Controlled Payload Release by Magnetic Field Triggered Neural Stem Cell Destruction for Malignant Glioma Treatment

Stem cells have recently garnered attention as drug and particle carriers to sites of tumors, due to their natural ability to track to the site of interest. Specifically, neural stem cells (NSCs) have demonstrated to be a promising candidate for delivering therapeutics to malignant glioma, a primary brain tumor that is not curable by current treatments, and inevitably fatal. In this article, we demonstrate that NSCs are able to internalize 2 μm magnetic discs (SD), without affecting the health of the cells. The SD can then be remotely triggered in an applied 1 T rotating magnetic field to deliver a payload. Furthermore, we use this NSC-SD delivery system to deliver the SD themselves as a therapeutic agent to mechanically destroy glioma cells. NSCs were incubated with the SD overnight before treatment with a 1T rotating magnetic field to trigger the SD release. The potential timed release effects of the magnetic particles were tested with migration assays, confocal microscopy and immunohistochemistry for apoptosis. After the magnetic field triggered SD release, glioma cells were added and allowed to internalize the particles. Once internalized, another dose of the magnetic field treatment was administered to trigger mechanically induced apoptotic cell death of the glioma cells by the rotating SD. We are able to determine that NSC-SD and magnetic field treatment can achieve over 50% glioma cell death when loaded at 50 SD/cell, making this a promising therapeutic for the treatment of glioma.干细胞凭借其天然的靶向归巢能力，近年来作为药物与颗粒载体向肿瘤病灶递送的应用受到广泛关注。具体而言，神经干细胞（Neural Stem Cells, NSCs）已被证实是向恶性胶质瘤递送治疗制剂的极具前景的候选载体；恶性胶质瘤作为一类经当前治疗手段无法治愈且必然致命的原发性脑肿瘤，临床治疗难度极大。本研究证实，神经干细胞可内化2微米磁性圆盘（Magnetic Discs, SD），且不会对细胞活性造成不良影响。随后，可通过施加1特斯拉旋转磁场对该磁性圆盘进行远程触发，以实现治疗载荷的递送。此外，本研究利用该NSC-SD递送系统，将磁性圆盘本身作为治疗制剂，通过机械作用直接摧毁胶质瘤细胞。实验中，我们将神经干细胞与磁性圆盘共孵育过夜，随后施加1特斯拉旋转磁场以触发磁性圆盘的释放。我们通过迁移实验、共聚焦显微镜成像及凋亡免疫组化检测，评估了该磁性颗粒潜在的定时释放效应。在磁场触发磁性圆盘释放后，我们加入胶质瘤细胞并使其内化该颗粒。待颗粒被胶质瘤细胞内化后，再次施加磁场处理，通过旋转的磁性圆盘触发机械诱导的胶质瘤细胞凋亡性死亡。实验结果表明，当每细胞负载50个磁性圆盘时，NSC-SD联合磁场治疗可实现超过50%的胶质瘤细胞死亡率，证实该方案是治疗胶质瘤的极具潜力的新治疗策略。