MOLECULES
·
2024
·Vol. 29
·期 8
·1845
·
IF 4.2
Sitong Lai,Bing Wang,Kunhui Sun,Fan Li,Qian Liu,Xie-An Yu,Lihe Jiang,Lisheng Wang
The integration of a multidimensional treatment dominated by active ingredients of traditional Chinese medicine (TCM), including enhanced chemotherapy and synergistically amplification of oxidative damage, into a nanoplatform would be of great significance for furthering accurate and effective cancer treatment with the active ingredients of TCM. Herein, in this study, we designed and synthesized four matrine-proteolysis-targeting chimeras (PROTACs) (depending on different lengths of the chains named LST-1, LST-2, LST-3, and LST-4) based on PROTAC technology to overcome the limitations of matrine. LST-4, with better anti-tumor activity than matrine, still degrades p-Erk and p-Akt proteins. Moreover, LST-4 NPs formed via LST-4 self-assembly with stronger anti-tumor activity and glutathione (GSH) depletion ability could be enriched in lysosomes through their outstanding enhanced permeability and retention (EPR) effect. Then, we synthesized LST-4@ZnPc NPs with a low-pH-triggered drug release property that could release zinc(II) phthalocyanine (ZnPc) in tumor sites. LST-4@ZnPc NPs combine the application of chemotherapy and phototherapy, including both enhanced chemotherapy from LST-4 NPs and the synergistic amplification of oxidative damage, through increasing the reactive oxygen species (ROS) by photodynamic therapy (PDT), causing an GSH decrease via LST-4 mediation to effectively kill tumor cells. Therefore, multifunctional LST-4@ZnPc NPs are a promising method for killing cancer cells, which also provides a new paradigm for using natural products to kill tumors.
研究领域:
药学
·
肿瘤学
·
纳米医学
✓ 已验证
DOI
PubMed
高影响因子
Materials Chemistry Frontiers
·
2021
·Vol. 5
·期 5
·2442-2451
·
IF 6.482
Niu Niu,Huipeng Zhou,Na Yang,Dong Wang,Cong Yu
Polymeric nanoparticles that can respond to a specific tumor microenvironment (TME) show great potential as anticancer agents. In this study, a highly water-soluble polymeric nanoparticle BPP was obtained via atom transfer radical polymerization (ATRP). The strong tendency of self-aggregation of the grafted aromatic benzoperylene facilitated the self-assembly of the polymer into nanoparticles. BPP showed strong excimer emission and could chelate with various metal ions with quenched emission. Cu2+ was then chelated with BPP to form BPC nanoparticles, which were subsequently used as chemodynamic therapy agents. After entering into the cancer cells, BPC could deplete GSH and produce Cu+. Cu+ reacted with intracellular H2O2 and generated toxic hydroxyl radicals (˙OH) via the Fenton-like reaction, which had a fast reaction rate in TME. Because of the high GSH and H2O2 concentrations in tumor cells, BPC NPs exhibited selective cytotoxicity to cancer cells. Additionally, the excimer fluorescence of BPC recovered after entering into the cancer cells, denoting the potential for real time tracking/visualization of drug delivery. The in vivo results also demonstrate that BPC NPs efficiently inhibited tumor growth without obvious systemic toxicity. As a novel Cu2+ chelated polymeric nanomaterial responsive to TME, BPC NPs show excellent potential in chemodynamic cancer therapy.
研究领域:
生物医学工程
·
癌症治疗
·
材料科学
✓ 已验证
DOI
高影响因子
MOLECULAR PHARMACEUTICS
·
2023
·
IF 4.9
Zhaomin Tang,Shuting Jiang,Wanlan Tang,Qian He,Huangzhao Wei,Chengyu Jin,Shuai Wang,Hui Zhang
Chemodynamic therapy (CDT) that involves the use of Fenton catalysts to convert endogenous hydrogen peroxide (H2O2) to hydroxyl radicals (·OH) constitutes a promising strategy for cancer therapy; however, insufficient endogenous H2O2 and glutathione (GSH) overexpression render its efficiency unsatisfactory. Herein, we present an intelligent nanocatalyst that comprises copper peroxide nanodots and DOX-loaded mesoporous silica nanoparticles (MSNs) (DOX@MSN@CuO2) and can self-supply exogenous H2O2 and respond to specific tumor microenvironments (TME). Following endocytosis into tumor cells, DOX@MSN@CuO2 initially decomposes into Cu2+ and exogenous H2O2 in the weakly acidic TME. Subsequently, Cu2+ reacts with high GSH concentrations, thereby inducing GSH depletion and reducing Cu2+ to Cu+ Next, the generated Cu+ undergoes Fenton-like reactions with exogenous H2O2 to accelerate toxic ·OH production, which exhibits a rapid reaction rate and is responsible for tumor cell apoptosis, thereby enhancing CDT. Furthermore, the successful delivery of DOX from the MSNs achieves chemotherapy and CDT integration. Thus, this excellent strategy can resolve the problem of insufficient CDT efficacy due to limited H2O2 and GSH overexpression. Integrating H2O2 self-supply and GSH deletion enhances CDT, and DOX-induced chemotherapy endows DOX@MSN@CuO2 with effective tumor growth-inhibiting properties alongside minimal side effects in vivo.
研究领域:
肿瘤学
·
生物医学工程
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2025
·
IF 9.6
Hua Chai,Renpeng Xia,Nan Ouyang,Jingyu Yao,Jiukun Hu,Minxuan Sun,Peng Miao
Reactive oxygen species (ROS) mediated cell damage is one of the most popular and effective ways for cancer therapy. However, overexpressed antioxidant of reduced glutathione (GSH) is always activated in tumor cells, which maintains redox equilibrium. Attempts to deplete GSH and elevate ROS levels can be potent therapeutic strategies. Herein, tumor cell membrane-encapsulated Fe 3 O 4 @MnO and 2′,3′-cyclic GMP-AMP (cGAMP) are prepared as the nanocatalyst for cancer therapy. The ionized Fe 3+ /Fe 2+ redox couple is utilized to initiate the Fenton reaction. Intracellular GSH level can thus be efficaciously controlled, and peroxide oxidation is catalyzed to produce excessive ROS. Meanwhile, cGAMP is released to trigger the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling axis. This targeted activation enhances the recruitment of macrophages, stimulates the secretion of critical pro-inflammatory cytokines, and consequently bolsters the efficacy of innate immune responses within the tumor microenvironment.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nanoscale
·
2020
·Vol. 12
·期 32
·16738-16754
·
IF 6.895
Weidong Fei,Danfei Chen,Hongxia Tang,Chaoqun Li,Weizeng Zheng,Fengying Chen,Qianqian Song,Yunchun Zhao,Yu Zou,Caihong Zheng
Ferroptosis, a cell death path induced by the generation of reactive oxygen species (ROS), will cause the accumulation of lipid peroxides (PL-PUFA-OOH) and achieve potent tumor-regression. However, glutathione (GSH)-dependent glutathione peroxidase 4 (GPx4) can reduce PL-PUFA-OOH and antagonize the ferroptosis inducing effect of ROS. Herein, folate-PEG modified dihydroartemisinin (DHA) loaded manganese doped mesoporous silica nanoparticles (described as nanomissiles) were constructed for integrating the effect of GSH exhaustion and ROS generation. After endocytosis by tumor cells, intracellular GSH triggered the degradation of nanomissiles, which allowed the simultaneous release of DHA and Fenton catalytic Mn2+ due to the redox reaction between the manganese–oxygen bonds and GSH. The degradation would lead to GSH exhaustion, activation of Mn2+-based magnetic resonance imaging (MRI), and DHA-driven ˙OH generation. The GSH-free environment inhibited the activity of GPx4 and enhanced the accumulation of PL-PUFA-OOH oxidized by ˙OH. Furthermore, the cooperative effects suppressed tumor metastasis by destroying the structure of polyunsaturated fatty acids in the cell membranes and showed potent antitumor activity. This innovative ferroptotic therapy integrating the GSH exhaustion and ROS generation will be a promising strategy for cancer therapy.
研究领域:
纳米技术
·
癌症研究
·
磁共振成像
·
诊疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Nano Materials
·
2024
·
IF 5.3
Yujia Luo,Fang Zheng,Yuanyuan Gao,Wenyu Chen,Xinrui Xue,Chujie Xiao,Kun Wei
Chemodynamic therapy (CDT) generating hydroxyl radicals (•OH) by utilizing metal ions reacting with hydrogen peroxide (H2O2) is a highly encouraging strategy for cancer treatment. However, highly expressed GSH in tumor cells severely limits the efficacy of CDT, and CDT alone is also not sufficient to produce excellent antitumor efficiency. Herein, a dual GSH depletion nanosystem (MnO2@PDA@PEG@DOX) was designed and synthesized to achieve synergistic cancer treatment under ultrasound (US) irritation. To achieve an acidic response, dopamine (DA) was loaded onto manganese dioxide, and the water solubility and stability were greatly improved after PEG modification; finally, the loading of doxorubicin (DOX) achieved the combinational therapy. When the nanoparticles arrived at the tumor site, the acidic and high expression of GSH in the tumor microenvironment prompted the degrading of the nanosystem, followed by the release of MnO2 and DOX. The released MnO2 can react with intracellular GSH to produce Mn2+, which realizes chemodynamic therapy by catalyzing H2O2 to generate highly toxic hydroxyl radicals (•OH) at the tumor site; also, the depletion of GSH will significantly promote the level of •OH, improving the efficiency of CDT simultaneously. Moreover, the release of DOX could be boosted by US irradiation, thus enhancing the effect of chemotherapy on DOX and achieving sonodynamic therapy (SDT). Therefore, strategies to enhance CDT efficiency by dual GSH depletion and combining chemotherapy and sonodynamic therapy modalities can provide more ideas and approaches for combination therapy in cancer treatment.
研究领域:
纳米医学
·
肿瘤学
·
生物材料学
✓ 已验证
产品关联
DOI
高影响因子
RSC Advances
·
2023
·Vol. 13
·期 32
·22367-22374
·
IF 3.9
Datian Fu,Yan Wang,Kaiwen Lin,Liangjiu Huang,Jin Xu,Haimei Wu
Although disrupted redox homeostasis has emerged as a promising approach for tumor therapy, most existing photosensitizers are not able to simultaneously improve the reactive oxygen species level and reduce the glutathione (GSH) level. Therefore, designing photosensitizers that can achieve these two aspects of this goal is still urgent and challenging. In this work, an organic activatable near-infrared (NIR) photosensitizer, CyI-S-diCF3, is developed for GSH depletion-assisted enhanced photodynamic therapy. CyI-S-diCF3, composed of an iodinated heptamethine cyanine skeleton linked with a recognition unit of 3,5-bis(trifluoromethyl)benzenethiol, can specifically react with GSH by nucleophilic substitution, resulting in intracellular GSH depletion and redox imbalance. Moreover, the activated photosensitizer can produce abundant singlet oxygen (1O2) under NIR light irradiation, further heightening the cellular oxidative stress. By this unique nature, CyI-S-diCF3 exhibits excellent toxicity to cancer cells, followed by inducing earlier apoptosis. Thus, our study may propose a new strategy to design an activatable photosensitizer for breaking the redox homeostasis in tumor cells.
研究领域:
生物医学工程
·
药学
·
癌症研究
·
化学生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Science & Engineering C-Materials for Biological Applications
·
2021
·
IF 7.328
Boyi Niu,Kaixin Liao,Yixian Zhou,Ting Wen,Guilan Quan,Chuanbin Wu,Xin Pan
Cellular defense system represented by glutathione (GSH) greatly weakens the outcomes of cancer therapy by antioxidation and detoxification. GSH depletion has been proved to be an effective way to enhance the efficacy of reactive oxygen species (ROS)-based therapies and chemotherapy. However, the existing strategies of GSH depletion still face the problems of unclear biosafety and high complexity of multicomponent co-delivery. In this study, we developed a GSH-depleting carrier platform based on disulfide-bridged mesoporous organosilica nanoparticles (MONs) to destroy the cellular defense system for cancer therapy. Responding to the high level of GSH in cancer cells, the disulfide bonds in the framework of MONs could be broken and consumed substantial GSH at the same time. Moreover, this process also promoted the degradation of MONs. In order to evaluate the effect of this platform in cancer therapy, chemotherapeutic drug cisplatin was loaded into MONs ( [email protected] ) to treat drug-resistant non-small cell lung cancer. In vitro and in vivo results indicated that [email protected] efficiently triggered GSH depletion, promoted platinum-DNA adduct formation, and induced cell apoptosis, resulting in significant tumor growth inhibition without marked toxicity. Taken together, the cellular defense system-destroying nanoparticles provide a promising platform for enhanced cancer therapy.
研究领域:
癌症治疗
·
纳米技术
·
药学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2018
·Vol. 9
·期 5
·1-12
·
IF 5.638
Sun Jiahong,Wen Yajie,Zhou Yanying,Jiang Yiming,Chen Yixin,Zhang Huizheng,Guan Lihuan,Yao Xinpeng,Huang Min,Bi Huichang
Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. Inhibition of APAP metabolic activation and promotion in APAP disposition are important to protect against APAP-induced liver injury. Tumor suppressor p53 is traditionally recognized as a surveillance molecule to preserve genome integrity. Recent studies have emerged on discovering its functions in metabolic regulation. Our previous study reported that p53 promoted bile acid disposition and alleviated cholestastic syndrome. Here, we examined the effect of doxorubicin (Dox)-mediated p53 activation on APAP-induced hepatotoxicity in mice and revealed a novel role of p53 in regulating APAP metabolism and disposition. Histopathological and biochemical assessments demonstrated that administration of Dox (10 mg/kg/d) before APAP treatment (400 mg/kg) significantly alleviated APAP-induced hepatotoxicity. Dox treatment prevented APAP-induced GSH depletion and lipid peroxidation. p53-null mice were more susceptible to APAP-induced liver injury. Further, we found that the expression of drug-metabolizing enzymes and transporters CYPs, SULTs and MRPs was regulated by p53. Dox treatment also promoted Nrf2 activation and increased the expression of Nrf2 target genes including GSTα/μ and NQO1, which contribute to APAP detoxification. Overall, this study is the first to demonstrate the protective role of p53 in regulating APAP metabolism and disposition, which provides a potential new therapeutic target for APAP-induced liver injury.
研究领域:
药理学
·
毒理学
·
分子生物学
·
肝病学
✓ 已验证
DOI
PubMed
高影响因子
BIOMATERIALS
·
2020
·
IF 10.317
Shiyan Fu,Ruihao Yang,Lei Zhang,Weiwei Liu,Guangyuan Du,Yang Cao,Zhigang Xu,Hongjuan Cui,Yuejun Kang,Peng Xue
Chemodynamic therapy (CDT), an emerging therapeutic strategy, has been recently exploited for in situ treatment through Fenton or Fenton-like reactions to generate cytotoxic reactive oxygen species (ROS). However, current systems rely significantly on the high local oxygen levels and strongly acidic conditions (pH = 3.0–5.0). Simultaneously, the produced ROS can be rapidly consumed by intracellular glutathione (GSH) in the electron transport chain. Herein, an original and biomimetic [email protected] nanocatalyst was prepared based on the assembly of Au and Pt nanoparticles (NPs) on the surface of hollow CoO nanocapsules . The as-synthesized nanozyme exhibits extremely high stability under physiological conditions , whereas it undergoes spontaneous disintegration in the unique tumor microenvironment (TME). Subsequently, the decomposition products can catalyze a cascade of biochemical reactions to produce abundant ROS without any external stimuli. Thus, the present nanoplatform can increase intracellular ROS levels through continuous supply of H 2 O 2 , relief of local hypoxia and depletion of GSH, which result in remarkable and specific tumor damage both in vitro and in vivo . The findings of this study highlight the promising potential of [email protected] nanocatalyst as a TME-responsive CDT nanomagnet for highly efficient tumor therapy.
研究领域:
纳米技术
·
癌症治疗
·
生物医学工程
·
材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DALTON TRANSACTIONS
·
2020
·Vol. 49
·期 34
·11851-11858
·
IF 4.174
Shuhua Cao,Xuezhao Li,Yong Gao,Fahui Li,Kaoxue Li,Xuanxuan Cao,Yiwen Dai,Lirong Mao,Shanshan Wang,Xishi Tai
A bimetallic Cu(II) complex as a novel antitumor chemodynamic therapy agent with glutathione (GSH) depletion properties is successfully synthesized and well characterized. In tumor cells, the Cu2+ ions of the complex are reduced to Cu+ ions by GSH and then catalyzed by the overexpressed H2O2 to generate highly cytotoxic hydroxyl radicals (˙OH) that kill cancer cells. The complex is quickly taken up by cancer cells and distributed in multiple organelles including mitochondria and the nucleus. The complex demonstrates good cytotoxicity toward various cancer cell lines. However, its toxicity toward normal cells is significantly lower than that toward cancer cells due to the limited expression of H2O2. In addition, the complex could arrest the cell cycle of the G0/G1 phase, thereby inducing apoptosis rather than necrosis.
研究领域:
化学
·
药学
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Biao-Qi Chen,Yu-Hong Shi,Yang Zhang,Da-Gui Zhang,Xiao-Chang Lu,Qin-Xi Xu,Yu-Jing Pan,Ranjith Kumar Kankala,Shi-Bin Wang,Ai-Zheng Chen
Triple-negative breast cancer (TNBC) is a highly aggressive subtype lacking specific molecular targets, rendering conventional therapies ineffective. Key obstacles in treatment include elevated intracellular glutathione (GSH), poor drug penetration, and an immunosuppressive tumor microenvironment. Herein, a four-in-one Janus-type near-infrared (NIR)-driven nanomotor is employed, composed of copper selenide (Cu 2-x Se) asymmetrically coated with disulfide-bridged periodic mesoporous organosilica (PMO) and loaded with doxorubicin (DOX), termed C&P-DOX. Upon NIR irradiation, Cu 2-x Se generates localized hyperthermia, propelling the nanomotor into deep tumor regions due to their asymmetrical structure. After internalization, high GSH triggers disulfide cleavage, promoting GSH depletion, disrupting redox homeostasis, and achieving controlled DOX release. The uniform distribution and effective release of DOX throughout the tumor enhance cytotoxic effects, inducing significant tumor cell apoptosis. In addition, the synergistic mild photothermal therapy and chemotherapy induce immunogenic cell death, releasing damage-associated molecular patterns and tumor-associated antigens that promote dendritic cell maturation and T-cell activation. This process transforms the tumor immunosuppressive microenvironment into an immunogenic environment, enhancing cytotoxic T lymphocyte infiltration and synergizing with PD-L1 antibody therapy to amplify immune responses. The four-pronged C&P-DOX nanomotor effectively penetrates deep tumors, depletes GSH, combines tumor treatment, and enhances immunotherapy outcomes, integrating active synergistic chemo-photothermal-immune therapy for improved TNBC treatment.
研究领域:
纳米医学
·
肿瘤学
·
药学
·
免疫治疗
·
材料科学
·
生物医学工程
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）