CHEMICAL ENGINEERING JOURNAL
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2024
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IF 13.3
Xiangyu Meng,Jiayi Wu,Zunfu Hu,Xiuwen Zheng,Zhifei Wang
Ferroptosis therapy has recently been recognized as a promising strategy for cancer treatment. However, the therapeutic effects of ferroptosis are impaired by insufficient intracellular reactive oxygen species (ROS) production and undesirable drug accumulation. Herein, the metal-phenolic network formed by Cu 2+ and tannic acid (TA) as a gatekeeper coating on the surface of disulfiram (DSF)-loaded nanoscale metal–organic frameworks of Fe-TCPP (TCPP = tetrakis (4-carboxyphenyl) porphyrin) (denoted as DSF/Fe-TCPP@Cu-TA) was constructed to achieve apoptosis-ferroptosis collaborative therapy. The pH-depended Cu-TA complex can be broken to accelerate the release of Cu 2+ , and glutathione (GSH)-initiated DSF/Fe-TCPP degradation promotes the exposure of DSF, Fe 3+ , and TCPP. The in situ reaction of Cu 2+ and DSF can produce bis(diethyldithiocarbamate)-copper (CuET) and is accompanied by hydroxyl radical (·OH) generation for chemotherapy. GSH/TA-mediated Fe 3+ /Fe 2+ conversion can catalyze endogenous hydrogen peroxide (H 2 O 2 ) to produce ·OH, promoting overwhelming lipid peroxides (LPO) accumulation to sensitize the cancer cells to ferroptosis. When irradiated by a 660 nm laser, TCPP ligand encourages the production of 1 O 2 for photodynamic therapy (PDT), which can synergize with CuET-based chemotherapy for enhanced apoptosis. The excess generation of ·OH /CuET/ 1 O 2 in tumor cells indicates that DSF/Fe-TCPP@Cu-TA can be a satisfactory ferroptosis-apoptosis inducer for efficient cancer therapy.
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JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Kaili Deng,Hailong Tian,Tingting Zhang,Yajie Gao,Edouard C. Nice,Canhua Huang,Na Xie,Guoliang Ye,Yuping Zhou
Colorectal cancer (CRC) is a prevalent clinical malignancy of the gastrointestinal system, and its clinical drug resistance is the leading cause of poor prognosis. Mechanistically, CRC cells possess a specific oxidative stress defense mechanism composed of a significant number of endogenous antioxidants, such as glutathione , to combat the damage produced by drug-induced excessive reactive oxygen species (ROS). We report on a new anti-CRC nanoplatform, a multifunctional chemo-photothermal nanoplatform based on Camptothecin (CPT) and IR820, an indocyanine dye. The implementation of a GSH-triggered ferroptosis-integrated tumor chemo-photothermal nanoplatform successfully addressed the poor targeting ability of CPT and IR820 while exhibiting significant growth inhibitory effects on CRC cells. Mechanistically, to offset the oxidative stress created by the broken Se Se bonds, endogenous GSH was continuously depleted, which inactivated GPX4 to accumulate lipid peroxides and induce ferroptosis . Concurrently, exogenously administered linoleic acid was oxidized under photothermal conditions, resulting in an increase in LPO accumulation. With the breakdown of the oxidative stress defense system, chemotherapeutic efficacy could be effectively enhanced. In combination with photoacoustic imaging, the nanoplatform could eradicate solid tumors by means of ferroptosis-sensitized chemotherapy. This study indicates that chemotherapy involving a ferroptosis mechanism is a viable method for the treatment of CRC.
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Discover Oncology
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2024
·Vol. 15
·期 1
·1-11
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IF 2.8
Jiang Xinru,Li Hongdan,Liu Yang
Objective Hepatocellular carcinoma (HCC) is one cancer with high death rates. Nowadays, there are no effective drugs to treat it. Cyclovirobuxine D (CVB-D) is the primary ingredient of the traditional Chinese medicine (TCM) Buxus microphylla . Here, we try to explore the impacts of CVB-D on human HCC cells and explain the potential mechanisms. Methods HepG2 and Huh-7 cells were used for our experiments. The cell viability and half inhibitory concentration (IC50) were detected by MTT assays. The apoptosis ratio was examined by Annexin V-FITC/7AAD staining and flow cytometry (FCM). The Fe 2+ content was examined by ferrous ion content assays. The malondialdehyde (MDA) content was evaluated by lipid peroxidation MDA assays. The reactive oxygen species (ROS) level was examined by the DCFH-DA probe. The expression of apoptotic markers (Bax and Bcl-2) and ferroptosis-related proteins (GPX4 and FSP1) was detected by western blotting. The in vivo curative effect of CVB was explored using xenograft models established in C-NKG mice. Results The cell viability could be inhibited by CVB-D in HepG2 and Huh-7 cells. The IC50 value of CVB-D on HepG2 and Huh-7 cells are 91.19 and 96.29 µM at 48 h, and 65.60 and 72.80 µM at 72 h. FCM showed that the apoptosis rate was increased by CVB-D in HepG2 and Huh-7 cells. Next, ferrous ion content assays showed that the level of Fe 2+ was increased by CVB-D in HepG2 and Huh-7 cells. Then, we found the level of MDA and ROS was increased by CVB-D. And the Fe 2+ promotion by CVB-D could be reversed by Fer-1. Additionally, western blotting assays showed that the expression of GPX4 and FSP1 was inhibited by CVB-D in HepG2 and Huh-7 cells. Moreover, in vivo, CVB-D displayed excellent anticancer effects in HCC tumor-bearing C-NKG mice. Conclusion CVB-D suppresses the growth in HCC cells through ferroptosis.
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2024
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IF 4.2
Wenyuan Yu,Jianghuiwen Lu,Xinqi Huang,Huiru Zhuang,Yumei An,Mingyang Zhang
Background Effective drugs for preventing or treating skin flap necrosis remain elusive. In this study, we investigated the potential protective effect of exendin-4 against skin flap ischemia-reperfusion injury (IRI) through the inhibition of ferroptosis. Method A rat abdomen was constructed with an island skin flap, and the superficial vascular pedicle of the abdominal wall was closed using a vascular clamp, which was removed after 8 h. Before surgery, RSL3 and ferrostatin-1 solutions were intraperitoneally injected. After the surgery, subcutaneous injections of exendin-4 were administered daily. The number of inflammatory cells, mean vascular density, collagen fiber content, and apoptosis and ferroptosis indicators were quantified 24 h after reperfusion. Survival, contraction rate, and blood perfusion of the skin flap were evaluated on days 1, 3, 5, and 7 after reperfusion. Results The flap survival rate was significantly higher in the exendin-4 group than that in the injury group, whereas the contraction rate was lower. Compared with the injury group, the exendin-4 group showed less inflammatory cell infiltration, higher vascular density, and less collagen fiber loss. At the molecular level, the exendin-4 group demonstrated opposite or elevated expression of apoptosis and ferroptosis indicators than those in the injury group, with significantly increased glutathione peroxidase 4 (Gpx4). Ferroptosis inhibitors and agonists enhanced and reversed the protective effects of exendin-4, respectively. Conclusion Exendin-4 alleviates skin flap IRI by upregulating Gpx4 expression to inhibit ferroptosis. Therefore, exendin-4 may serve as a novel clinical treatment for skin flap IRI.
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Biomedical Materials
·
2025
·Vol. 20
·期 2
·025042
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IF 3.7
Hongchao Zhao,Hengcheng Zhu,Yang Du,Mu He,Mao Ding,Fan Cheng
Photodynamic therapy (PDT) holds promise for cancer treatment by generating reactive oxygen species via photosensitizers (PSs) activated by specific wavelengths of light. However, the poor water solubility of PSs and the tumor microenvironment, characterized by high glutathione (GSH) levels and hypoxia, limit its efficacy against hypoxic tumors. To overcome these challenges, we developed a novel nano-reactor, Zr(Cu)-MOF@Au@DHA, to augment PDT-ferroptosis therapy. By incorporating Cu2+ into the porphyrin ring of PCN-224 and decorating it with gold nanoparticles, we enhanced the photocatalytic efficiency of the metal–organic framework (MOF). Additionally, dihydroartemisinin (DHA) was loaded onto the nano-reactor to boost the ferroptosis sensitivity of bladder cancer cells. Both in vitro and in vivo studies confirm that under laser irradiation, Zr(Cu)-MOF@Au@DHA significantly elevates oxidative stress, depletes GSH, and triggers DHA release, sensitizing tumor cells to ferroptosis and enhancing PDT-ferroptosis therapy for bladder cancer. This innovative nano-platform integrates near-infrared light-triggered PDT with chemotherapy to induce ferroptosis, addressing critical limitations in bladder cancer treatment.
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Acta Pharmaceutica Sinica B
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2024
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IF 14.7
Danni Liu,Yaoqi Wang,Qi Sun,Dong Mei,Xiaoling Wang,Yan Su,Jie Zhang,Ran Huo,Yang Tian,Siyu Liu,Shuang Zhang,Chunying Cui
Ferroptosis has received great attention as an iron-dependent programmed cell death for efficient cancer therapy. However, with the accumulation of iron in tumor cells, the antioxidant system is activated by reducing glutathione (GSH) with glutathione peroxidase 4 (GPX4), which critically limits the ferroptosis therapeutic effect. Herein, an iron and GPX4 silencing siRNA (siGPX4) co-encapsulated ferritin nanocage (HFn@Fe/siGPX4) was developed to enhance ferroptosis by disruption of redox homeostasis and inhibition of antioxidant enzyme synergistically. The siGPX4 were loaded into the nanocages by pre-incubated with iron, which could significantly improve the loading efficiency of the gene drugs when compared with the reported gene drug loading strategy by ferritin nanocages. And more iron was overloaded into the ferritin through the diffusion method. When HFn@Fe/siGPX4 was taken up by human breast cancer cell MCF-7 in a TfR1-mediated pathway, the excess iron ions in the drug delivery system could for one thing induce ferroptosis by the production of reactive oxygen species (ROS), for another promote siGPX4 escaping from the lysosome to exert gene silencing effect more effectively. Both the in vitro and in vivo results demonstrated that HFn@Fe/siGPX4 could significantly inhibit tumor growth by synergistical ferroptosis. Thus, the developed HFn@Fe/siGPX4 afforded a combined ferroptosis strategy for ferroptosis-based antitumor as well as a novel and efficient gene drug delivery system.
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ACS Nano
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2024
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IF 15.8
Yu Wang,Qinjun Chen,Yifan Luo,Yangqi Qu,Xuwen Li,Haolin Song,Chufeng Li,Yiwen Zhang,Tao Sun,Chen Jiang
Aberrant energy and substance metabolic pathways of tumor cells critically support tumor cell proliferation by hijacking the resources from nonmalignant cells, thereby establishing a metabolite flow favorable to tumor progression. This metabolic adaptation of tumor cells further modulates the immune landscape, ultimately creating a tumor microenvironment characterized by drug resistance and immunosuppression. The synergistic regulation of energy and substance metabolic pathways might be a good antitumor therapeutic paradigm. However, due to the metabolic convergence, it is crucial to selectively modulate the aberrant metabolism of tumor cells without compromising the functionality of other cells. Small-molecule drugs have the ability to target a wide range of biomolecules for antitumor therapy, but their application is limited by undesirable toxicities. Constructing nanodrug delivery systems can improve their properties and allow for the inclusion of multiple drugs, thereby exerting synergistic antitumor effects. In this study, we developed a two-drug codelivery system using drugs-conjugated multibranched polymers to modulate tumor cell metabolism by exploiting synthetic lethal pathways for safe and effective antitumor therapy. By delivery of adapalene and erastin simultaneously through nanoparticles, the material and energy metabolism of tumor cells can be regulated. This nanoparticle construction achieves tumor tissue targeting and responsive drug release, alters metabolite flow within tumor cells, and effectively kills tumor cells. Additionally, the nanoparticles can reverse the tumor immunosuppressive microenvironment, starting from single-cell regulation to whole-lesion control.
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ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
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2024
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IF 3.8
Haiyan Zhu,Yijing Yang,Yenan Duan,Xin Zheng,Zixiong Lin,Jie Zhou
Sodium aescinate (SA), an active compound found in horse chestnut seeds, is widely used in clinical practice. Recently, the incidence of SA-induced adverse events , particularly renal impairment, has increased. Our previous work demonstrated that SA causes severe nephrotoxicity via nephrocyte ferroptosis ; however, the underlying mechanism remains to be fully elucidated. In the current study, we investigated additional molecular pathways involved in SA-induced nephrotoxicity. Our results showed that SA inhibited cell viability , disrupted cellular membrane integrity, and enhanced reactive oxygen species (ROS), ferrous iron (Fe 2+ ), and malondialdehyde (MDA) levels, as well as lipid peroxidation in rat proximal renal tubular epithelial cell line (NRK-52E) cells. SA also depleted coenzyme Q10 (CoQ10, ubiquinone) and nicotinamide adenine dinucleotide (NADH) and reduced ferroptosis suppressor protein 1 (FSP1) and polyprenyltransferase (coenzyme Q2, COQ2) activity, triggering lipid peroxidation and ROS accumulation in mouse kidneys and NRK-52E cells. The overexpression of COQ2, FSP1, or CoQ10 (ubiquinone) supplementation effectively attenuated SA-induced ferroptosis, whereas iFSP1 or 4-formylbenzoic acid (4-CBA) pretreatment exacerbated SA-induced nephrotoxicity. Additionally, SA decreased nuclear factor-erythroid-2-related factor 2 (Nrf2) levels and inhibited Nrf2 binding to the −1170/-1180 bp ARE site in FSP1 promoter, resulting in FSP1 suppression. Overexpression of Nrf2 or its agonist dimethyl fumarate (DMF) promoted FSP1 expression, thereby improving cellular antioxidant capacity and alleviating SA-induced ferroptosis. These results suggest that SA-triggers renal injury through oxidative stress and ferroptosis, driven by the suppression of the Nrf2/FSP1/CoQ10 axis.
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International Journal of Nanomedicine
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2024
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IF 6.6
Zhenkang Liang,Zehong Chen,Chaowei Zhang,Cui Chen,Wende Yang,Yuxuan Zhang,Hongbo Wei
Purpose Erectile dysfunction (ED) frequently arises as a complication of pelvic surgeries, including rectal and prostate surgery, and has no definitive cure. This study explored whether mitochondria-rich microvesicles (MVs) can be used to treat ED stemming from cavernous nerve injury (CNI) and investigated its potential mechanisms.Methods We isolated MVs and mitochondria (MT) from PC12. The apoptosis rate, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), mitochondrial derived reactive oxygen species (mtROS), iron content, malondialdehyde (MDA) content and endogenous antioxidant system activity of corpus cavernosum smooth muscle cells (CCSMCs) cultured with MVs and MT were detected in vitro. In vivo, twenty-four male Sprague Dawley rats were randomly divided into four groups: sham operation group and CNI group were injected with PBS, MVs and MT respectively. After fourteen days of treatment, the erectile function was measured and penile tissues were collected for histological analysis. Subsequently, inhibition of mitochondria in MV was performed to explore the mechanism of the rescue experiment.Results The CCSMCs, PC12-MVs and PC12-MT were successfully isolated and identified. After MVs culture, apoptosis rate, ROS, mtROS, iron content and MDA content of CCSMCs were significantly decreased, while MMP and the activities of endogenous antioxidant system were increased. MVs transplantation can significantly restore erectile function and smooth muscle content in CNIED rats. The rescue experiment suggested that MVs exerted the above therapeutic effect by transferring mitochondria within it.Conclusion MVs transplantation significantly improve erectile function in CNI ED rats. MVs may play a role in anti-OS and anti-ferroptosis at the transplant site through efficient transfer of mitochondria, providing a potential treatment vehicle for CNI ED.
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ANALYTICAL CHEMISTRY
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2025
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IF 6.7
Jiaheng Yu,Li Song,Guangyang Xu,Wei Li,Shiyi Liu,Han Xie,Jinping Tang,Jinyu Zhu,Xiao Xia Han
Inducing programmed cell death is an efficient strategy for cancer treatments, and a deep understanding of the molecular mechanisms underlying cell death pathways is of significance for the rational design of anticancer drugs. Herein, propiolamide-mediated crosstalk between ferroptosis and apoptosis is investigated. In situ monitoring of reactive oxygen species (ROS) formation and the structural changes of propiolamide compounds is achieved by Raman spectroscopy. The molecular mechanisms of propiolamides in inducing monooxygenase-mediated ROS generation and inhibiting GPX4 activities are revealed. Furthermore, the pro-ferroptotic and pro-apoptotic roles of the propiolamides containing terminal alkynes are verified. This study provides an in situ and label-free strategy for monitoring enzyme–drug interactions and their dynamics. It is a first attempt to study the structural basis of molecular crosstalk through two important enzymes in cell death. This study paves the way for designing novel drugs that are capable of triggering a synergistic contribution of multiple cell death forms to anticancer efficacy.
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ACS Applied Bio Materials
·
2024
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IF 4.6
He Ren,Minchao Hao,Gengqi Liu,Jiexin Li,Zhen Jiang,Wenlu Meng,Yumiao Zhang
Photodynamic therapy (PDT) and ferroptosis show significant potential in tumor treatment. However, their therapeutic efficacy is often hindered by the oxygen-deficient tumor microenvironment and the challenges associated with efficient intracellular drug delivery into tumor cells. Toward this end, this work synthesized perfluorocarbon (PFC)-modified Pluronic F127 (PFC-F127), and then exploits it as a carrier for codelivery of photosensitizer Chlorin e6 (Ce6) and the ferroptosis promoter sorafenib (Sor), yielding an oxygen self-supplying nanoplatform denoted as Ce6-Sor@PFC-F127. The PFCs on the surface of the micelle play a crucial role in efficiently solubilizing and delivering oxygen as well as increasing the hydrophobicity of the micelle surface, giving rise to enhanced endocytosis by cancer cells. The incorporation of an oxygen-carrying moiety into the micelles enhances the therapeutic impact of PDT and ferroptosis, leading to amplified endocytosis and cytotoxicity of tumor cells. Hypotonic saline technology was developed to enhance the cargo encapsulation efficiency. Notably, in a murine tumor model, Ce6-Sor@PFC-F127 effectively inhibited tumor growth through the combined use of oxygen-enhanced PDT and ferroptosis. Taken together, this work underscores the promising potential of Ce6-Sor@PFC-F127 as a multifunctional therapeutic nanoplatform for the codelivery of multiple cargos such as oxygen, photosensitizers, and ferroptosis inducers.
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ACS Omega
·
2024
·
IF 3.7
Boyao Sun,Xuewei Zheng,Xiaoyu Zhang,Huaiyu Zhang,Yang Jiang
Oxaliplatin (Oxa) is a commonly used chemotherapy drug in the treatment of gastric cancer, but its toxic side effects and drug resistance after long-term use have seriously limited its efficacy. Loading chemotherapy drugs with nanomaterials and delivering them to the tumor site are common ways to overcome the above problems. However, nanomaterials as carriers do not have therapeutic functions on their own, and the effect of single chemotherapy is relatively limited, so there is still room for progress in related research. Herein, we construct Oxa@Mil-100(Fe) nanocomposites by loading Oxa with a metal–organic framework (MOF) Mil-100(Fe) with high biocompatibility and a large specific surface area. The pore structure of Mil-100(Fe) is conducive to a large amount of Oxa loading with a drug-loading rate of up to 27.2%. Oxa@Mil-100(Fe) is responsive to the tumor microenvironment (TME) and can release Oxa and Fe3+ under external stimulation. On the one hand, Oxa can inhibit the synthesis of DNA and induce the apoptosis of gastric cancer cells. On the other hand, Fe3+ can clear overexpressed glutathione (GSH) in TME and be reduced to Fe2+, inhibiting the activity of glutathione peroxidase 4 (GPX4), leading to the accumulation of intracellular lipid peroxides (LPO), and at the same time releasing a large number of reactive oxygen species (ROS) through the Fenton reaction, inducing ferroptosis in gastric cancer cells. With the combination of apoptosis and ferroptosis, Oxa@Mil-100(Fe) shows a good therapeutic effect, and the killing effect on gastric cancer cells is obvious. In a nude mouse model of subcutaneous tumor transplantation, Oxa@Mil-100(Fe) shows a significant inhibitory effect on tumor growth, with an inhibition rate of nearly 60%. In addition to its excellent antitumor activity, Oxa@Mil-100(Fe) has no obvious toxic or side effects. This study provides a new idea and method for the combined treatment of gastric cancer.
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