El Kheir Wiam, Marcos Bernard, Virgilio Nick, Paquette Benoit, Faucheux Nathalie, Lauzon Marc-Antoine
Advanced Dynamic Cell Culture Systems Laboratory, Department of Chemical Engineering and Biotechnology Engineering, Faculty of Engineering, Université de Sherbrooke, 2500 Boul. Université, Sherbrooke, QC J1K 2R1, Canada.
Laboratory of Cell-Biomaterial Biohybrid Systems, Department of Chemical Engineering and Biotechnology Engineering, Faculty of Engineering, Université de Sherbrooke, 2500 Boul. Université, Sherbrooke, QC J1K 2R1, Canada.
Pharmaceutics. 2022 Jun 1;14(6):1189. doi: 10.3390/pharmaceutics14061189.
Glioblastoma multiforme (GBM) is a grade IV glioma considered the most fatal cancer of the central nervous system (CNS), with less than a 5% survival rate after five years. The tumor heterogeneity, the high infiltrative behavior of its cells, and the blood-brain barrier (BBB) that limits the access of therapeutic drugs to the brain are the main reasons hampering the current standard treatment efficiency. Following the tumor resection, the infiltrative remaining GBM cells, which are resistant to chemotherapy and radiotherapy, can further invade the surrounding brain parenchyma. Consequently, the development of new strategies to treat parenchyma-infiltrating GBM cells, such as vaccines, nanotherapies, and tumor cells traps including drug delivery systems, is required. For example, the chemoattractant CXCL12, by binding to its CXCR4 receptor, activates signaling pathways that play a critical role in tumor progression and invasion, making it an interesting therapeutic target to properly control the direction of GBM cell migration for treatment proposes. Moreover, the interstitial fluid flow (IFF) is also implicated in increasing the GBM cell migration through the activation of the CXCL12-CXCR4 signaling pathway. However, due to its complex and variable nature, the influence of the IFF on the efficiency of drug delivery systems is not well understood yet. Therefore, this review discusses novel drug delivery strategies to overcome the GBM treatment limitations, focusing on chemokines such as CXCL12 as an innovative approach to reverse the migration of infiltrated GBM. Furthermore, recent developments regarding in vitro 3D culture systems aiming to mimic the dynamic peritumoral environment for the optimization of new drug delivery technologies are highlighted.
多形性胶质母细胞瘤（GBM）是一种IV级神经胶质瘤，被认为是中枢神经系统（CNS）最致命的癌症，五年生存率低于5%。肿瘤异质性、其细胞的高浸润行为以及限制治疗药物进入大脑的血脑屏障（BBB）是阻碍当前标准治疗效率的主要原因。肿瘤切除后，对化疗和放疗有抗性的浸润性残留GBM细胞可进一步侵入周围脑实质。因此，需要开发新的策略来治疗浸润脑实质的GBM细胞，如疫苗、纳米疗法以及包括药物递送系统在内的肿瘤细胞陷阱。例如，趋化因子CXCL12通过与其CXCR4受体结合，激活在肿瘤进展和侵袭中起关键作用的信号通路，使其成为一个有趣的治疗靶点，以便为治疗目的适当控制GBM细胞迁移方向。此外，间质液流动（IFF）也通过激活CXCL12 - CXCR4信号通路参与增加GBM细胞迁移。然而，由于其性质复杂且多变，IFF对药物递送系统效率的影响尚未得到充分理解。因此，本综述讨论了克服GBM治疗局限性的新型药物递送策略，重点关注趋化因子如CXCL12，作为一种逆转浸润GBM迁移的创新方法。此外，还强调了旨在模拟肿瘤周围动态环境以优化新药物递送技术的体外3D培养系统的最新进展。
