DRUG DELIVERY
·
2025
·
IF 8.1
Jinguo Li,Yuhao Zhang,Changyu Shao,Yining Bai,Puxiu Wang,Tianyang Ren
Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer and is characterized by high invasiveness, rapid recurrence, and poor prognosis. To date, the ferroptosis-combined therapies have exerted their potential in the TNBC treatments via multi-mechanisms. Here, we reported a doxorubicin (DOX)–Fe complex and RSL3 co-loaded liposomes (DOX–Fe/RSL3@LIPs) for ferroptosis-enhanced chemotherapy on TNBC tumors. This nanoformulation performed a uniform spherical structure with a mean particle size of 126.9 nm, a zeta potential of −3.56 mV, and high colloidal stability. The pH-responsive dissociation of DOX–Fe and release of DOX were conducive to drug accumulation in the tumor microenvironment and tumor cells, meanwhile efficiently suppressed free DOX leakage in the blood circulation, potentially reducing the cardiotoxicity of DOX. In vitro cell and in vivo pharmacodynamic studies demonstrated a favorable anticancer effect of the DOX–Fe/RSL3@LIPs on 4T1 tumors by synchronously delivering biologically active DOX, Fe2+, and RSL3 to the tumor sites. DOX induced tumor cell death through a dual pathway of apoptosis/ferroptosis, and promoted the H2O2 generation. The tumor cell ferroptosis was observably enhanced via supplements of the ferrous ions and H2O2, and RSL3-derived GPX4 inhibition to severely destroy the oxidation balance in cells. In this paper, the DOX–Fe/RSL3@LIPs have exerted a synergistic anticancer effect on TNBC by combining ferroptosis and conventional chemotherapy, and made a meaningful exploration of new strategies for TNBC therapy.
研究领域:
肿瘤学
·
纳米医学
·
癌症治疗
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细胞死亡机制
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Wenyan Hao,Nan Sun,Yueyue Fan,Mengyu Chen,Qianqian Liu,Meiyan Yang,Yang Yang,Chunsheng Gao
Ferroptosis therapy and immunotherapy have been widely used in cancer treatment. However, nonselective induction of ferroptosis in tumors is prone to immunosuppression, limiting the therapeutic effect of ferroptosis cancer treatment. To address this issue, this study reports a customized hybrid nanovesicle composed of NK cell-derived extracellular versicles and RSL3-loaded liposomes (hNRVs), aiming to establish a positive cycle between ferroptosis therapy and immunotherapy. Thanks to the enhanced permeability and retention effect and the tumor homing characteristics of NK exosomes, our data indicate that hNRVs can actively accumulate in tumors and enhance cellular uptake. FASL, IFN-γ, and RSL3 are released into the tumor microenvironment, where FASL derived from NK cells effectively lyses tumor cells. RSL3 downregulates the expression of GPX4 in the tumor, leading to the accumulation of LPO and ROS, and promotes ferroptosis in tumor cells. The accumulation of IFN-γ and TNF-α stimulates the maturation of dendritic cells and effectively induces the inactivation of GPX4, promoting lipid peroxidation, making them sensitive to ferroptosis and indirectly promoting the occurrence of ferroptosis. This study highlights the role of the customized hNRV platform in enhancing the effectiveness of synergistic treatment with selective delivery of ferroptosis inducers and immune activation against glioma without causing additional side effects on healthy organs.
研究领域:
肿瘤学
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药理学
·
纳米医学
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DOI
PubMed
高影响因子
Journal of Environmental Sciences
·
2024
·
IF 5.9
Zijuan Qi,Xiaofeng Huang,Jiajun Jing,Wenya Feng,Ming Xu,Li Yan,Ming Gao,Sijin Liu,Xue-Feng Yu
Iron oxide nanoparticles (IONPs) have wide applications in the biomedical field due to their outstanding physical and chemical properties. However, the potential adverse effects and related mechanisms of IONPs in human organs, especially the lung, are still largely ignored. In this study, we found that group-modified IONPs (carboxylated, aminated and silica coated) induce slight lung cell damage (in terms of the cell cycle, reactive oxygen species (ROS) production, cell membrane integrity and DNA damage) at a sublethal dosage. However, aminated IONPs could release more iron ions in the lysosome than the other two types of IONPs, but the abnormally elevated iron ion concentration did not induce ferroptosis. Intriguingly, amino-modified IONPs aggravated the accumulation of intracellular peroxides induced by the ferroptosis activator RSL3 and thus caused ferroptosis in vitro , and the coadministration of amino-modified IONPs and RSL3 induced more severe lung injury in vivo. Therefore, our data revealed that the surface functionalization of IONPs plays an important role in determining their potential pulmonary toxicity, as surface modification influences their degradation behavior. These results provide guidance for the design of future IONPs and the corresponding safety evaluations and predictions.
研究领域:
纳米技术
·
生物医学工程
·
毒理学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2023
·
IF 7.4
Daohui Gong,Xueping Liu,Pengfei Wu,Yue Chen,Yuhang Xu,Zhan Gao,Hang Qian,Guansong Wang,Binfeng He
Macrophage dysfunction is a significant contributor to more than 70 % of sepsis-related deaths, specifically secondary bacterial infections, during the immunosuppression stage of sepsis. Nevertheless, the role of Rab26 in this context remains unclear. In this study, we observed a substantial decrease in Rab26 expression in macrophages during the immunosuppressive phase of sepsis, which was also found to be suppressed by high extracellular levels of HMGB1 . During the progression of sepsis, Rab26 deficiency promotes a polarization shift from the M1 to the M2-like phenotype in macrophages, rendering them susceptible to ferroptosis . Subsequent experimentation has revealed that Rab26 deficiency facilitates the degradation of GPX4, thereby aggravating macrophage ferroptosis through the upregulation of levels of lipid ROS , MDA , and ferrous iron induced by RSL3, a ferroptosis inducer. Additionally, Rab26-deficient mice in the immunosuppressed phase of sepsis exhibit heightened susceptibility to secondary infections, leading to exacerbated lung tissue damage and increased mortality rate. Overall, these findings indicate that Rab26 plays a crucial role in sepsis-induced macrophage immunosuppression by regulating macrophage ferroptosis and polarization. Hence, it represents a potential novel target for sepsis therapy.
研究领域:
免疫学
·
细胞生物学
·
传染病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF GENE MEDICINE
·
2024
·Vol. 26
·期 10
·e3742
·
IF 3.2
Fuyun Zhu,Dezeng Zou,Ping Shi,Lianhua Tang,Dan Wu,Xiaoxue Hu,Fei Yin,Jianhui Liu
Background With its rapidly increasing incidence and prevalence, ulcerative colitis (UC) has become a major global health challenge. Recent evidence suggests that ferroptosis plays a significant role in the development of UC. However, the relationship between ferroptosis and the progression of UC needs to be extensively studied. Methods The differentially expressed genes in UC patients were screened from the GEO database. The ferroptosis-related genes were obtained from FErrDB and GeneCards. The UC subtypes were identified with the R package “CancerSubtype” and evaluated with consensus clustering (CC) to identify gene expression patterns in patients with UC. The key genes were detected with qRT-PCR, Western blot, and immunohistochemistry in vitro and in vivo models. Ferroptosis was identified with western blotting on ferrotic-associated proteins and staining on Fe 2+ with commercial FerroOrange kits. Results Dipeptidyl peptidase 4 (DPP4), also known as CD26, is a potential biomarker for ferroptosis in UC patients. Transcriptome sequencing data showed a positive correlation between decreased DPP4 expression and proinflammatory cytokines such as TNF-α, IL-6, and IL-β, as well as immune cell infiltration in the colon tissues of UC patients. Furthermore, DPP4 was strongly associated with ferroptosis biomarkers, particularly in Subtype 2 of UC. Interestingly, our study also found that DPP4 expression was significantly reduced in RSL3-treated ferroptotic intestinal epithelial cells, more so than in LPS-treated cell models. Inhibition of DPP4 had a significant impact on the expression of ferroptotic biomarkers. Additionally, DPP4 expression was decreased in the colon tissues of DSS-treated mice, and the ferroptosis inhibitor Ferritin-1 effectively counteracted the effects of DSS on immune cell infiltration, colon length, and DPP4 expression. Conclusions DPP4 can serve as a biomarker for ferroptosis in the diagnosis and management of UC. Highlights DPP4-mediated ferroptosis is involved in ulcerative colitis DPP4 is a novel diagnostic biomarker of ulcerative colitis Ferroptosis involves intestinal epithelial cell death in ulcerative colitis
研究领域:
胃肠病学
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分子生物学
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免疫学
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药理学
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产品关联
DOI
PubMed
高影响因子
Fundamental Research
·
2023
·
IF 6.2
Zhuo Cheng,Yan Hu,Yingqi Liu,Xuan Wang,Rui Xue,Kaiyong Cai,Liqi Li,Menghuan Li,Zhong Luo
ABSTRACT Post-resection tumors with microscopic foci and immunosuppressive microenvironments have high risk of recurrence and metastasis but respond poorly to various therapies. Herein, we propose a biomimetic hydrogel as a biocompatible, biodegradable and bioadhesive postoperative dressing that could be formed in situ by NaIO 4 -initiated thiourea-catechol crosslinking after syringe-injection into the resection cavity. The thiourea or catechol-bearing hyaluronic acid (HA) precursors are also separately engineered with phenylboronic acid and β-cyclodextrin (β-CD) groups, potentiating the reversible immobilization of (1S, 3R) RAS-selective lethal 3 (RSL3) and glycosylated granulocyte macrophage-colony stimulating factor (GM-CSF) without invasive chemical reactions. Meanwhile, the interconnected porous superstructure of the hydrogels allows the incorporation and self-regulated delivery of PD-L1 antibody (aPD-L1). RSL3-induced immunogenic ferroptosis and GM-CSF could cooperatively trigger robust adaptive tumor-specific immune responses, while aPD-L1 further alleviates the accumulated immunoresistance of tumor cells due to interferon γ-mediated PD-L1 upregulation, thus stimulating potent local and whole-body antitumor immunity to prevent postoperative tumor recurrence and metastasis. The biomimetic hydrogel may serve as a promising solution for the postoperative treatment of solid tumors.
研究领域:
生物医学工程
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免疫疗法
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癌症研究
·
材料科学
✓ 已验证
产品关联
DOI
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2022
·
IF 5.572
Hui Chen,Lixing Cao,Kai Han,Han Zhang,Jinling Cui,Xuan Ma,Shuang Zhao,Chong Zhao,Shutao Yin,Lihong Fan,Hongbo Hu
Patulin (PAT) is a common food-borne mycotoxin with diverse toxic effects including nephrotoxicity . The induction of oxidative stress is suggested to be a key mechanism contributed to toxicities of PAT. Reduced glutathione (GSH), a sulfhydryl-containing tripeptide , is a key reason for PAT-mediated oxidative stress. Cystine/glutamate antiporter (system x c − )-mediated cystine uptake plays a critical role in maintaining redox balance via promoting GSH biosynthesis. In this study, we addressed if GSH reduction by PAT was associated with inhibition of system x c − -mediated GSH biosynthesis. Results showed that PAT significantly decreased activity of SLC7A11, a core subunit of system x c − , through activating AMPK-mediated formation of beclin1-SLC7A11 complex. Furthermore, PAT promoted ferroptosis induced by a known ferroptosis inducer RSL3 in normal renal cells, and exacerbated folic acid-induced nephrotoxicity in a mouse model of acute kidney injury . The findings of the present study provide new insights into PAT-induced kidney toxicity, and implicate that patients with ferroptosis-associated diseases maybe more susceptible to PAT.
研究领域:
毒理学
·
药理学
·
细胞生物学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
Biomedical Materials
·
2025
·Vol. 20
·期 4
·045029
·
IF 3.7
Danhong Yan,Chaiqiong Guo,Yang Wang,Yan Wei
In cancer treatment, single modalities such as chemotherapy or photothermal therapy (PTT) often face significant limitations, leading to suboptimal therapeutic outcomes. In recent years, the combination of chemotherapy and PTT has garnered significant attention as a promising approach for enhancing cancer treatment efficacy. In this study, we designed a nanodrug delivery system based on black phosphorus nanosheets (BPNS) and Fe3O4 composites, incorporating molecular and magnetic targeting strategies. The system loaded the small-molecule anticancer drug RSL3 and was encapsulated with hepatocellular carcinoma cell membrane proteins to form the Pro@Fe3O4/BPNS-RSL3 composite nanosystem. The goal was to enhance targeted chemo-photothermal combination therapy. The physical and chemical properties, photothermal performance and stability, drug release kinetics, in vitro cellular uptake, cell compatibility, and synergistic therapeutic effects were all evaluated. The results demonstrated that the composite nanosystem exhibited excellent photothermal performance and stability. After 72 h at pH 5.5, the cumulative release of RSL3 reached 69.93%, indicating a faster and higher drug release profile under acidic conditions. In vitro cell uptake experiments showed significantly higher uptake by liver cancer cells (Huh7) compared to normal cells (LO2), suggesting that the system effectively targets liver cancer cells. Additionally, in vitro synergistic therapeutic results revealed that the composite nanosystem reduced the survival rate of liver cancer cells to less than 15%. Western blot analysis further confirmed that the system downregulated the expression of FACL4, Ferritin, and GPX4, thereby promoting the ferroptosis of cancer cells. Overall, the findings highlight that this nanosystem exhibits remarkable cancer cell-killing effects and offers a promising novel strategy for tumor therapy. Its potential for application in cancer treatment is significant, providing a new avenue for more effective and targeted therapies.
研究领域:
纳米医学
·
肿瘤学
·
药学
·
材料科学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2023
·
IF 5.8
Ziwei Liang,Yuhui Wang,Jiapu Wang,Tao Xu,Shilong Ma,Qi Liu,Liqin Zhao,Yan Wei,Xiaojie Lian,Di Huang
Ferroptosis is a novel form of regulated cell death induced by iron-dependent lipid peroxidation imbalance. It has emerged as a promising antitumor therapeutic strategy in recent years. In this work, we successfully synthesized a complex magnetic nanocube Fe 3 O 4 modified with PEI and HA by the thermal decomposition method. While loading a ferroptosis inducer RSL3 inhibited cancer cells through the ferroptosis signal transduction pathway. The drug delivery system could actively target tumor cells through an external magnetic field and HA-CD44 binding. Zeta potential analysis showed that Fe 3 O 4 [email protected] nanoparticles were more stable and uniformly dispersed in tumor acidic environment. Moreover, cellular experiments demonstrated that Fe 3 O 4 [email protected] nanoparticles could significantly inhibit the proliferation of hepatoma cells without a cytotoxic effect on normal hepatic cells. In addition, Fe 3 O 4 [email protected] played a vital role in ferroptosis by accelerating ROS production. The expression of ferroptosis-related genes Lactoferrin, FACL 4, GPX 4 and Ferritin was significantly suppressed with increasing treatment of Fe 3 O 4 [email protected] nanocubes. Therefore, this ferroptosis nanomaterial has great potential in Hepatocellular carcinoma (HCC) therapy.
研究领域:
纳米技术
·
癌症生物学
·
药学
·
分子生物学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2023
·
IF 9.7
Yuan Chen,Zhuo Yao,Peilian Liu,Qida Hu,Yong Huang,Li Ping,Fu Zhang,Honglin Tang,Tao Wan,Yuan Ping,Bowen Li
Chemotherapeutics have been recommended as the standard protocol for inoperable patients with triple-negative breast cancer (TNBC) at advanced stage, yet limited success has been achieved in prolonging survival rates by this monotherapy. A major reason for this failure is the chemo-resistance from traditional apoptotic pathways resulting in poor therapeutic effect. Ferroptosis has become a powerful modality of no-apoptotic cell death, which can effectively evade chemo-resistance in apoptotic pathways. Herein, we propose an active-targeting small-molecular self-assembly nano-prodrug for co-delivery of chemotherapeutics (CPT), Ferrocene (Fc) and GPX4 inhibitor (RSL3) to overcome the chemo-resistance from traditional apoptotic pathways. In this nano-prodrug, the disulfide linkage not only serves as a GSH-responsive trigger, but also exhibits a stable self-assembly behavior that forms nanoparticle . Interestingly, the RSL3 can be loaded during this self-assembly process that forms a three-components nano-prodrug. In tumor environment, the high GSH level can disassemble the nano-prodrug to trigger the release of the parent drug, which can improve the therapeutic effect by synergistic effects of ferroptosis and apoptosis. In different TNBC mice models, the nano-prodrug is encapsulated into RGD-modified phospholipid micelles (DSPE-PEG2000-RGD) and exhibits high anti-tumor and anti-metastasis efficacy, especially in orthotopic models. The application of ferroptosis to assist the enhancement of chemotherapeutics may serve as a promising strategy for TNBC treatment. Statement of significance Chemotherapeutics have been recommended as the standard of care for palliative and adjuvant treatment in patients with triple-negative breast cancer (TNBC), yet limited success has been achieved in prolonging the overall survival of patients by this monotherapy. A major reason for this failure is the chemo-resistance from traditional apoptotic pathways resulting in poor therapeutic effect. Thus, the co-delivery of the apoptosis and ferroptosis drug may overcome or evade the resistance in chemotherapy-induced apoptotic pathways and provide a promising strategy to combat TNBC. In this work, we developed a small-molecular self-assembly nano-prodrug for co-delivery of chemotherapeutics (CPT), Ferrocene (Fc) and ferroptosis resistance inhibitor (RSL3), which could overcome the chemo-resistance and improve the therapeutic effect by synergistic effects of ferroptosis and apoptosis.
研究领域:
肿瘤学
·
药物科学
·
纳米技术
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Lu Wang,Chenyang Ye,Xiangjie Xue,Mingjun Xie,Yicheng Zhi,Xiao Feng,Pengcheng Zhao,Jichun Zhou,Mi Mi,Jinrui Li,Qinhao Gu,Ye Zhao,Jiaxin Chen,Yi Zhou,Yanan Xue,Zexin Fu,Liuyi Zhou,Lulu Chen,Lei Pan,Yi Sun,Linbo Wang,Sufan Wu,Yong He,Ji Wang
Breast reconstruction is essential for improving the appearance of patients after cancer surgery. Traditional breast prostheses are not appropriate for those undergoing partial resections and cannot detect and treat locoregional recurrence. Personalized shape prostheses that can smartly sense tumor relapse and deliver therapeutics are needed. A 3D-printed prosthesis that contains a therapeutic hydrogel is developed. The hydrogel, which is fabricated by crosslinking the polyvinyl alcohol with N1 -(4-boronobenzyl)- N3 -(4-boronophenyl)- N1 , N1 , N3 , N3 -tetramethylpropane-1,3-diaminium, is responsive to reactive oxygen species (ROS) in the tumor microenvironment. Specifically, RSL3, a ferroptosis inducer that is loaded in hydrogels, can trigger tumor ferroptosis. Intriguingly, RSL3 encapsulated in the ROS-responsive hydrogel exerts antitumor effects by increasing the numbers of tumor-infiltrated CD4+ T cells, CD8+ T cells, and M1 macrophages while reducing the number of M2 macrophages. Therefore, this new prosthesis not only allows personalized shape reconstruction, but also detects and inhibits tumor recurrence. This combination of aesthetic appearance and therapeutic function can be very beneficial for breast cancer patients undergoing surgery.
研究领域:
生物医学工程
·
癌症研究
·
组织工程
·
药物递送系统
·
免疫疗法
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Redox Biology
·
2021
·
IF 11.799
Sufang Shui,Zenglu Zhao,Hao Wang,Marcus Conrad,Guoquan Liu
Ferroptosis is primarily triggered by a failure of the glutathione (GSH)-glutathione peroxidase 4 (GPX4) reductive system and associated overwhelming lipid peroxidation, in which enzymes regulating polyunsaturated fatty acid (PUFA) metabolism, and in particular acyl-CoA synthetase long chain family member 4 (ACSL4), are central. Here, we found that exogenous oxygen radicals generated by photodynamic therapy (PDT) can directly peroxidize PUFAs and initiate lipid autoxidation, coinciding with cellular GSH depletion. Different from canonical ferroptosis induced by RSL3 or erastin, PDT-initiated lipid peroxidation and ferroptotis-like cell death is independent of lipoxygenase (ALOXs) and ACSL4. Especially, this form of cell death modality can be triggered in malignant cells insensitive to or acquired resistance to canonical ferroptosis inducers. We also observed a distinct iron metabolism pathway in this PDT-triggered cell death modality, in which cytosolic labile iron is decreased probably due to its relocation to mitochondria. Inhibition of the mitochondrial Ca 2+ and Fe 2+ uniporter (MCU) effectively prevented PDT-triggered lipid peroxidation and subsequent cell death. Therefore, we tentatively term this distinct ferroptosis-like cell death as liperoptosis. Moreover, using the clinically approved photosensitizer Verteporfin, PDT inhibited tumor growth through inducing prevailing ferroptosis-like cell death in a mouse xenograft model. With its site-specific advantages, these findings highlight the value of using PDT to trigger lipid peroxidation and ferroptosis-like cell death in vivo , and will benefit exploring the exact molecular mechanism of immunological effects of PDT in cancer treatment.
研究领域:
肿瘤学
·
细胞生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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