The Construction and Application of Mn3O4/DOX@Lip Nano-drug Delivery System Based on Fenton-Like Reaction

doi:10.6023/A20120583

Abstract

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

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Zheng Cai, Yingwen Zhang, Liping Jiang, Junjie Zhu. The Construction and Application of Mn₃O₄/DOX@Lip Nano-drug Delivery System Based on Fenton-Like Reaction[J]. Acta Chimica Sinica, 2021, 79(4): 481-489.

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Fig. & Tab. 10

Figure 1. The preparation and application of tumor microenvironment responsive Mn3O4/DOX@Lip drug delivery system

Figure 2. TEM images of Mn3O4 nanoparticles: in cyclohexane solvent (a); after treated by PAA in water solvent (b); Mn3O4@Lip (phosphotungstic acid negative staining) (c); SEM image of Mn3O4 nanoparticles (d); hydrodynamic size distributions of Mn3O4, Mn3O4/DOX and Mn3O4/DOX@Lip particles in water (e); the zeta potential of Mn3O4, Mn3O4/DOX, blank Lip and Mn3O4/DOX@Lip (f)

Figure 3. X-ray diffraction pattern of Mn3O4 particles (a) and FT-IR spectra of Mn3O4/OA and Mn3O4/PAA (b)

Figure 4. The cumulative release of DOX from Mn3O4/DOX (a) in different buffer solutions (pH=7.4, 5.0); in different concentration of GSH (b); in the same GSH solution (10 μmol/mL), with different buffer solution, pH=5.0, and pH=7.4 (c)

Figure 5. TEM images of Mn3O4 nanoparticles in buffer solution (pH=5.0) including GSH (10 μmol/mL) for 2, 8 and 24 h

Figure 6. The absorption change of methylene blue solutions at 665 nm during treated with the supernatant and H2O2. The supernatant was got after Mn3O4 reacted with GSH

Figure 8. Flow cytometry analysis of MCF-7 cells apoptosis induced by different formulations with DOX 3 µg/mL, Mn 3O460 μg/mL for 24 h, using Annexin V-FITC/PI staining, (Ⅰ) Control; (Ⅱ) Free-DOX; (Ⅲ) Mn 3O4; (Ⅳ) Mn3O4/DOX; (Ⅴ) Mn3O4/DOX@Lip

Figure 9. Confocal microscopy images of MCF-7 cells incubated with Mn3O4/DOX@Lip for 12 h. Red ?uorescence was from DOX released from drug delivery system, and blue ?uorescence came from the cell nuclei stained by DAPI to local the site of the complex. The red scale bar is 50 μm

Figure 10. Confocal microscopy images of MCF-7 cells (a) incubated with 20 μg/mL Mn 3O4 for 2, 4, 8 h, respectively; (b) incubated with 5, 10, 20 μg/mL Mn 3O4 for 4 h, respectively. The green fluorescence came from the DCFH-DA probe. The red scale bar is 50 μm and the green scale bar is 75 μm. Quantitative median fluorescence intensity (MFI) of DCFH-DA in cells. Different incubation time (c); different concentration of Mn 3O4 (d). Use Image J to analyze at least 40 cells each time.

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基于类芬顿反应的Mn₃O₄/DOX@Lip纳米递药体系的构建及应用

The Construction and Application of Mn₃O₄/DOX@Lip Nano-drug Delivery System Based on Fenton-Like Reaction

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基于类芬顿反应的Mn3O4/DOX@Lip纳米递药体系的构建及应用