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基于Salphen结构的Fe-N2O2@C材料用于声动力协同化学动力治疗肿瘤

Salphen-Based Fe-N2O2@C Nanomaterial Applied in Synergistic Sonodynamic and Chemodynamic Therapy of Tumors

    摘要
  • 摘要:
    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-N2O2@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-N2O2，通过掺入科琴黑碳基底制备Fe-N2O2@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-N2O2@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-N2O2@C联合超声辐照杀伤肿瘤的能力。
    结果 Fe-N2O2@C与Fe-N2O2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-N2O2及Fe-N2O2@C具备M-N2O2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-N2O2，Fe-N2O2@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-N2O2@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-N2O2@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-N2O2@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。

     

    Abstract:
    Objective  To synthesize a Salphen-based Fe-N2O2@C material with high peroxidase (POD)-mimicking activity and sonosensitivity for the synergistic sonodynamic (SDT) and chemodynamic (CDT) therapy of tumors.
    Methods Fe-N2O2 was synthesized via the hydrothermal method, and Fe-N2O2@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-N2O2@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-N2O2@C combined with ultrasound irradiation was investigated using a subcutaneous 4T1 tumor-bearing mouse model.
    Results FFe-N2O2 and Fe-N2O2@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-N2O2 and Fe-N2O2@C possessed a Salphen covalent organic framework structure with M-N2O2 coordination, and the ketjen black loading had no significant impact on this structure. Compared to Fe-N2O2, Fe-N2O2@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-N2O2@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-N2O2@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-N2O2@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-N2O2@C nanomaterial shows promising potential for multimodal tumor therapy.

     

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