基于聚偏氟乙烯-三氟乙烯的复合压电纳米粒子用于脑胶质瘤细胞的精准成像与靶向治疗

doi:10.3969/j.issn.1006-7795.2023.06.002

摘要/Abstract

摘要： 目的探讨基于偏氟乙烯（vinylidene fluoride, VDF)和三氟乙烯（trifluoroethylene, TrFE)的共聚物［poly (VDF-TrFE), P(VDF-TrFE)］构建的复合压电纳米粒子在脑胶质瘤细胞中治疗和成像的效能。方法对P(VDF-TrFE)压电材料进行晶型重塑和亲水性改善，通过点击化学反应将精氨酰－甘氨酰－天冬氨酸合成肽 (Arg-Gly-Asp, RGD) 连接到二硬脂酰基磷脂酰乙醇胺－聚乙二醇－马来酰亚胺脂［1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol)-maleimide, DSPE-PEG-Mal］上；同时以DSPE-PEG-四氮杂环配体 (DSPE-PEG-tetranitroheterocyclic ligand, DSPE-PEG-DOTA) 为底液，加入一定量醋酸钆溶液，通过螯合获得DSPE-PEG-DOTA-钆造影剂 (DSPE-PEG-DOTA-Gd)；按比例将重塑后的P(VDF-TrFE)、DAPE-PEG-Mal-RGD和DSPE-PEG-DOTA-Gd混合，最后获得复合压电纳米粒子P(VDF-TrFE)@DOTA-Gd@RGD，对其进行表征以及用于细胞层面实验研究。结果 P(VDF-TrFE)@DOTA-Gd@RGD复合压电纳米粒子具有优异的稳定性，尤其是在达尔伯克氏必需基本培养基 (Dulbecco's modified eagle medium, DMEM) 中，其粒径随时间变化保持在160 nm左右；经过晶型重塑后，P(VDF-TrFE)@DOTA-Gd@RGD的压电性能明显提高，表面电势约为4.2 mV；该纳米粒子可作为磁共振成像(magnetic resonance imaging, MRI) 显像剂，而且在超声激发下，P(VDF-TrFE)@DOTA-Gd@RGD复合压电纳米粒子能产生大量活性氧，抑制了胶质瘤细胞的增殖、侵袭和迁移能力，同时还促进其凋亡。结论 P(VDF-TrFE)@DOTA-Gd@RGD复合压电纳米粒子作为MRI显像剂可以用于脑胶质瘤的定位，且可以作为一种声敏剂用于脑胶质瘤细胞的声动力治疗。

关键词: 脑胶质瘤, 压电材料, 声动力治疗, 磁共振成像

Abstract: Objective To explore the efficacy of composite piezoelectric nanoparticles constructed based on poly（vinylidene fluoride)-trifluoroethylene ［P(VDF-TrFE)］ in the treatment and imaging of glioma. Methods P(VDF-TrFE) piezoelectric materials were reshaped in crystal form and improved in hydrophilicity, and Arg-Gly-Asp (RGD) targeted peptides were connected to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol)-maleimide (DSPE-PEG-Mal) by click chemistry reaction. In addition, DSPE-PEG- tetranitroheterocyclic ligand (DSPE-PEG-DOTA) was mixed with a certain amount of gadolinium acetate solution was added to obtain DSPE-PEG-DOTA-Gd through chelation. And then the P(VDF-TrFE), DAPE-PEG-Mal RGD, and DSPE-PEG-DOTA-Gd in proportion were mixed to obtain composite piezoelectric nanoparticles P(VDF-TrFE)@DOTA-Gd@RGD. The obtained nanoparticles were characterized and assesed. Results P(VDF-TrFE)@DOTA-Gd@RGD composite piezoelectric nanoparticles have excellent stability, especially in Dulbecco's modified eagle medium (DMEM) solutions where their particle size remained around 160 nm over time. After crystal reshaping, the piezoelectric performance of P(VDF-TrFE)@DOTA-Gd@RGD is significantly improved, with a surface potential of approximately 4.2 mV. The nanoparticles could be used as a magnetic resonance imaging (MRI) agent. Under ultrasound excitation, P(VDF-TrFE)@DOTA-Gd@RGD composite piezoelectric nanoparticles generated a large amount of reactive oxygen species, inhibited the proliferation, invasion, and migration ability of glioma cells, and promoted their apoptosis. Conclusion P(VDF-TrFE)@DOTA-Gd@RGD composite piezoelectric nanoparticles could be used as an MRI agent for the localization of brain gliomas and as a sound sensitive agent for sonodynamic therapy of glioma.

Key words: glioma, piezoelectric materials, sonodynamic therapy, magnetic resonance imaging

中图分类号:

陈治光, 张巍, 何文. 基于聚偏氟乙烯-三氟乙烯的复合压电纳米粒子用于脑胶质瘤细胞的精准成像与靶向治疗[J]. 首都医科大学学报, 2023, 44(6): 912-920.

Chen Zhiguang, Zhang Wei, He Wen. Composite piezoelectric nanoparticles based on P(VDF-TrFE) for precise imaging and targeted therapy of glioma[J]. Journal of Capital Medical University, 2023, 44(6): 912-920.

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