CHEMICAL ENGINEERING JOURNAL
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2023
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IF 15.1
Hui Yu,Haoyi Zhao,Yujie Zhang,Yuemin Hou,Runqing Li,Ting Liang,Yuanyuan Zhang,Cheng Li,Jingjie Zhao,Mingzhen Zhang,Ruifang An
Choriocarcinoma is a malignant tumor caused by aberrant proliferation and excessive invasion of trophoblastic cells in the uterus. Treatment for choriocarcinoma is hampered by severe side effects and drug resistance caused by insufficient delivery of chemotherapeutics. This dilemma can be solved by a novel approach of nanoparticle-based antineoplastic drug delivery through homologous targeting. Therefore, we developed a cancer cell membrane-coated biomimetic nanoreactor (MMC) built on a ferric metal–organic framework (MIL-100) encapsulating methotrexate (MTX) to achieve maximum therapeutic effects with negligible side effects. MMC could specifically target tumor cells and accumulate within tumor sites. MMC showed significant anticancer effects on JEG-3 cells, including inhibiting cell proliferation by cell cycle arrest at G 0 /G 1 stage, and reducing endocrine function and migration ability. Furthermore, OH overproduction by the Fenton reaction caused apoptosis and remarkable chemodynamic therapy (CDT) effects, glutathione scavenging led to intracellular redox dyshomeostasis and lipid peroxidation resulted in ferroptosis. In vivo studies demonstrated satisfactory tumor inhibition effects on tumor-bearing mice without appreciable toxicity. Further transcriptomics analysis revealed that MMC influences multiple pathways in cancer and cell death, including apoptosis and ferroptosis. This elaborately synthesized biomimetic nanoreactor offers a multifunctional reference for cancer therapy by presenting a new strategy for combining chemotherapy with CDT through synergistic apoptosis and ferroptosis.
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高影响因子
ACS Applied Nano Materials
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2023
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IF 5.9
Yuhang Li,Rui Cai,Kang Chen,Yujing Zhang,Xu Chen,Bo Sun,Yu Jiang,Chaochao Tan,Chuang Peng,Yinghui Song,Ling Wu,Sulai Liu
Severe acute pancreatitis (SAP) is a serious inflammatory disease that is often associated with high mortality rate. It tends to trigger a cascade of systemic inflammation that causes damage to multiple organs, such as the lungs and kidneys. Currently, there is no effective treatment plan to reverse the progress of SAP. The occurrence and development of SAP are associated with oxidative stress (OS) and ferroptosis. In this study, the Ca/Fe-based nanozymes are used as multi-enzyme simulants, which can effectively remove the reactive oxygen species and regulate ferroptosis to prevent and treat SAP. Notably, we make two trials for prevention and treatment of SAP. Under the condition of good biocompatibility, the Ca/Fe-based nanozymes effectively reduce the levels of serum pancreatitis-related biomarkers and inflammatory factors which involved in local and systemic inflammatory response. Moreover, the Ca/Fe nanozymes significantly increase the level of ferroptosis regulator of glutathione peroxidase 4 (GPx4) and ferritin heavy chain 1 (FTH1) in pancreas. These results demonstrate that the Ca/Fe-based nanozymes not only alleviate SAP but also mitigate subsequent multi-organ damage, thus providing an effective strategy of Ca/Fe nanozymes for treating SAP-related disorders in clinical research.
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CHEMICAL ENGINEERING JOURNAL
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2023
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IF 15.1
Qi Meng,Jia Tan,Weifang Tong,Changxiao Chen,Zhendong Liu,Sainan Liu,Meifang Wang,Ziyong Cheng,Binbin Ding,Ping'an Ma,Jun Lin
Chemodynamic therapy (CDT) is an antitumor strategy based on the Fenton response. However, the mild acidity in the tumor microenvironment (TME) limits the efficiency of the Fenton response. Lactic acid has the potential to regulate pH in TME by regulating its metabolism. α-cyano-4-hydroxycinnamic acid (CHCA) can block lactate transport and induce lactate accumulation in cells, thus enhancing intracellular acidity. Nevertheless, CHCA is insoluble in water and the existing nanodrug delivery systems have complex synthesis and low drug-loading. Herein, we use Fe 3+ and CHCA to form ultrahigh drug-loading supramolecular nanoparticles (FC NPs) by an ultrafast self-assembly strategy at room temperature for only 5 min. Polyethylene glycol (PEG) modified FC (FCP) NPs undergo lactate metabolism regulation-enhanced CDT in tumor cells to generate toxic hydroxyl radicals to induce apoptosis. Besides, glutathione is consumed and glutathione peroxidase 4 is down-regulated to induce ferroptosis due to the oxidation of Fe 3+ . In vitro and in vivo experiments show FCP induced synergetic effect of CDT and ferroptosis as well as the excellent therapeutic effect compared with either CHCA or Fe 3+ alone. We believe that the ideal design of the CHCA supramolecular nanosystem will provide more revelations on the future research about CDT and lactate metabolism therapy.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2023
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IF 9.9
Yuyun Ye,Hongli Yu,Bohan Chen,Yifan Zhao,Bai Lv,Guanghe Xue,Yong Sun,Jie Cao
Photodynamic therapy (PDT), as a promising strategy in cancer treatment that utilizes photosensitizers (PSs) to produce reactive oxygen species, has been widely used for eliminating cancer cells under specific wavelength light irradiation. However, the low aqueous solubility of PSs and special tumor microenvironments (TME), such as high glutathione (GSH) and tumor hypoxia remain challenges towards PDT for hypoxic tumor treatment. To address these problems, we constructed a novel nanoenzyme for enhanced PDT-ferroptosis therapy by integrating small Pt nanoparticles (Pt NPs) and near-infrared photosensitizer CyI into iron-based metal organic frameworks (MOFs). In addition, hyaluronic acid was adhered to the surface of the nanoenzymes to enhance the targeting ability. In this design, MOFs act not only as a delivery vector for PSs, but also a ferroptosis inducer. Pt NPs stabilized by MOFs were functioned as an oxygen (O 2 ) generator by catalyzing hydrogen peroxide into O 2 to relieve tumor hypoxia and increase singlet oxygen generation. In vitro and in vivo results demonstrated that under laser irradiation, this nanoenzyme could effectively relive the tumor hypoxia and decrease the level of GSH, resulting in enhanced PDT-ferroptosis therapy against hypoxic tumor. The proposed nanoenzymes represent an important advance in altering TME for improved clinical PDT-ferroptosis therapy, as well as their potential as effective theranostic agents for hypoxic tumors.
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PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2023
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IF 7.5
Zhangnian Liu,Shiquan Gan,Lingyun Fu,Yini Xu,Shengquan Wang,Guangqiong Zhang,Di Pan,Ling Tao,Xiangchun Shen
1,8-Cineole, the main component of volatile oil in aromatic plants, has diverse pharmacological properties, including antioxidant, anti-inflammatory, and anti-cancer properties. Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus (DM). Here, we investigated the protective effect of 1,8-cineole on DR and found that 1,8-cineole treatment could alter the expression of several genes in both high glucose (HG)-induced ARPE-19 cells and retinal tissues of DM mice, as well as inhibit ferroptosis. Subsequent investigations into the molecular mechanisms underlying this inhibition revealed that expression of thioredoxin-interacting protein (TXNIP) was significantly upregulated while that of peroxisome proliferator-activated receptor γ (PPAR-γ) was significantly downregulated in HG-induced ARPE-19 cells, and treatment with 1,8-cineole could effectively reverse these changes. Treatment with a PPAR-γ pharmacological agonist (rosiglitazone), alone or combined with 1,8-cineole, significantly inhibited the transcription of TXNIP and ferroptosis in HG-induced ARPE-19 cells. Conversely, pretreatment with GW9662, a PPAR-γ inhibitor, upregulated the transcription and expression of TXNIP in HG-induced ARPE-19 cells; 1,8-cineole failed to reverse this upregulated expression. To explore these relationships, we constructed a PPAR-γ adenovirus shRNA to elucidate the effect of 1,8-cineole on the negative regulation of TXNIP by PPAR-γ. Taken together, the present findings indicate that HG-induced ferroptosis in retinal tissue plays an essential role in the pathogenesis of DR, which can be ameliorated by 1,8-cineole.
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高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2023
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IF 5.1
Xinyu Qian,Lin Zhu,Mengzhen Xu,Haoli Liu,Xinyan Yu,Qiuyue Shao,Jing Qin
Small cell lung cancer (SCLC) is a subtype of lung cancer with a very poor overall survival rate due to its extremely high proliferation and metastasis predilection. Shikonin is an active ingredient extracted from the roots of Lithospermum erythrorhizon, and exerts multiple anti-tumor functions in many cancers. In the present study, the role and underlying mechanism of shikonin in SCLC were investigated for the first time. We found that shikonin effectively suppressed cell proliferation , apoptosis , migration, invasion, and colony formation and slightly induced apoptosis in SCLC cells. Further experiment indicated the shikonin could also induced ferroptosis in SCLC cells. Shikonin treatment effectively suppressed the activation of ERK, the expression of ferroptosis inhibitor GPX4 , and elevated the level of 4-HNE, a biomarker of ferroptosis. Both total ROS and lipid ROS were increased, while the GSH levels were decreased in SCLC cells after shikonin treatment. More importantly, our data identified that the function of shikonin was dependent on the up-regulation of ATF3 by performing rescue experiments using shRNA to silence the expression of ATF3, especially in the total and lipid ROS accumulaiton. Xenograft model was established using SBC-2 cells, and the results revealed that shikonin also significantly inhibited tumor growth by inducing ferroptosis. Finally, our data further confirmed that shikonin activated ATF3 transcription by impairing the recruitment of HDAC1 mediated by c-myc on the ATF3 promoter , and subsequently elevating of histone acetylation . Our data documented that shikonin suppressed SCLC by inducing ferroptosis in a ATF3-dependent manner. Shikonin upregulated the expression of ATF3 expression via promoting the histone acetylation by inhibiting c-myc-mediated HDAC1 binding on ATF3 promoter.
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高影响因子
ACS Nano
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2023
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IF 17.1
Fangqin Fu,Wenhao Wang,Linjing Wu,Wenhua Wang,Zhengwei Huang,Ying Huang,Chuanbin Wu,Xin Pan
Lung cancer with the highest mortality poses a great threat to human health. Ferroptosis therapy has recently been raised as a promising strategy for lung cancer treatment by boosting the reactive species (ROS) production and lipid peroxidation (LPO) accumulation intracellularly. However, the insufficient intracellular ROS level and the unsatisfactory drug accumulation in lung cancer lesions hamper the efficacy of ferroptosis therapy. Here, an inhalable biomineralized liposome LDM co-loaded with dihydroartemisinin (DHA) and pH-responsive calcium phosphate (CaP) was constructed as a ferroptosis nanoinducer for achieving Ca2+-burst-centered endoplasmic reticulum (ER) stress enhanced lung cancer ferroptosis therapy. Equipped with excellent nebulization properties, about 6.80-fold higher lung lesions drug accumulation than intravenous injection made the proposed inhalable LDM an ideal nanoplatform for lung cancer treatment. The Fenton-like reaction mediated by DHA with peroxide bridge structure could contribute to intracellular ROS production and induce ferroptosis. Assisted by DHA-mediated sarco-/endoplasmic reticulum calcium ATPase (SERCA) inhibition, the initial Ca2+ burst caused by CaP shell degradation triggered the Ca2+-mediated intense ER stress and subsequently induced mitochondria dysfunction to further boost ROS accumulation, which strengthens ferroptosis. The second Ca2+ burst occurred as a result of Ca2+ influx through ferroptotic pores on cell membranes, thus sequentially constructing the lethal “Ca2+ burst-ER stress-ferroptosis” cycle. Consequently, the Ca2+-burst-centered ER stress enhanced ferroptosis process was confirmed as a cell swelling and cell membrane disruption process driven by notable intracellular ROS and LPO accumulation. The proposed LDM showed an encouraging lung retention property and extraordinary antitumor ability in an orthotropic lung tumor murine model. In conclusion, the constructed ferroptosis nanoinducer could be a potential tailored nanoplatform for nebulization-based pulmonary delivery and underscore the application of Ca2+-burst-centered ER stress enhanced lung cancer ferroptosis therapy.
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高影响因子
JOURNAL OF CONTROLLED RELEASE
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2023
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IF 10.8
Chuang Yang,Zheng Chen,Min Wei,Shen Hu,Mengyuan Cai,Nan Wang,Yunan Guan,Fangyuan Li,Qiang Ding,Daishun Ling
Ferroptosis has recently become an attractive strategy to combat the chemoresistance of cancer cells, but the intracellular ferroptosis defense system greatly challenges the efficient ferroptosis induction. Herein, we report a ferrous metal-organic framework-based nanoagent (FMN) that inhibits the intracellular upstream glutathione synthesis and induces self-amplified ferroptosis of cancer cells, for reversing chemoresistance and boosting chemotherapy. The FMN is loaded with SLC7A11 siRNA (siSLC7A11) and chemotherapeutic doxorubicin (DOX), which shows enhanced tumor cell uptake and retention, thus ensuring the effective DOX delivery and tumor intracellular iron accumulation. Importantly, the FMN simultaneously catalyzes the iron-dependent Fenton reaction and triggers the siSLC7A11-mediated suppression of upstream glutathione synthesis for intracellularly self-amplified ferroptosis, which further inhibits P-glycoprotein activity for DOX retention, and regulates the expression of Bcl-2/Bax to reverse the apoptotic resistance state of tumor cells. The FMN-mediated ferroptosis is also demonstrated in ex vivo patient-derived tumor fragment platform. Consequently, FMN successfully reverses cancer chemoresistance and achieves a highly efficient in vivo therapeutic efficacy in MCF7/ADR tumor-bearing mice. Our study provides a self-amplified ferroptosis strategy via inhibiting intracellular upstream glutathione synthesis, which is effective to reverse cancer chemoresistance.
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高影响因子
ACS Nano
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2018
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IF 13.709
Tao Liu,Wenlong Liu,Mingkang Zhang,Wuyang Yu,Fan Gao,Chuxin Li,Shi-Bo Wang,Jun Feng,Xian-Zheng Zhang
Non-apoptotic ferroptosis is of clinical importance because it offers a solution to the inevitable biocarriers of traditional apoptotic therapeutic means. Inspired by industrial electro-Fenton technology featured with electrochemical iron cycling, we construct ferrous-supply-regeneration nanoengineering to intervene tumorous iron metabolism for enhanced ferroptosis. Fe3+ ion and naturally derived tannic acid (TA) spontaneously form a network-like corona onto sorafenib (SRF) nanocores. The formed SRF@FeIIITA nanoparticles can respond to a lysosomal acid environment with corona dissociation, permitting SRF release to inhibit GPX4 enzyme for ferroptosis initiation. TA is arranged to chemically reduce the liberated and the ferroptosis-generated Fe3+ to Fe2+, offering iron redox cycling to, thus, effectively produce lipid peroxide required in ferroptosis. Sustained Fe2+ supply leads to long-term cytotoxicity, which is identified to be specific to H2O2-overloaded cancer cells but minimal in normal cells. SRF@FeIIITA-mediated cell death proves to follow the ferroptosis pathway and strongly inhibits tumor proliferation. Moreover, SRF@FeIIITA provides a powerful platform capable of versatile integration between apoptosis and non-apoptosis means. Typically, photosensitizer-adsorbed SRF@FeIIITA demonstrates rapid tumor imaging owing to the acid-responsive fluorescence recovery. Together with ferroptosis, imaging-guided photodynamic therapy induces complete tumor elimination. This study offers ideas about how to advance anticancer ferroptosis through rational material design.
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高影响因子
BRAIN RESEARCH BULLETIN
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2019
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IF 3.103
Bin Chen,Zhenghong Chen,Mingjian Liu,Xiaorong Gao,Yijun Cheng,Yongxu Wei,Zhebao Wu,Derong Cui,Hanbing Shang
Intracerebral hemorrhage (ICH) is a devastating subtype of stroke because it has few viable therapeutic options to intervene against primary or second brain injury. Recently, evidence has suggested that ferroptosis, a nonapoptotic form of cell death, is involved in ICH. In this study, we examined whether ICH-induced neuron death is partly ferroptotic in humans and assessed its temporal and spatial characteristics in mice. Furthermore, the ferroptosis inhibitor ferrostatin-1 (Fer-1) was used to examine the role of ferroptosis after ICH. Fold changes in ferroptosis-related gene expression, intracellular iron levels, malondialdehyde (MDA) levels, and both protein levels and cellular localization of cyclooxygenase-2 (COX-2) were measured to monitor ferroptosis. Transmission electron microscopy (TEM) was also performed to examine the ultrastructure of cells after ICH. We found that the expression level of prostaglandin-endoperoxide synthase (PTGS2) was increased in both in vitro and in vivo ICH models; by comparison, expression level of RPL8 was increased in human brain tissue. In mice, iron and MDA levels were significantly increased 3 h after ICH; COX-2 levels were increased at 12 h after ICH and peaked at 3 days after ICH; COX-2 colocalized with NeuN (a neuronal biomarker); and TEM showed that shrunken mitochondria were found at 3 h, 3 days, and 7 days after ICH. Moreover, ICH-induced neurological deficits, memory impairment and brain atrophy were reduced by Fer-1 treatment. Our results demonstrated that neuronal ferroptosis occurs during the acute phase of ICH in brain areas distant from the hematoma and that inhibition of ferroptosis by Fer-1 exerted a long-term cerebroprotective effect.
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高影响因子
BIOMATERIALS
·
2024
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IF 12.8
Mengyao Chen,Xiaohan Tong,Yanting Sun,Chunyan Dong,Chen Li,Chunhui Wang,Minyi Zhang,Yixuan Wen,Pinting Ye,Ruihao Li,Jie Wan,Shujing Liang,Shuo Shi
As an iron dependent regulatory cell death process driven by excessive lipid peroxides (LPO), ferroptosis is recognized as a powerful weapon for pancreatic cancer (PC) therapy. However, the tumor microenvironment (TME) with hypoxia and elevated glutathione (GSH) expression not only inhibits LPO production, but also induces glutathione peroxidase 4 (GPX4) mediated LPO clearance, which greatly compromise the therapeutic outcomes of ferroptosis. To address these issues, herein, a novel triple-enhanced ferroptosis amplifier (denoted as Zal@HM-PTBC) is rationally designed. After intravenous injection, the overexpressed H 2 O 2 /GSH in TME induces the collapse of Zal@HM-PTBC and triggers the production of oxygen and reactive oxygen species (ROS), which synergistically amplify the degree of lipid peroxidation (broaden sources). Concurrently, GSH consumption because of the degradation of the hollow manganese dioxide (HM) significantly weakens the activity of GPX4, resulting in a decrease in LPO clearance (reduce expenditure). Moreover, the loading and site-directed release of zalcitabine further promotes autophagy-dependent LPO accumulation (enhance effectiveness). Both in vitro and in vivo results validated that the ferroptosis amplifier demonstrated superior specificity and favorable therapeutic responses. Overall, this triple-enhanced LPO accumulation strategy demonstrates the ability to facilitate the efficacy of ferroptosis, injecting vigorous vitality into the treatment of PC.
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高影响因子
CHEMICAL ENGINEERING JOURNAL
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2024
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IF 13.3
Yanxuan Xiao,Caiyong Song,Hongping Ye,Dan Li,Jiayi Shi,Xiaoke Huang,Qianming Chen,Rui Liu
Radiation-induced oral mucositis (RIOM) is a common complication among patients undergoing radiotherapy. Ionizing radiation (IR) has been shown to induce the excessive production of reactive oxygen species (ROS) and ferroptosis, both of which play critical roles in the development of RIOM. This study fabricates a novel detachable dissolvable microneedle patch DC@MNs for the therapy of RIOM. The nano-enzyme Ceria nanoparticles (Ceria NPs) at the top of needle tips can scavenge ROS and enhance penetration capability of DC@MNs. Additionally, the microneedles (MNs) incorporate deferoxamine (DFO), a known ferroptosis inhibitor, to form a combined therapeutic strategy for RIOM. Cell viability assays demonstrate that the combination of DFO and Ceria NPs effectively mitigates IR-induced cell death. Furthermore, in vivo studies using rat RIOM models further confirm that DC@MNs can penetrate the mucosal epithelium, thereby facilitating drug delivery. Finally, measurement of intracellular ROS, lipid peroxidation, and ferrous ion levels reveals that the DC@MNs protect oral mucosal cell through ROS scavenging and ferroptosis inhibition. This study provides a novel radiation protection strategy and highlights its potential applicability in drug delivery to oral mucosal for patients receiving radiotherapy.
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