Suleixin Yang,Ka Hong Wong,Peng Hua,Chengwei He,Hua Yu,Dan Shao,Zhi Shi,Meiwan Chen
Ferroptosis is a newly discovered non-apoptotic cell death form but its therapeutic efficacy triggered by traditional iron-based nanomaterials or classic drug inducers has been far from satisfactory due to the high glutathione (GSH) level in cancer cells and insufficient lipid peroxide production. Here we reported a ferroptosis/apoptosis combinational therapy by depleting GSH and downregulating GPX4 to disrupt redox homeostasis and amplify ferroptosis-related oxidation effect. In this study, we developed reactive oxygen species (ROS)-responsive serum-resistant nanoparticles with thioketal-crosslinked fluorinated polyethyleneimine 1.8K ( TK PF) as the core, which were wrapped with hyaluronic acid (HA) as the shell ( TK PFH NP) to co-deliver shGPX4 and shMTHFD2 plasmids for cancer treatment. The highly efficient and tumor-selective gene carrier TK PFH NPs revealed outstanding transfection efficiency (∼100 %) and sustained the efficiency (∼50 %) even in media containing 90 % FBS. Mediated by HA, TK PFH NPs actively targeted CD44 receptors, thus enabling efficient uptake by tumor cells and experiencing surface charge conversion to induce subsequent lysosomal escape. Then the TK PF NPs were effectively disintegrated by the abundant ROS in cancer cells, which facilitated the release of plasmids and avoided the cytotoxicity of cationic polymers. shGPX4 plasmid induced ferroptosis by producing ROS and lipid peroxides via downregulating GPX4, while shMTHFD2 triggered apoptosis by modulating NADPH/NADP and depleting GSH of the cancer cells. Moreover, GSH consumption caused by shMTHFD2 indirectly suppressed GPX4 and further augmented ferroptosis, showing synergistic anticancer effect against B16-F10 cells. Taken together, the rationally designed dual-gene loaded TK PFH NPs provided a safe and high-performance platform for enhanced ferroptosis-apoptosis combined anticancer efficacy based on gene therapy. Statement of significance The therapeutic efficacy of ferroptosis has been far from satisfactory due to high GSH level and insufficient lipid peroxide production in cancer cells. Herein, we reported a ferroptosis/apoptosis combinational therapy by depleting GSH and downregulating GPX4 to disrupt redox homeostasis and amplify ferroptosis-related oxidation effect. ROS-responsive serum-resistant nanoparticles were fabricated with thioketal-crosslinked fluorinated PEI 1.8K ( TK PF) as the core and hyaluronic acid (HA) as the shell ( TK PFH NP) to co-deliver shGPX4 and shMTHFD2 plasmids. The shGPX4 plasmid induced ferroptosis by producing ROS and lipid peroxides via downregulating GPX4, while shMTHFD2 triggered apoptosis by modulating NADPH/NADP and depleting GSH. The rationally designed dual-gene loaded TK PFH NPs provided a safe and high-performance platform aimed for enhanced ferroptosis-apoptosis combined anticancer efficacy.
Yanyan Meng,Shaoqing Chen,Pengyin Li,Cheli Wang,Xinye Ni
Melanoma is a highly invasive and lethal skin cancer with a strong tendency to metastasize and has a poor prognosis. Radiotherapy is one of the important treatments for melanoma. In this study, monoglyceride solid lipid nanoparticles (MG SLNs) were wrapped with the B16-F10 cell membrane (B16 CM) for the fabrication of B16@MG. B16@MG had low toxicity and specifically targeted B16-F10 cells. B16-F10 tumor–bearing mouse model showed that indocyanine green (ICG) -loaded B16@MG achieved long-term accumulation in the tumor and facilitated the localization of the tumor boundary. MG SLNs were encapsulated with methyl 5-aminolevulinate (MLA) and desferrioxamine (DFO), and B16 CM was wrapped around their surfaces to obtain B16@MG–MLA–DFO.MLA was metabolized to protoporphyrin IX (PpIX) in the cells and DFO reduced the content of iron ion in the cells, blocked the biotransformation of PpIX, and promoted the accumulation of PpIX in the cells. The results of mitochondrial reactive oxygen species (ROS) and membrane potential detection showed that PpIX enhanced the generation of ROS, caused DNA and mitochondrial damage, and led to the apoptosis of tumor cells under radiotherapy. In B16-F10 tumor–bearing mice, B16@MG–MLA–DFO can improve the efficacy of radiotherapy and allow the integration of diagnosis and treatment.
Yu-Dan Wang,Lu-Sheng Han,Gen-Yue Li,Kai-Li Yang,Yan-Long Shen,Hao Zhang,Jian-Feng Hou,En-Peng Wang
This study was conducted to investigate the differences in chemical composition between red (RGBs) and yellow ginseng berries (YGBs) and their whitening and anti-aging skincare effects. The differences in the chemical composition between RGB and YGB were analyzed by ultra-high-performance liquid chromatography tandem quadrupole electrostatic field orbit trap mass spectrometry (UHPLC-Q-Exactive-MS/MS) combined with multivariate statistics. An aging model was established using UVB radiation induction, and the whitening and anti-aging effects of the two ginseng berries were verified in vitro and in vivo using cell biology (HaCaT and B16-F10 cells) and zebrafish model organisms. A total of 31 differential compounds, including saponins, flavonoids, phenolic acids, and other chemical constituents, were identified between the two groups. Superoxide dismutase (SOD) activity was more significantly increased (p< 0.05) and malondialdehyde (MDA) content was more significantly decreased (p< 0.01) in RGB more than YGB induced by UVB ultraviolet radiation. In terms of whitening effects, YGB was more effective in inhibiting the melanin content of B16-F10 cells (p< 0.01). The results of zebrafish experiments were consistent with those of in vitro experiments and cell biology experiments. The DCFH fluorescence staining results revealed that both ginseng berries were able to significantly reduce the level of reactive oxygen species (ROS) in zebrafish (p< 0.01). Comparison of chemical composition and skin care activities based on RGB and YGB can provide a theoretical basis for the deep development and utilization of ginseng berry resources.
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