Suita Yusuke, Miriyala Saradha, Merih-Toruner Deniz, Pizzagalli Mattia, Leary Owen P, Yue Weizhou, Xie Lingxiao, Akobundu Blessing, Pertsch Nathan, Fiser Andras, Fajardo Eduardo, Shen Jie, Tapinos Nikos
Laboratory of Cancer Epigenetics and Plasticity, Brown University, Rhode Island Hospital, 593 Eddy Street, Providence, RI, 02903, USA.
Departments of Biomedical and Pharmaceutical Sciences and Chemical Engineering, University of Rhode Island, Kingston, RI, USA.
Sci Rep. 2025 May 22;15(1):17811. doi: 10.1038/s41598-025-02977-x.
A significant factor in relapse and dismal prognosis of glioblastoma is the migrating glioblastoma cells, which diffuse away from the tumor mass into the brain parenchyma. Post-resection application of biomaterials to deliver cytotoxic agents against the invading glioblastoma cells has recently gained attention. The aim of this study was to develop a non-swelling, non-inflammatory biomimetic hydrogel with sustained release of a chemoattractant for glioblastoma cells and perform in vivo proof-of-concept studies to show chemoattraction of invading glioblastoma cells in orthotopic models of human glioblastoma. We used hyaluronic/collagen II-based (HA/Col) hydrogel that incorporates liposomes loaded with CXCL12 to develop GliaTrap. Sustained release of CXCL12 was measured with an ELISA assay. The non-inflammatory properties of GliaTrap were assessed in-vivo after stereotactic implantation in the mouse brain using a cytokine array and immunohistochemistry. The efficacy of GliaTrap on attracting GSCs was determined in-vivo employing 3D light-sheet microscopy on orthotopic human glioblastoma xenografts. We show that GliaTrap is an injectable, non-swelling biomimetic hydrogel that attains sustained release of CXCL12 and does not induce inflammation in the mouse brain. GliaTrap significantly attracts invading glioblastoma cells in orthotopic xenograft models of human glioblastoma as shown with 3D light sheet microscopy. Our findings indicate that GliaTrap can be safely used to attract invading glioblastoma cells by sustained release of a chemoattractant without inducing inflammatory conditions in the brain or local swelling.
胶质母细胞瘤复发及预后不良的一个重要因素是迁移的胶质母细胞瘤细胞，这些细胞从肿瘤块扩散到脑实质中。切除术后应用生物材料来递送针对侵袭性胶质母细胞瘤细胞的细胞毒性药物最近受到了关注。本研究的目的是开发一种不膨胀、无炎症的仿生水凝胶，其能持续释放胶质母细胞瘤细胞的趋化因子，并进行体内概念验证研究，以显示在人胶质母细胞瘤原位模型中侵袭性胶质母细胞瘤细胞的化学吸引作用。我们使用基于透明质酸/胶原蛋白II（HA/Col）的水凝胶，该水凝胶包含负载有CXCL12的脂质体，以开发GliaTrap。用ELISA测定法测量CXCL12的持续释放。在小鼠脑内立体定向植入后，使用细胞因子阵列和免疫组织化学在体内评估GliaTrap的非炎症特性。在人胶质母细胞瘤原位异种移植模型上采用3D光片显微镜在体内确定GliaTrap对吸引胶质瘤干细胞（GSCs）的功效。我们表明，GliaTrap是一种可注射的、不膨胀的仿生水凝胶，其能实现CXCL12的持续释放，并且不会在小鼠脑中诱导炎症。如3D光片显微镜所示，GliaTrap在人胶质母细胞瘤原位异种移植模型中能显著吸引侵袭性胶质母细胞瘤细胞。我们的研究结果表明，GliaTrap可以安全地用于通过持续释放趋化因子来吸引侵袭性胶质母细胞瘤细胞，而不会在脑中诱导炎症或局部肿胀。
