Magnetic Nano-Amorphous-Iron-Oxide-Based Drug Delivery System with Dual Therapeutic Mechanisms
doi: 10.1063/1674-0068/cjcp1906123
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摘要: 合成一种具有pH响应性的聚乙二醇(PEG)修饰无定形介孔氧化铁纳米粒子(AFe-PEG).这种纳米粒子可以高效负载药物分子如阿霉素(DOX)，构成新型多功能AFe-PEG/DOX药物递送体系. DOX的负载率高达948 mg/g-纳米粒子.在酸性溶液中，AFe-PEG/DOX纳米粒子不仅可以有效释放DOX，同时可以释放Fe离子进行Fenton反应，将H$ _2 $O$ _2 $转变成$ \cdot $OH自由基.体外实验结果表明，AFe-PEG/DOX纳米粒子对HeLa细胞同时具有化疗和化学动力学疗法的疗效.同时，由于AFe-PEG/DOX纳米粒子本身的磁性，使其在外部磁场中的细胞内化效率也得到了提高.Abstract: Smart nanoparticles that respond to pathophysiological parameters, such as pH, GSH, and H$ _2 $O$ _2 $, have been developed with the huge and urgent demand for the high-efficient drug delivery systems (DDS) for cancer therapy. Herein, cubic poly(ethylene glycol) (PEG)-modified mesoporous amorphous iron oxide (AFe) nanoparticles (AFe-PEG) have been successfully prepared as pH-stimulated drug carriers, which can combine doxorubicin (DOX) with a high loading capacity of 948 mg/g, forming a novel multifunctional AFe-PEG/DOX nanoparticulate DDS. In an acidic microenvironment, the AFe-PEG/DOX nanoparticles will not only release DOX efficiently, but also release Fe ions to catalyze the transformation of H$ _2 $O$ _2 $ to $ \cdot $OH, acting as fenton reagents. In vitro experimental results proved that the AFe-PEG/DOX nanoparticles can achieve combination of chemotherapeutic (CTT) and chemodynamic therapeutic (CDT) effects on Hela tumor cells. Furthermore, the intrinsic magnetism of AFe-PEG/DOX makes its cellular internalization efficiency be improved under an external magnetic field. Therefore, this work develops a new and promising magnetically targeted delivery and dual CTT/CDT therapeutic nano-medicine platform based on amorphous iron oxide.
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Figure 2. TEM images of (a) PB and (b) AFe. (c) XRD and (d) FTIR spectra of PB and AFe nanoparticles. (e) N$ _2 $ adsorption-desorption isotherms and (f) BJH pore size distribution of AFe nanoparticles.
Figure 3. (a) FTIR spectra of DOX and AFe-PEG/DOX nanoparticles. (b) UV-Vis spectra of the PBS (pH = 7.4) solution of DOX (2 mg/mL) before and after the addition of AFe nanoparticles. (c) Release profiles of DOX from AFe-PEG/DOX under different pH values.
Figure 4. (a) The real-time release percentage of Fe ion in PBS (at different pH) that contains AFe-PEG nanoparticles. (b) ESR spectra of different reaction systems with 5, 5-dimethyl-1-pyrroline-N-oxide (DMPO) as the spin trap. (c) The real-time absorption of MB in acetate buffer solution (pH = 5.4) containing H$ _2 $O$ _2 $ in the absence and presence of AFe-PEG nanoparticles.
Figure 5. (a) Illustration of the dual-mode chemo/chemodynamic therapy mechanism of AFe-PEG/DOX nanoparticles. (b) Cell viabilities of Hela cells after various therapeutic treatments.
Figure 6. (a) Representative CLSM images of Hela cells incubated in PBS for 2, 4, 8, and 12 h after the cells had been incubated with AFe-PEG/DOX nanoparticles for 2 h. The cells were co-stained with LysoTracker green (green channel) and DAPI (blue channel). Scale bar is 50 μm. (b) Relative fluorescence intensities of DOX in nuclei and (c) the colocalization ratios of red channel (DOX) and green channel (LysoTracker green) fluorescence deduced from (a).
Figure 7. (a) VSM of AFe-PEG nanoparticles. Inset: digital photos of PBS containing AFe-PEG nanoparticles with and without a magnetic field. (b) Representative CLSM images of Hela cells after 2-h's incubation in PBS containing AFe-PEG/DOX in the presence and absence of an external magnetic field. Scale bar is 50 μm. (c) Normalized fluorescence intensities (red channel) of Hela cells calculated from (b).
S6. Fluorescence images of Hela cells after being treated with different concentration of AFe-PEG/DOX. Scale bar is 50 μm.
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