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. 2019 Aug 14;9(21):6209-6223.
doi: 10.7150/thno.36283. eCollection 2019.

Mitochondrial membrane anchored photosensitive nano-device for lipid hydroperoxides burst and inducing ferroptosis to surmount therapy-resistant cancer (V体育2025版)

Mangmang Sang  1 , Renjie Luo  1 , Yidan Bai  1 , Jun Dou  1 , Zhongtao Zhang  2 , Fulei Liu  3   4 , Feng Feng  2   5 , Jian Xu  2 , Wenyuan Liu  1   6
Affiliations

"VSports手机版" Mitochondrial membrane anchored photosensitive nano-device for lipid hydroperoxides burst and inducing ferroptosis to surmount therapy-resistant cancer

VSports app下载 - Mangmang Sang et al. Theranostics. .

"VSports在线直播" Abstract

Rationale: Ferroptosis is a regulated process of cell death caused by iron-dependent accumulation of lipid hydroperoxides (LPO). It is sensitive to epithelial-to-mesenchymal transition (EMT) cells, a well-known therapy-resistant state of cancer. Previous studies on nanomaterials did not investigate the immense value of ferroptosis therapy (FT) in epithelial cell carcinoma during EMT. Herein, we describe an EMT-specific nanodevice for a comprehensive FT strategy involving LPO burst. Methods: Mitochondrial membrane anchored oxidation/reduction response and Fenton-Reaction-Accelerable magnetic nanophotosensitizer complex self-assemblies loading sorafenib (CSO-SS-Cy7-Hex/SPION/Srfn) were constructed in this study for LPO produced to overcome the therapy-resistant state of cancer. Both in vitro and in vivo experiments were performed using breast cancer cells to investigate the anti-tumor efficacy of the complex self-assemblies. Results: The nano-device enriched the tumor sites by magnetic targeting of enhanced permeability and retention effects (EPR), which were disassembled by the redox response under high levels of ROS and GSH in FT cells. Superparamagnetic iron oxide nanoparticles (SPION) released Fe2+ and Fe3+ in the acidic environment of lysosomes, and the NIR photosensitizer Cy7-Hex anchored to the mitochondrial membrane, combined sorafenib (Srfn) leading to LPO burst, which was accumulated ~18-fold of treatment group in breast cancer cells. In vivo pharmacodynamic test results showed that this nanodevice with small particle size and high cytotoxicity increased Srfn circulation and shortened the period of epithelial cancer treatment VSports手机版. Conclusion: Ferroptosis therapy had a successful effect on EMT cells. These findings have great potential in the treatment of therapy-resistant epithelial cell carcinomas. .

Keywords: Ferroptosis; epithelial-to-mesenchymal transition; lipid hydroperoxides V体育安卓版. .

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Scheme 1
Scheme 1
Construction of the comprehensive ferroptosis treatment strategy, which was a tumor and mitochondrial membrane targeted oxidation/reduction response, and Fenton-Reaction-Accelerable magnetic NIR nanophotosensitizer complex self-assemblies (CSO-SS-Cy7-Hex/SPION/Srfn). There are three ways to produce LPO leading to ferroptosis: (i) the oxidation/reduction response disulfide bond can consume GSH and release drug, then Sorafenib expression of system xCT, in conjunction with depression of GSH production to produce LPO; (ii) SPION (Fe2+, Fe3+) can release Fe2+ in late endosomes for Fenton reaction to produce LPO. (iii) the NIR nanophotosensitizer (Cy7-Hex) targets mitochondrial membranes and produces LPO under illumination.
Figure 1
Figure 1
(A) Schematic illustration for the preparation of CSO-SS-Cy7-Hex/SPION/Srfn. TEM images of (B) CSO-SS-Cy7-Hex, (C) CSO-SS-Cy7-Hex/Srfn, (D) CSO-SS-Cy7-Hex/SPION, and (E) CSO-SS-Cy7-Hex/SPION/Srfn. (F) and (G) Fluorescence and absorption spectra of the CSO-SS-Cy7-Hex, CSO-SS-Cy7-Hex/SPION, CSO-SS-Cy7-Hex/Srfn, and CSO-SS-Cy7-Hex/SPION/Srfn. (H) and (I) In vitro release profiles of sorafenib and iron from CSO-SS-Cy7-Hex/SPION/Srfn complex self-assemblies under different simulated conditions at 37°C. The error bars in the graph represent standard deviation (n = 3). (J) Disassembly TEM images of the complex self-assemblies after incubating in 10 mM GSH for 0 h, 2 h, 8 h and 12 h. (K) and (L) Hysteresis loops and XRD pattern of SPION and CSO-SS-Cy7-Hex/SPION/Srfn complex self-assembly solution. The CLSM image (M) and (N) indicate the CSO-SS-Cy7-Hex and CSO-SS-Cy7-Hex/SPION/Srfn. Scale bar, 5 μm. (H) Stability of the CSO-SS-Cy7-Hex/SPION/Srfn in FBS and PBS at 37°C for 72 h.
Figure 2
Figure 2
Cell uptake, DCFH-DA assay and intracellular drug release of complex self-assemblies in 4T1 and MDA-MB-231 cells. (A, E) 4T1 cells were incubated with CSO-SS-Cy7-Hex/SPION/Srfn at different times. (scale bar: 5 μm). (B) Micrographs of CSO-SS-Cy7-Hex/SPION/Srfn complex self-assemblies after 3 h incubation in an external magnetic field of MDA-MB-231 cells, (1 and 2) refer to Nile red fluorescent, (3 and 4) refer to Prussian blue staining of cells. Left and right circles indicate the control area and targeted area, respectively (scale bar: 50 μm). (C, F) DCFH-DA assay of 4T1 cells treated with CSO-SS-Cy7-Hex/SPION/Srfn Light/No Light, CSO-SS-Cy7-Hex/Srfn, CSO-SS-Cy7-Hex/SPION, CSO-SS-Cy7-Hex, and DMEM and labeled with DAPI (blue) to identify cell nuclei (scale bar: 5 μm). (D, G) MDA-MB-231 cells were incubated with NR loaded CSO-SS-Cy7-Hex/SPION/NR for 3 h after pretreatment with NEM (1 mM) and GSH (10 mM), after which cells were labeled with DAPI (blue) to identify cell nuclei. (scale bar: 5 μm).
Figure 3
Figure 3
Colocalization imaging and dynamic distribution of CSO-SS-Cy7-Hex/SPION/Srfn complex self-assemblies. (A) The mechanism chart of mitochondrial membrane colocalization of CSO-SS-Cy7-Hex/SPION/Srfn. (B) CLSM images and linear profiles of 4T1 cells were used to characterize the overlap degree of mitochondrion green fluorescence of Mito-Tracker and red fluorescence of NIR photosensitizer (scale bar: 5 μm). (C) Morphological characteristics of 4T1 cells after uptake of Cy7-Hex-SS-COOH and CSO-SS-Cy7-Hex/SPION/Srfn self-assemblies and labeled with DAPI (blue) to identify cell nuclei. (scale bar: 5μm). (D) Luciferase labeled 4T1 cells bearing tumor tissue colocalization of the NIR photosensitizer. (scale bar: 5 μm). (E1, E2 and E3) Tumor tissue colocalization confocal magnifying scan and 3D Z-scan of tumor bearing mice. (The arrow points to the height coincidence zone. Scale bar: 5 μm).
Figure 4
Figure 4
Analyses of the mechanism, efficiency, and cellular factors involved in complex self-assemblies mediated ferroptosis. (A) Schematic illustration of ferroptosis mechanism under combined treatment strategy. (B) Transmission electron microscopy of 4T1 cells treated with DMEM and CSO-SS-Cy7-Hex/SPION/Srfn self-assemblies (100 μg/mL, 3 h). (i) arrowheads, cytoplasmic and organelle swelling and plasma membrane rupture; (ii) arrowheads, nuclear atrophy; (iii) arrowheads, chromatin margination; (iv), shrunken mitochondria; (v), mitochondrial ridge decreased or disappeared. A minimum of 104 cells per treatment condition were examined. (C) Western blot analysis of xCT and GPX-4 expression in 4T1 cells after the treatment with (1-6) control, CSO-SS-Cy7-Hex, CSO-SS-Cy7-Hex/SPION, CSO-SS-Cy7-Hex/Srfn, CSO-SS-Cy7-Hex/SPION/Srfn, and CSO-SS-Cy7-Hex/SPION/Srfn with light, respectively. (D) Western blot analysis of xCT and GPX-4 expression in 4T1 cells after treatment with different concentrations of the CSO-SS-Cy7-Hex/SPION/Srfn with light. (E) Immunofluorescence images of GPX-4 in 4T1 tumor tissues after treatment with different self-assemblies. (scale bar: 5 μm). (F1, F2, F3) Cell viability of different self-assemblies treated 4T1 cells, MCF-7 cells, and MDA-MB-231 cells, respectively. (n=6). (G1) Indicates knockdown 4T1 cells, MCF-7 cells and MDA-MB-231 cells were treated with different self-assemblies for 24 hours and MDA levels were assayed (n=3). (G2) 4T1 cells were treated with different self-assemblies for 24 hours and carbonyl protein levels were assayed (n=3). (H, I) Iron and GSH concentrations of different self-assemblies treated 4T1 cells, MCF-7 cells, and MDA-MB-231 cells. (J) Relative cell viability of different self-assemblies treated 4T1 cells after the addition of deferoxamine (DFO, 200 μM), Baicalein (10 μM) and DMEM, respectively.
Figure 5
Figure 5
The mechanism of EMT and the efficiency of FT on EMT breast cancer cells. (A) Schematic illustration of the invasion-metastatic by EMT, which was sensitive to Ferroptosis. The scheme reference to Zhang et al . (B) In vitro scratch assays to test the 4T1 cells migration with or without TGF-β1 stimulation (5 ng/mL; 48 hours). The scale bar represents 200 μm. (C) Morphological changes of 4T1 cells under epithelial, mesenchymal and mesenchymal with FT. The scale bar represents 200 μm. (D) Western blot analysis of EMT markers E-cadherin and snail expression in quiescent or TGF-β1-stimulated 4T1 cells. (E) The MDA levels in TGF-β1-stimulated 4T1 cells after incubated with six groups (DMEM, Paclitaxel, Adriamycin, Gemcitabine, Camptothecin, and CSO-SS-Cy7-Hex/SPION/Srfn with light). (F) showed the cell viability after treatment with different chemotherapeutic drugs before or after TGF-β1 stimulated. (G) The cell viability after treated with complex self-assemblies before or after TGF-β1 stimulated.
Figure 6
Figure 6
In vivo application of oxidation/reduction NIR nanophotosensitizer magnetic complex self-assemblies in mouse. (A) Schematic diagram of administration cycles in mice. (B) Mean blood concentration-time curve of Sprague Dawley female rats after caudal vein administration of CSO-SS-Cy7-Hex/SPION/Srfn complex self-assemblies and free sorafenib (each value represents the mean ± SD, n=6). (C and D) Showed the in vivo tumor magnetic targeting dynamic distribution of CSO-SS-Cy7-Hex/SPION/Srfn complex self-assemblies at different time points in tumor bearing mice monitored by the NIR fluorescence imaging system. The red ring refers to the location of the tumor. It showed the tumor exposing (MF+) (C) or not exposing (MF-) (D) to magnetic fields at 24 h, the red circle indicates an area of tumor position. Ex vivo fluorescence images of isolated organs (heart, liver, spleen, lung, kidney, stomach, and intestine) from the mice at 24 h after administration the complex self-assemblies. Change of mice body weight (E) and tumor volume (F) curves of six different groups (control, CSO-SS-Cy7-Hex, CSO-SS-Cy7-Hex/SPION, CSO-SS-Cy7-Hex/Srfn, CSO-SS-Cy7-Hex/SPION/Srfn, and CSO-SS-Cy7-Hex/SPION/Srfn with light) of tumor-bearing mice after FT (n=5). The irradiation power was 2.6 W/cm2. (G) Photographs of mice taken after treatment (n=5). (H) H&E staining of tumor tissue of six different samples as (E). (scale bar: 200 μm).
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