Huang Xiaoyu, Gao Lu, Ge Wei, Li Shuxian, Liu Yi, Fan Xiaoyun, Tu Shengxian, Wang Fu
Biomedical Instrument Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
Guangdong Key Laboratory of Environmental Pollution and Health, School of Environment, Jinan University, Guangzhou 510632, China.
Acta Biomater. 2024 Dec;190:435-446. doi: 10.1016/j.actbio.2024.10.051. Epub 2024 Nov 5.
Despite the significant advancements in piezoelectric materials for sonodynamic therapy (SDT), the suppression of orthotopic glioma remains challenging, primarily due to the unclear mechanism and the restriction of blood-brain barrier (BBB). Herein, we proposed that layered piezoelectric SrBiTaO nanoparticles (SBTO NPs) could effectively depolarize the mitochondrial membrane potential (ΔΨ) of glioma cells under ultrasound (US) exposure. The US-induced band bending in SBTO NPs enhanced redox ability, promoting an increase in reactive oxygen species (ROS) generation. The in vitro results proved that SBTO NPs selectively accumulated in mitochondria under US and induced apoptosis in a mitochondrial depolarization manner mediated by the generation of ROS and free charges. Furthermore, SBTO NPs could cross the BBB and then accumulate in gliomas through US/microbubbles (MBs) procedure and protein-mediated transport. The therapeutic effect of piezoelectric SBTO NPs mediated SDT was proved in the orthotopic glioma mouse model. As validated by the histopathological observation and the long-term evaluation, the good biocompatibility and biosafety of SBTO NPs make it possible for deep tumor therapy, and worthy for further preclinical study. STATEMENT OF SIGNIFICANCE: Employing piezoelectric sonosensitizers for sonodynamic therapy (SDT) has emerged as a promising strategy for cancer treatment; however, the unclear mechanism and blood-brain barrier (BBB) limit the effectiveness of SDT in glioma. Herein, we developed piezoelectric SrBiTaO nanoparticles (SBTO NPs) with a built-in electric field for glioma treatment and explored the underlying therapeutic mechanism. Notably, SBTO NPs selectively accumulated in mitochondria under ultrasound (US) and induced apoptosis in a mitochondrial depolarization manner, which is mediated by the generation of reactive oxygen species (ROS) and free charges. In an orthotopic glioma mouse model, SBTO NPs were delivered into the glioma through US/microbubbles and transferrin-mediated transport pathways, inhibiting tumor growth. This work provides a new paradigm for the treatment of orthotopic glioma and other tumor types.
尽管用于声动力疗法（SDT）的压电材料取得了重大进展，但原位胶质瘤的抑制仍然具有挑战性，主要原因是机制不明和血脑屏障（BBB）的限制。在此，我们提出层状压电SrBiTaO纳米颗粒（SBTO NPs）在超声（US）照射下可有效使胶质瘤细胞的线粒体膜电位（ΔΨ）去极化。超声诱导的SBTO NPs能带弯曲增强了氧化还原能力，促进活性氧（ROS）生成增加。体外结果证明，SBTO NPs在超声作用下选择性地在线粒体中积累，并以由ROS和自由电荷生成介导的线粒体去极化方式诱导细胞凋亡。此外，SBTO NPs可以穿过血脑屏障，然后通过超声/微泡（MBs）程序和蛋白质介导的转运在胶质瘤中积累。压电SBTO NPs介导的声动力疗法在原位胶质瘤小鼠模型中被证明具有治疗效果。经组织病理学观察和长期评估验证，SBTO NPs良好的生物相容性和生物安全性使其有可能用于深部肿瘤治疗，值得进一步进行临床前研究。重要性声明：采用压电超声敏化剂进行声动力疗法（SDT）已成为一种有前景的癌症治疗策略；然而，机制不明和血脑屏障（BBB）限制了SDT在胶质瘤治疗中的有效性。在此，我们开发了具有内置电场的压电SrBiTaO纳米颗粒（SBTO NPs）用于胶质瘤治疗，并探索了潜在的治疗机制。值得注意的是，SBTO NPs在超声（US）作用下选择性地在线粒体中积累，并以由活性氧（ROS）和自由电荷生成介导的线粒体去极化方式诱导细胞凋亡。在原位胶质瘤小鼠模型中，SBTO NPs通过超声/微泡和转铁蛋白介导的转运途径输送到胶质瘤中，抑制肿瘤生长。这项工作为原位胶质瘤和其他肿瘤类型的治疗提供了一种新的范例。
