摘要/Abstract

利用肿瘤微环境与普通组织的差异, 我们设计了一种基于类芬顿反应(Fenton-like reaction)的微环境响应的纳米递药体系(Mn₃O₄/DOX@Lip). 首先利用热分解法制备得到锰的氧化物(Mn₃O₄)纳米粒子, 基于化疗药物阿霉素(DOX)与Mn原子的配位作用, 该纳米粒子可以负载并递送DOX, 其最外层包裹的酸敏脂质体能有效防止药物在递送过程中的泄露. 在肿瘤细胞的弱酸性和高浓度谷胱甘肽的微环境中, 脂质体膜破裂, 其中的Mn₃O₄纳米粒子被谷胱甘肽还原、分解, 并释放出DOX. 共聚焦成像结果表明, MCF-7细胞与Mn₃O₄/DOX@Lip共孵育后, 细胞中活性氧探针的荧光显著增加, 表明该递药体系可以通过下调细胞中的谷胱甘肽的含量引发细胞中的活性氧含量增加. 噻唑蓝(MTT)和流式细胞实验结果表明, 相比于单一的化疗药物, Mn₃O₄/DOX@Lip的细胞毒性增强, 这可能归因于还原产物Mn²⁺触发了类芬顿反应从而将细胞中内源性的H₂O₂转化为毒性更强的•OH. 氧化活性物质介导的细胞凋亡与化疗药物的细胞毒性相互促进, 增强了对细胞的凋亡能力. 本体系利用外源性的物质激发内源性的细胞毒性, 增强了化疗药物的治疗效果, 为肿瘤治疗提供了新的研究策略.
关键词: 锰的氧化物, 纳米递药体系, 类芬顿反应, 肿瘤微环境
The tumor microenvironment with low pH and high-level glutathione is different from other issues, which provides more possible strategies for designing drug delivery systems (DDSs). In this manuscript, we designed a microenvironment-responsive Mn₃O₄/DOX@Lip nano-DDS. Mn₃O₄ nanoparticles were prepared by thermal decomposition. Based on coordination of the chemotherapy drug doxorubicin (DOX) with Mn atom, the Mn₃O₄ nanoparticles could load and deliver DOX. A layer of sensitive liposomes was assembled on the outermost layer to further effectively prevent the leakage of DOX during the delivery process. X-ray diffraction (XRD) and energy dispersive X-ray spectroscopy (EDX) analysis results showed the manganese oxide was Mn₃O₄. The morphology and particle size of Mn₃O₄ were characterized by transmission electron microscope (TEM) and dynamic light scattering (DLS). Results showed that the Mn₃O₄ nanoparticles were a relatively uniform polyhedron with a particle size of around 20 nm. The drug loading of particles was 100 μg/mg. In weakly acidic microenvironment of tumor cells, the liposome membrane ruptured. In addition, the high-level glutathione microenvironment was also conducive to the decomposition of Mn ₃O₄ and the DOX was released in cells. Confocal imaging results demonstrated that after co-incubation with the Mn₃O₄ particles, the fluorescence of reactive oxygen species (ROS) probe in cancer cells increased significantly, indicating that the DDS could trigger an increase of ROS in cells by down-regulating the content of glutathione. The amount of ROS depended on the concentration of added particles and the incubation time. MTT and flow cytometry experiment results showed that Mn₃O₄/DOX@Lip had more cell cytotoxic compared to the single chemotherapy drug. It might be ascribed to the Fenton-like reaction triggered by the reduction product Mn²⁺, which converted the H₂O₂ in the cell into the more toxic •OH and promoted apoptosis. The ROS-mediated apoptosis and chemotherapy played a synergistic effect to enhance the ability of cell apoptosis. This proposed Mn ₃O₄/DOX@Lip nano-DDS uses exogenous substances to stimulate endogenous cytotoxicity and enhance the effect of chemotherapy drug, providing new research strategies for tumor treatment.
Key words: manganese oxide, nano-drug delivery system, Fenton-like reaction, tumor microenvironment


PDF全文下载地址:

点我下载PDF