近表面的活细胞通过纤维连接蛋白沉积来增强水凝胶。因此，这种合成水凝胶为吸引和捕获对 CXCL12 趋化性有反应的迁移性 GBM 细胞和 GSCs 提供了一种很有前途的方法。
