基于Salphen结构的Fe-N_(2)O_(2)@C材料用于声动力协同化学动力治疗肿瘤

Salphen-Based Fe-N_(2)O_(2)@C Nanomaterial Applied in Synergistic Sonodynamic and Chemodynamic Therapy of Tumors

目的 制备一种基于Salphen结构,具备高效仿过氧化物酶(peroxidase,POD)能力及声敏性的Fe-N_(2)O_(2)@C材料,用于声动力(SDT)协同化学动力(CDT)治疗肿瘤。方法 通过水热法合成Fe-N_(2)O_(2),通过掺入科琴黑碳基底制备FeN_(2)O_(2)@C,并表征该材料的形貌、结构、成分、仿酶产活性氧(ROS)能力及声敏性。通过体外实验探索Fe-N_(2)O_(2)@C实现SDT协同CDT杀伤4T1小鼠乳腺癌细胞的能力与机制。通过构建皮下4T1荷瘤小鼠模型探索Fe-N_(2)O_(2)@C联合超声辐照杀伤肿瘤的能力。结果 Fe-N_(2)O_(2)@C与Fe-N_(2)O_(2)均为形貌不规则纳米球,平均粒径分别为25.9 nm及36.2 nm;经XRD、FTIR及XPS分析证实Fe-N_(2)O_(2)及Fe-N_(2)O_(2)@C具备M-N_(2)O_(2)配位的Salphen共价有机框架结构,且科琴黑负载对该结构无明显影响。相较于Fe-N_(2)O_(2),Fe-N_(2)O_(2)@C具备高效的仿POD酶活性及声敏性,Km从19.32降低至5.82 mmol/L,vmax从2.51×10^(-8)提升至8.92×10^(-8) mol/(L·s)。Fe-N_(2)O_(2)@C协同超声辐照可实现细胞内大量产生ROS进而导致线粒体膜电位明显下降,从而诱导TEM可观测的线粒体损伤并导致细胞凋亡和死亡。体内实验表明Fe-N_(2)O_(2)@C协同超声辐照可以有效地抑制4T1皮下荷瘤鼠模型瘤体生长,且不具备明显的体内毒性。结论 本实验制备了一种基于Salphen结构的Fe-N_(2)O_(2)@C材料,该材料生物相容性好,可联合超声辐照实现SDT协同CDT杀伤肿瘤细胞,抑制肿瘤生长,在多模态肿瘤治疗中具有良好的应用前景。

Objective To synthesize a Salphen-based Fe-N_(2)O_(2)@C material with high peroxidase(POD)-mimicking activity and sonosensitivity for the synergistic sonodynamic(SDT)and chemodynamic(CDT)therapy of tumors.Methods Fe-N_(2)O_(2) was synthesized via the hydrothermal method,and Fe-N_(2)O_(2)@C was prepared by incorporating a ketjen black substrate.The morphology,structure,composition,enzyme mimic activity for reactive oxygen species(ROS)production,and sonosensitivity of the material were characterized.The ability and mechanism of Fe-N_(2)O_(2)@C to perform synergistic SDT and CDT killing of 4T1 mouse breast cancer cells were explored through in vitro experiments.The in vivo tumor-killing ability of Fe-N_(2)O_(2)@C combined with ultrasound irradiation was investigated using a subcutaneous 4T1 tumor-bearing mouse model.Results FFe-N_(2)O_(2) and Fe-N_(2)O_(2)@C were both irregularly shaped nanospheres with average particle sizes of 25.9 nm and 36.2 nm,respectively.XRD,FTIR,and XPS analyses confirmed that both Fe-N_(2)O_(2) and Fe-N_(2)O_(2)@C possessed a Salphen covalent organic framework structure with M-N_(2)O_(2) coordination,and the ketjen black loading had no significant impact on this structure.Compared to Fe-N_(2)O_(2),Fe-N_(2)O_(2)@C exhibited high POD-mimicking activity(with Km reduced from 19.32 to 5.82 mmol/L and vmax increased from 2.51×10^(-8) to 8.92×10^(-8) mol/[L·s])and sonosensitivity.Fe-N_(2)O_(2)@C in combination with ultrasound irradiation could produce a large amount of ROS within cells and a subsequent significant decrease in mitochondrial membrane potential,thereby inducing TEM-observable mitochondrial damage and causing cell apoptosis and death.In addition,in vivo experiments showed that Fe-N_(2)O_(2)@C in combination with ultrasound irradiation could effectively inhibit tumor growth in a 4T1 subcutaneous tumor-bearing mouse model without significant in vivo toxicity.Conclusion In this study,we prepared a Salphen-based Fe-N_(2)O_(2)@C material with good biocompatibility,which can be used in combination with ultrasound irradiation to achieve SDT and CDT synergistic killing of tumor cells and inhibit tumor growth.This Salphen-based Fe-N_(2)O_(2)@C nanomaterial shows promising potential for multimodal tumor therapy.