CHEMICAL ENGINEERING JOURNAL
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2023
·
IF 15.1
Wenhua Wang,Wenhao Wang,Shiwei Jin,Fangqin Fu,Zhengwei Huang,Ying Huang,Chuanbin Wu,Xin Pan
Cisplatin (DDP)-based ferroptosis-apoptosis synergetic therapy is a novel strategy of lung cancer treatment based on the targeted induction of high oxidative stress levels in tumor cells. Nevertheless, the strong antioxidant system in tumor cells and low accumulation at the lesion site result in its low sensitivity as well as systemic side effects. To circumvent the strong antioxidant system, the combination of Reactive Oxygen Species (ROS) generator DDP and a glutathione (GSH) scavenger β-Phenethyl isothiocyanate (PEITC) was a potential strategy. Besides, pulmonary delivery equipped with lung tumor targeting nanoformulations was expected to promote tumor lesions accumulation. Herein, an inhalable core–shell nanocomposite, PEITC-loaded solid lipid nanocores coated with DDP-encapsulated hyaluronic acid (HA) shell (PNDH) based on the strategy of “open pocket and tighten holes” was developed. The nicotinamide adenine dinucleotide phosphate oxidases 4 (NOX4) was upregulated by DDP to “open pocket for ROS” while the PEITC could deplete the GSH to “tighten holes”, preventing ROS consumption. Upon nebulization, improved lung drug accumulation with about 6.7 times higher than intravenous injection and excellent lung retention was exhibited. Equipped with tumor membrane CD44 targeted HA, the tumor recognizing efficiency was elevated about two times. The remarkably enhanced tumor inhibition effect was revealed both in vitro and in vivo, and the PNDH-driven cell damage process was described as a result of mitochondrial dysfunction and osmotic pressure mediated cell membrane broken. Taken together, the rationally designed PNDH enhanced the effectiveness of ferroptosis-apoptosis synergetic therapy by the “open pocket and tighten holes” strategy.
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Frontiers in Genetics
·
2023
·
IF 3.7
Huang Hui,Ye Zhifang,Li Zhengzhao,Wang Bo,Li Ke,Zhou Kai,Cao Huiyuan,Zheng Jiaxuan,Wang Guangji
Identifying effective biomarkers in osteosarcoma (OS) is important for predicting prognosis. We investigated the prognostic value of ferroptosis-related genes (FRGs) in OS. Transcriptome and clinical data were obtained from The Cancer Genome Atlas and Gene Expression Omnibus. FRGs were obtained from the ferroptosis database. Univariate COX regression and LASSO regression screening were performed and an FRG-based prognostic model was constructed, which was validated using the Gene Expression Omnibus cohort. The predictive power of the model was assessed via a subgroup analysis. A nomogram was constructed using clinical markers with independent prognostic significance and risk score results. The CIBERSORT algorithm was used to detect the correlation between prognostic genes and 22 tumor-infiltrating lymphocytes. The expression of prognostic genes in erastin-treated OS cell lines was verified via real-time PCR. Six prognostic FRGs (ACSL5, ATF4, CBS, CDO1, SCD, and SLC3A2) were obtained and used to construct the risk prognosis model. Subjects were divided into high- and low-risk groups. Prognosis was worse in the high-risk group, and the model had satisfactory prediction performance for patients younger than 18 years, males, females, and those with non-metastatic disease. Univariate COX regression analysis showed that metastasis and risk score were independent risk factors for patients with OS. Nomogram was built on independent prognostic factors with superior predictive power and patient benefit. There was a significant correlation between prognostic genes and tumor immunity. Six prognostic genes were differentially expressed in ferroptosis inducer-treated OS cell lines. The identified prognostic genes can regulate tumor growth and progression by affecting the tumor microenvironment.
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Small
·
2022
·Vol. 18
·期 20
·2200330
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IF 15.153
Meng Xu,Haidong Zha,Run Han,Yaxin Cheng,Jiamao Chen,Ludan Yue,Ruibing Wang,Ying Zheng
Nowadays, destruction of redox homeostasis to induce cancer cell death is an emerging anti-cancer strategy. Here, the authors utilized pH-sensitive acetalated β-cyclodextrin (Ac-β-CD) to efficiently deliver dihydroartemisinin (DHA) for tumor ferroptosis therapy and chemodynamic therapy in a synergistic manner. The Ac-β-CD-DHA based nanoparticles are coated by an iron-containing polyphenol network. In response to the tumor microenvironment, Fe 2+ /Fe 3+ can consume glutathione (GSH) and trigger the Fenton reaction in the presence of hydrogen peroxide (H 2 O 2 ), leading to the generation of lethal reactive oxygen species (ROS). Meanwhile, the O O bridge bonds of DHA are also disintegrated to enable ferroptosis of cancer cells. Their results demonstrate that these nanoparticles acted as a ROS generator to break the redox balance of cancer cells, showing an effective anticancer efficacy, which is different from traditional approaches.
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BIOMATERIALS
·
2022
·
IF 15.304
Yue Yu,Zhusheng Huang,Qian Chen,Zhicheng Zhang,Haojie Jiang,Rong Gu,Yitao Ding,Yiqiao Hu
Iron is indispensable for cancer cell survival and cancer cells are more vulnerable to ferroptosis than normal cells. Ferroptosis holds promise for overcoming chemoresistance and inducing tumor immunogenic cell death, which offers new possibilities for cancer immunotherapy. However, the prevalence of immunogenic ferroptosis in cancer cells is diminished because of the high levels of reducing substances within tumor microenvironments. Ferroptosis-needed iron is overdose for livings, which is also an obstacle for effective immune responses. In this study, we construct self-assembled carrier-free nanoscale coordination polymers based on iron and methotrexate (MFe-NCPs). The low-dose-iron-induced immunogenic ferroptosis is obviously enhanced by methotrexate via inhibiting dihydrofolate reductase and abating substance reduction, respectively. Of note, MFe-NCPs sequentially promoted antigen presentation, immune activation, T cell infiltration and boosted the therapeutic effect of immune checkpoint blockade therapy.
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Asian Journal of Pharmaceutical Sciences
·
2022
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IF 9.273
Ziting Zhang,You Ji,Nan Hu,Qinqi Yu,Xinrui Zhang,Jie Li,Fenglei Wu,Huae Xu,Qiyun Tang,Xiaolin Li
Ferroptosis is a novel form of programmed cell death impelled by iron-dependent lipid peroxidation, which may be a potential strategy for cancer therapy. Here we demonstrated for the first time that Resveratrol (RSV), a traditional Chinese medicine (TCM) chemical monomer, could effectually inhibit the growth of colon cancer cells through the ROS-dependent ferroptosis pathway. Mechanistically, RSV evoked the increase of reactive oxygen species and lipid peroxidation in colorectal cancer cells, and eventually lead to ferroptosis. Furthermore, RSV could promote ferroptosis by downregulating the expression of the channel protein solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). To improve the delivery efficiency of RSV, a biomimetic nanocarrier was developed by coating RSV-loaded poly(ε-caprolactone)–poly(ethylene glycol) (PCL-PEG) nanoparticles with erythrocyte membrane ( [email protected] ). The [email protected] provide the possibility to escape macrophage phagocytosis and have a long circulation effect. In addition, when coupled with a tumor-penetrating peptide iRGD, which could trigger enhanced tissue penetration tumor-specifically, the delivery of [email protected] into tumors would be significantly improved results from the in vivo study demonstrated an excellent treatment efficacy for CRC. Altogether, our study highlighted the therapeutic potential of RSV as a ferroptosis-inducing anticancer agent and when loaded into a biomimetic nanoplatform, it might pave the way for the application of RSV loaded nanosystems for colorectal cancer treatment.
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Small
·
2021
·Vol. 17
·期 47
·2102269
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IF 13.281
Xuan Wang,Yuanyuan Zhao,Yan Hu,Yang Fei,Youbo Zhao,Chencheng Xue,Kaiyong Cai,Menghuan Li,Zhong Luo
Ferroptosis is a new form of regulated cell death with significant therapeutic prospect, but its application against drug-resistant tumor cells is challenging due to their ability to effuse antitumor agents via p-glycoprotein (P-gp) and anti-lipid peroxidation alkaline intracellular environment. Herein, an amorphous calcium phosphate (ACP)-based nanoplatform is reported for the targeted combinational ferroptosis/apoptosis therapy of drug resistant tumor cells by blocking the MCT4-mediated efflux of lactic acid (LA). The nanoplatform is fabricated through the biomineralization of doxorubicin-Fe 2+ (DOX-Fe 2+ ) complex and MCT4-inhibiting siRNAs (siMCT4) and can release them to the tumor cytoplasm after the hydrolysis of ACP and dissociation of DOX-Fe 2+ in the acidic lysosomes. siMCT4 can inhibit MCT4 expression and force the glycolysis-generated lactic acid (LA) to remain in cytoplasm for rapid acidification. The nanoplatform-induced remodeling of the tumor intracellular environment can not only interrupt the ATP supply required for P-gp-dependent DOX effusion to enhance H 2 O 2 production, but also increase the overall catalytic efficiency of Fe 2+ for the initiation and propagation of lipid peroxidation. These features could act in concert to enhance the efficacy of the combinational ferroptosis/chemotherapy and prolong the survival of tumor-bearing mice. This study may provide new avenues for the treatment of multidrug-resistant tumors.
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Acta Biomaterialia
·
2021
·
IF 8.947
Shiwei Luo,Di Ma,Ruili Wei,Wang Yao,Xinrui Pang,Ye Wang,Xiangdong Xu,Xinhua Wei,Yuan Guo,Xinqing Jiang,Youyong Yuan,Ruimeng Yang
As a promising new form of non-apoptotic regulated cell death, ferroptosis has potential as an effective supplement to apoptosis-based cancer treatments. However, high intracellular glutathione (GSH) levels and insufficient hydrogen peroxide (H 2 O 2 ) in the tumor limit the efficacy of ferroptosis. Here, we designed a theranostic nanoplatform, named FCS/GCS, by incorporating amphiphilic polymer skeletal (P-SS-D), cinnamaldehyde prodrug (CA-OH) and iron ions (Fe 3+ )/gadolinium ions (Gd 3+ ) via chelation reactions between Fe 3+ /Gd 3+ and polyphenols. When delivered in the tumor microenvironment with high GSH level, the nanoparticles are depolymerized by the poly(disulfide) backbone of P-SS-D. The activated CA consumes the GSH and elevates intracellular H 2 O 2 , followed by a high level of Fenton reaction to generate abundant •OH levels. The generation of reactive oxygen species (ROS) further accelerates CA activation. The GSH consumption by disulfide , CA and Fe 3+ , downregulates GPX4 and generates •OH, which accelerate lipid peroxides (LPO) accumulation and consequently enhances ferroptosis. Additionally, the released Gd 3+ may serve as a contrast agent for tumor-specific T 1 -weighted magnetic resonance imaging (MRI). Thus, the rationally designed FCS/GCS system is a promising strategy for effective MRI-based visual ferroptosis therapy. Statement of significance Ferroptosis is a new form of non-apoptotic regulated cell death and has potential as an effective supplement to apoptosis-based cancer treatment. However, the efficiency of ferroptosis is limited by excessive glutathione level and insufficient hydrogen peroxide level in tumor site. In this study, we fabricate a theranostic nanoplatform (FCS/GCS) to amplify oxidation stress in tumor site for effective ferroptosis-based cancer treatment, and tumor specific magnetic resonance imaging is introduced for supervision. Our nanoplatform may provide a promising strategy for MRI-based visual ferroptosis therapy with high specificity and efficiency.
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JOURNAL OF CONTROLLED RELEASE
·
2021
·
IF 9.776
Hui Xiong,Cheng Wang,Zihan Wang,Haipeng Lu,Jing Yao
Ferroptosis had shown huge potential for antitumor treatment due to its capacity of improving the limited efficiency of traditional antitumor strategies. On the other hand, low confidence in clinical application prospects impeded their development as a result of use of toxic-dose iron. Herein, we prepared a nano-activator (DAR) which was assembled by doxorubicin (DOX), tannic-acid (TA) and IR820 as a photosensitizer to make full use of endogenous iron stored in endo -lysosome, realizing ferroptosis and its related oxidative stress through artificially intracellular positive feedback loop. Interestingly, this process could also promote immunogenic cell death (ICD)-associated immunotherapy through endoplasmic reticulum (ER) stress. After DAR + laser treatment, the intracellular oxidative stress response was intensified. The produced ROS could be effectively distributed in intracellular lysosomes and ERs to facilitate ferroptosis and immunotherapy respectively. The pharmacodynamics study revealed that DAR + laser had excellent antitumor combination therapy efficiency even under the adverse combined drug ratio of DOX and IR820 due to the unique synergism activation effect of DAR mediated ferroptosis-immunotherapy. In summary, our study provided an innovative solution for the development of antitumor treatment based on ferroptosis-immunotherapy.
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JOURNAL OF CONTROLLED RELEASE
·
2021
·
IF 9.776
Jie Yang,Siyu Ma,Rui Xu,Yawen Wei,Jun Zhang,Tiantian Zuo,Zhihua Wang,Huizi Deng,Ning Yang,Qi Shen
Antitumor immunotherapy is limited by low tumor immunogenicity and immunosuppressive microenvironment (TIME), which could be improved by “ROS-ferroptosis-glycolysis regulation” strategy. Herein, a cancer cell membrane coated metal organic framework (MOF) loading with glucose oxidase (GOx) and doxorubicin (DOX) was constructed (denoted as mFe(SS)/DG). Benefiting from the homotypic targeting of cancer cell membrane, the nanoplatform effectively accumulated in tumors. mFe(SS)/DG based on coordination between Fe 3+ and disulfide-bearing ligand scavenged GSH and downregulated glutathione peroxide 4 (GPX4) to trigger ferroptosis. GOx catalyzed glucose to generate abundant H 2 O 2 for enhancing Fenton reaction, resulting in excessive ROS in tumors. The ROS burst simultaneously promoted ferroptosis and inhibited glycolysis. Ferroptosis combined with DOX induced immunogenic cell death (ICD) and released tumor antigens to initiate antitumor immunity. Glycolysis repression remodeled TIME by decreasing lactate to solidify and boost the antitumor immunity. The smart biomimetic nanoplatform integrates tumor metabolism and immunity based on ROS-ferroptosis-glycolysis regulation, providing a potential anti-tumor strategy.
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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.
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FREE RADICAL BIOLOGY AND MEDICINE
·
2021
·
IF 7.376
Rong Fan,Jidong Sui,Xuepeng Dong,Biao Jing,Zhenming Gao
Acute pancreatitis (AP) is an inflammatory disorder associated with multiple organ failure . Pyroptosis and ferroptosis are two newly recognized cell death , and whether pyroptosis and ferroptosis are involved in AP remain largely elusive. The nature compound Wedelolactone (Wed) exhibits strong anti-inflammatory and antioxidant activities , the present study aims to investigate the effect of Wed on AP and unravel whether Wed could protect against AP and relevant lung injury against pyroptosis and ferroptosis. Our results showed that the pyroptosis inhibitor disulfiram or ferroptosis inhibitor ferrostatin-1 significantly alleviated AP and associated lung injury in the taurocholate or caerulein-induced murine AP model. Administration with Wed ameliorated AP and lung injury as evidenced by improved pathological injuries, reduced serum pancreatic digestive enzymes , and proinflammatory cytokines . The in vivo and in vitro data demonstrated that Wed broadly inhibited caspase1/caspase11 activation, reduced mature interleukin-1β (IL-1β) and N-terminal domain of gasdermin D (GSDMD-N) level. The oxidative stress and lipid peroxidation were also suppressed along with the up-regulation of the ferroptosis antagonism marker glutathione peroxidase-4 (GPX4) in Wed treatment group. Wed promoted the transcriptional activity and the selenium sensitivity of GPX4. Moreover, the protective effects of Wed in caerulein-stimulated pancreatic acinar cells were markedly abrogated by the down-regulation of GPX4. Collectively, our data suggest that pyroptosis and ferroptosis play crucial roles in AP. Wed mitigated AP and associated lung injury via GPX4 mediated suppression of pyroptosis and ferroptosis.
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Journal of Materials Chemistry B
·
2020
·Vol. 8
·期 39
·9129-9138
·
IF 5.344
Xiang Xu,Yiwei Chen,Yongxin Zhang,Yansheng Yao,Peng Ji
Intracellular amplification of oxidative stress has been proved to be an effective strategy to induce cancer cell death and the Fenton reaction was regarded as a robust way to generate ROS which are the main cause of amplified oxidative stress. However, current Fenton reaction-inducing agents lacked stability in the bio-environment and failed to exert their ideal catalytic performance. We, hereby, designed an Fe2+-based metal–organic framework (MOF) to deliver Fe2+ to cancer cells to trigger the Fenton reaction and produce excessive ROS. The obtained nano-scale MOF that was constructed by ferrous acetate and organic ligands (BDC-NH2) endowed itself with excellent stability in bio-media and pH responsively degraded itself to release Fe2+ in the acid tumor microenvironment. Such a characteristic demonstrated robust capacity to catalyze the Fenton reaction and produce considerable ROS and thus induced distinct Fe2+-mediated cell ferroptosis. Meanwhile, directly exploiting an Fe2+-based MOF to inhibit and kill cancer cells circumvented the potential adverse effects of loading drugs (like the cardiotoxicity of doxorubicin, and the nephrotoxicity and ototoxicity of cisplatin) and proved to be biocompatible in in vivo experiments. More importantly, observations of the in vivo antitumor experiment attested its impressive inhibition on cancer cells and amelioration on the physical health of treated mice. Our study thus presented a novel and biocompatible ferroptosis strategy to be applied in effective clinical cancer therapy.
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