JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·759
·
IF 12.6
Wang Jia,Wang Zhiji,Li Kaiming,Liu Yue,Tang Chunming,Gao Huimin,Zhou Yupeng,Wang Pengpeng,Wu Haisi,Liu Pengfei,Xu Huae,Li Xiaolin
The clinical therapeutic effect of immune-checkpoint blockade (ICB) on triple-negative breast cancer (TNBC) is limited due to low tumor immunogenicity and tumor immunosuppressive microenvironment. Combination therapies of chemotherapy and ICB have been confirmed efficacious. Herein, poly(L-lysine) dendrimer (PLLD) nanosphere (PR-T@PLLD) integrating chemotherapeutic drug paclitaxel (PTX), natural anti-tumor compound Rubioncolin C (RC) and TIGIT/PVR blocking peptide D TBP-3 is constructed for chemo-immunotherapy of anti-PD-1 resistant tumor. The PEGylation and D TBP-3 modification endow PR-T@PLLD with prolonged blood circulation, enhanced tumor penetration and improved internalization. In the acidic environment of lysosomes, PR-T@PLLD disassembles and releases PTX, RC and D TBP-PLLD. The cell death induced by PTX is significantly enhanced through synergy with RC. RC collaborated PTX also triggers robust immunogenic cell death that efficiently increases tumor infiltration of cytotoxic T lymphocytes (CTLs). Additionally, the released D TBP-PLLD inhibits the exhaustion of CTLs via directly binding to TIGIT and blocking the interaction of TIGIT with its ligand PVR. Thus, PR-T@PLLD arouses a conspicuous anti-tumor immune response via increasing income and reducing expenditure of CTLs. Moreover, PR-T@PLLD reduces the recruitment of immunosuppressive cells in tumor. PR-T@PLLD also inhibits tumor metastasis through evoking immune memory response and inhibiting epithelial-mesenchymal transition and extracellular matrix degradation. In general, PR-T@PLLD is a promising nanoplatform realizing synergistic enhancement of chemo-immunotherapy against anti-PD-1 resistant TNBC. Graphical
研究领域:
纳米医学
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癌症免疫治疗
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药物递送系统
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分子肿瘤学
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免疫学
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DOI
PubMed
高影响因子
Advanced Science
·
2023
·Vol. 10
·期 16
·2206707
·
IF 15.1
Zuqin Chen,Sunfan Li,Fangzhou Li,Cheng Qin,Xianlei Li,Guangchao Qing,Jinjin Wang,Bozhang Xia,Fuxue Zhang,Liangliang Meng,Xing-Jie Liang,Yueyong Xiao
Patients with triple-negative breast cancer (TNBC) have the worst clinical outcomes when compared to other subtypes of breast cancer. Nanotechnology-assisted photothermal therapy (PTT) opens new opportunities for precise cancer treatment. However, thermoresistance caused by PTT, as well as uncertainty in the physiological metabolism of existing phototherapeutic nanoformulations, severely limit their clinical applications. Herein, based on the clinically chemotherapeutic drug mitoxantrone (MTO), a multifunctional nanoplatform (MTO-micelles) is developed to realize mutually synergistic mild-photothermal chemotherapy. MTO with excellent near-infrared absorption (≈669 nm) can function not only as a chemotherapeutic agent but also as a photothermal transduction agent with elevated photothermal conversion efficacy ( ƞ = 54.62%). MTO-micelles can accumulate at the tumor site through the enhanced permeability and retention effect. Following local near-infrared irradiation, mild hyperthermia (<50 °C) assists MTO in binding tumor cell DNA, resulting in chemotherapeutic sensitization. In addition, downregulation of heat shock protein 70 (HSP70) expression due to enhanced DNA damage can in turn weaken tumor thermoresistance, boosting the efficacy of mild PTT. Both in vitro and in vivo studies indicate that MTO-micelles possess excellent synergetic tumor inhibition effects. Therefore, the mild-photothermal chemotherapy strategy based on MTO-micelles has a promising prospect in the clinical transformation of TNBC treatment.
研究领域:
肿瘤学
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纳米医学
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治疗学
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生物医学工程
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 6.7
Xinxin Li,Cheng Wang,Shang Li,Fucheng Yin,Heng Luo,Yonglei Zhang,Zhongwen Luo,Yifan Chen,Siyuan Wan,Lingyi Kong,Xiaobing Wang
Currently available PARP inhibitors are mainly used for the treatment of BRCA-mutated triple-negative breast cancer (TNBC), with a narrow application range of approximately 15% of patients. Recent studies have shown that EZH2 inhibitors have an obvious effect on breast cancer xenograft models and can promote the sensitivity of ovarian cancer cells to PARP inhibitors. Here, a series of new dual-target PARP1/EZH2 inhibitors for wild-BRCA type TNBC were designed and synthesized. SAR studies helped us identify compound 12e , encoded KWLX-12e , with good inhibitory activity against PARP1 (IC 50 = 6.89 nM) and EZH2 (IC 50 = 27.34 nM). Meanwhile, KWLX-12e showed an optimal cytotoxicity against MDA-MB-231 cells (IC 50 = 2.84 μM) and BT-549 cells (IC 50 = 0.91 μM), with no toxicity on normal breast cell lines. KWLX-12e also exhibited good antitumor activity with the TGI value of 75.94%, more effective than Niraparib plus GSK126 (TGI = 57.24%). Mechanistic studies showed that KWLX-12e achieved synthetic lethality indirectly by inhibiting EZH2 to increase the sensitivity to PARP1, and induced cell death by regulating excessive autophagy. KWLX-12e is expected to be a potential candidate for the treatment of TNBC.
研究领域:
肿瘤学
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药理学
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癌症生物学
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分子生物学
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DOI
PubMed
高影响因子
Frontiers in Bioscience-Landmark
·
2025
·Vol. 30
·期 6
·36615
·
IF 3.1
Shanli Wu,Gun Yang,Xiaosha Wen,Yi Lin,Shenglong Wang,Jing Wang,Quan Liu,Dixian Luo
Background:Aldo-keto reductase 1B10 (AKR1B10) is expressed in various malignant tissues. Several studies have highlighted the essential function of AKR1B10 in lipid metabolism and in the detoxification of lipid peroxides. The aim of this research was to explore the role of AKR1B10 in the susceptibility of MDA-MB-231 cells to ferroptosis. These cells serve as a model for triple-negative breast cancer (TNBC).Methods:Lentiviral transfection was used to establish stable cell lines with high or low expression of AKR1B10. Our model of ferroptosis used the ferroptosis activator RSL3, and the specific ferroptosis inhibitor ferrostatin-1 (Fer-1) to rescue cell death. Stable cell lines were treated with the specific inhibitor OSU-T315 directed against phosphorylation of Ser473 in protein kinase B (AKT) and Ser9 in glycogen synthase kinase 3 beta (GSK3β), either alone or in combination with RSL3. A fatty acid stress model was established using palmitic acid (PA) or arachidonic acid (AA), either in the presence or absence of serum starvation and with or without co-treatment with RSL3. Cell viability was evaluated with the cell counting kit-8 (CCK8) assay and lipid peroxidation levels by flow cytometry after staining with C11 BODIPY 581/591. Exploration of the underlying mechanisms was conducted through RNA sequencing and bioinformatics analysis. Western blotting was performed to evaluate protein levels, and quantitative real-time polymerase chain reaction (qPCR) was used to evaluate transcript levels.Results:Western blot and qPCR analyses validated the successful establishment of stable MDA-MB-231 cell lines with and without AKR1B10 overexpression. Cell viability and lipid reactive oxygen species (ROS) assays showed that AKR1B10 suppressed ferroptosis in the RSL3-induced cell death model. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) analyses indicated the phosphatidylinositol 3-kinase (PI3K)-AKT pathway was likely to play a role in the underlying mechanisms. AKR1B10 increased the expression of glutathione peroxidase 4 (GPX4), thus potentially implicating the AKT/GSK3β/nuclear factor erythroid 2-related factor 2 (NRF2)/GPX4 pathway in the mechanism. These changes in protein levels were also observed by Western blot analysis after 6 h of RSL3 treatment. Under the influence of RSL3, the transcript levels of NRF2-related genes including GPX4, ferritin heavy chain 1 (FTH1), heme oxygenase 1 (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO-1) were significantly elevated in the AKR1B10 overexpression cell line, whereas that of prostaglandin-endoperoxide synthase 2 (PTGS2) was significantly reduced. Similar changes were observed after treatment with OSU-T315. AKR1B10 was found to suppress the sensitivity to ferroptosis induced by treatment with OSU-T315, PA, or AA. These phenomena were rescued by the ferroptosis inhibitor Fer-1.Conclusions:AKR1B10 appears to be an important mechanism protecting MDA-MB-231 cells from ferroptosis, possibly through the AKT Ser473/GSK3β Ser9/NRF2/GPX4 pathway. AKR1B10 may be a key factor underlying the therapeutic effect of RSL3 under different exogenous fatty acid microenvironments.
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高影响因子
BIOMATERIALS
·
2025
·
IF 12.9
Zhiwei Yang,Bianfei Shao,Danni Wang,Hongwei Chen,Xiaohui Zhao,Minghui Zeng,Yimin Liu,Qingjian Li,Zhuofei Bi
Radioresistance in triple-negative breast cancer (TNBC) frequently results in local recurrence and distant metastasis, seriously affecting the prognosis of patients. The increased generation of cellular glutathione (GSH) and the upregulation of pro-malignant molecules are two major causes of radioresistance in TNBC, which need to be comprehensively considered in treatment. Herein, a TNBC-targeted reduction-responsive RNA interference (RNAi) nano-radiosensitizer (TREARA) was developed to reverse radioresistance by synergizing GSH depletion with combined inhibition of two promising pro-malignant molecules, Trophoblast cell surface antigen 2 (Trop2) and lncRNA Motor neuron and pancreas homeobox 1–antisense RNA1 (lncMNX1-AS1). Once arriving at the tumor sites with the prolonged circulation maintained by PEGylation, TREARA was rapidly internalized by tumor cells and blocked the Trop2-dominant pro-metastatic signaling through the anti-Trop2 antibody (αTrop2) modified on its surface. Subsequently, in response to the highly concentrated GSH in the cytoplasm, the shell of TREARA containing poly(disulfide amide) polymer (PDSA) was broken, unlashing the loaded lncMNX1-AS1 siRNA (siMNX1-AS1), which would suppress tumor progression by inactivating JAK3/STAT3 signaling. Benefiting from the integration of GSH-scavenging and dual-targeted inhibition of Trop2 and lncMNX1-AS1, TREARA significantly reversed radioresistance and restrained metastasis in murine models. Taken together, TREARA provides a promising comprehensive perspective for refractory radioresistant TNBC treatment.
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高影响因子
International Journal of Nanomedicine
·
2024
·
IF 6.6
Mengqi Wang,Shuting Lan,Mingjun Song,Rongrong Zhang,Wenqi Zhang,Xiaomei Sun,Gang Liu
Introduction The anti-cancer properties of zinc oxide-doped carbon dots (CDs/ZnO) in inhibiting triple-negative breast cancer (TNBC) progression merit more investigation.Methods With citric acid as the carbon source, urea applied as the nitrogen source, and zinc oxide (ZnO) used as a reactive dopant, CDs/ZnO were synthesized by microwave heating in the current study, followed by the characterization and biocompatibility assessments. Subsequently, the anti-cancer capabilities of CDs/ZnO against TNBC progression were evaluated by various biochemical and molecular techniques, including viability, proliferation, migration, invasion, adhesion, clonogenicity, cell cycle distribution, apoptosis, redox homeostasis, metabolome, and transcriptome assays of MDA-MB-231 cells. Additionally, the in vivo anti-cancer potentials of CDs/ZnO against TNBC progression were analyzed using TNBC xenograft mouse models.Results The biocompatibility of CDs/ZnO was supported by the non-significant changes in the pathological and physiological parameters in the CDs/ZnO treated mice, alongside a non-cytotoxic effect of CDs/ZnO on the proliferation of normal cells. Notably, the CDs/ZnO treatments effectively decreased the viability, proliferation, migration, invasion, adhesion, and clonogenicity of MDA-MB-231 cells. Furthermore, the CDs/ZnO treatments induced cell cycle arrest, apoptosis, redox imbalance, metabolome disturbances, and transcriptomic alterations of MDA-MB-231 cells by regulating the MAPK signaling pathway. Additionally, the CDs/ZnO treatments markedly suppressed the in vivo tumor growth in the TNBC xenograft mouse models.Conclusion In this study, we synthesized CDs/ZnO via microwave heating, using citric acid as the carbon source, urea as the nitrogen source, and ZnO as a reactive dopant. We confirmed the biosafety and potent anti-cancer efficacy of CDs/ZnO in inhibiting TNBC progression by disrupting malignant cell behaviors through modulation of the MAPK signaling pathway.
研究领域:
癌症研究
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材料科学
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分子生物学
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生物医学工程
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DOI
PubMed
高影响因子
Materials Today Bio
·
2026
·
IF 11
Shanlingzi Huang,Lu Gao,Yujun Chen,Zhaoming Fu,Ziyou Wang,Yifan Liu,Zhicheng Zhou,Ru Huang,Wen Song,Feifan Zhou
Triple-negative breast cancer (TNBC), characterized by low immunogenicity, is a challenging issue in clinical treatment due to its poor response to various therapies. The transformation of TNBC from a “cold tumor” with low immunogenicity into a “hot tumor” that elicits stronger immune responses is a key research focus. Photodynamic therapy (PDT) has emerged as a promising solution for TNBC treatment because it can effectively induce immunogenic cell death (ICD), which prompts the release of damage-associated molecular patterns (DAMPs) and activates immune responses. The role of MHC-I molecules in antigen presentation is crucial, but TNBC cells often evade immune surveillance by downregulating or losing MHC-I expression. Recent studies have shown that inhibiting the activity of complex II (CII) in the mitochondrial electron transport chain of tumor cells can promote MHC-I expression. Based on this finding, the combination of the PDT photosensitizer PCN-224 with the CII inhibitor 3-nitropropionic acid (3NPA) to form PCN@3NPA has been innovatively developed. Furthermore, modification with hyaluronic acid (HA) enables targeted delivery to TNBC cells that overexpress CD44. PDT induces ICD in tumor cells, releasing large amounts of DAMPs, while the sustained release of 3NPA effectively inhibits CII activity, significantly enhances MHC-I expression, thereby boosting tumor cell immunogenicity. This process significantly improves the recognition and killing of tumor cells by CD8 + T cells, markedly strengthening the body's anti-tumor immune response. This approach offers a novel and promising strategy for efficiently treating not only low-immunogenic TNBC but also other similar tumors, bringing new hope for future clinical treatments.
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高影响因子
BIOORGANIC CHEMISTRY
·
2024
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IF 4.5
Hongwei Han,Minkai Yang,Zhongling Wen,Feng Mei,Qingqing Chen,Yudi Ma,Xiaohui Lai,Yahan Zhang,Rongjun Fang,Tongming Yin,Shucun Sun,Xiaoming Wang,Jinliang Qi,Hongyan Lin,Yonghua Yang
Triple negative breast cancer (TNBC) is associated with a poor prognosis and limited response to traditional chemotherapy, necessitating the exploration of novel treatment approaches. Recent researches have highlighted the interconnected roles of the PI3K/AKT pathway and MAPK pathway in TNBC cells, contributing to the efficacy of treatments. Therefore, the concurrent inhibition of both pathways presents a potential new therapeutic strategy for TNBC patients. This study aimed to evaluate the antitumor efficacy of M17, an AKT allosteric inhibitor and a new synthesized shikonin derivative, both alone and in combination with the MEK inhibitor trametinib. We applied various cellular assays and a subcutaneous 4T1 tumor bearing BALB/c mice model were utilized to assess the in vitro and in vivo antitumor effects. Computational docking and Bio-Layer Interferometry (BLI) were employed to investigate the binding of M17 with AKT. Additionally, flow cytometry, transwell assays, western blotting, and tumor xenograft assays were conducted to explore the potential synergistic mechanisms of the combined therapy. The results demonstrated that M17 exhibited moderate antitumor activity against TNBC cells, but significantly enhanced the apoptotic effects and inhibited proliferation and migration when combined with trametinib. Furthermore, the combination of M17 and trametinib showed even more pronounced antitumor activity in vivo . Mechanistically, the dual therapy synergistically suppressed TNBC by targeting the AKT/mTOR and MEK/ERK signaling pathways and inhibiting epithelial-mesenchymal transition. In conclusion, the findings suggested that the combination of M17 and trametinib holds promise as a synergistic treatment option for TNBC patients.
研究领域:
肿瘤学
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癌症研究
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Heliyon
·
2024
·
IF 3.4
Wen-Juan Tang,Di Xu,Ming-Xing Liang,Guan-Qun Wo,Wen-Quan Chen,Jin-Hai Tang,Wei Zhang
Triple-negative breast cancer (TNBC) is more prone to recurrence and metastasis relative to other subtypes of breast cancer, leading to an extremely poor prognosis. The increasing potential chemoresistance of TNBC patients is mainly due to that tumor cells escape from apoptosis. In recent years, statins have demonstrated extensive anti-tumor effects. It is worth noting that statins have more effective anti-tumor effects on TNBC cells and drug-resistant breast cancer cells. Therefore, this study examines the superior cytotoxic effects of statins on TNBC cell lines and further explores their potential therapeutic mechanisms. We detected different cell phenotypes and found that statins significantly reduced the cell viability of TNBC cells. Specifically, pitavastatin showed an obvious induction in cell death, cell cycle arrest and oxidative stress in TNBC MDA-MB-231 cells. The reversal effect of iron chelator desferrioxamine (DFO) on the morphological and molecular biological changes induced by pitavastatin has revealed a new mode of cell death induced by pitavastatin: ferroptosis. This ferroptotic effect was strengthened by the decreased expression of glutathione peroxidase 4 (GPx4) as well as newly discovered ferroptosis suppressor protein 1 (FSP1). The data showed that ferroptotic death of MDA-MB-231 cells is autophagy-dependent and mediated by the mevalonate pathway. Finally, we found that therapeutic oral doses of statins can inhibit the growth of transplanted tumors, which establishes statins as a potential treatment for TNBC patients. In conclusion, we found pitavastatin could induce autophagy-dependent ferroptosis in TNBC cells via the mevalonate pathway which may become a potential adjuvant treatment option for TNBC patients.
研究领域:
肿瘤学
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药理学
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细胞生物学
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癌症研究
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Yonglei Zhang,Fucheng Yin,Zhongwen Luo,Yiwei Zheng,Shunxin Guo,Sijie Wu,Yuhan Jiang,Long Zheng,Liangliang Ma,Meiting Zou,Xiaobing Wang,Lingyi Kong
Poly(ADP-ribose) polymerase (PARP) inhibitors have been approved and marketed for the treatment of BRCA-mutated breast and ovarian cancers. Recent studies have demonstrated that cyclin-dependent kinase 4/6 (CDK4/6) inhibitors can induce defects in homologous recombination (HR) repair, thereby sensitizing breast cancer cells with HR proficiency to PARP inhibitors through a synthetic lethal mechanism. Here, we report the rational design and synthesis of a potent dual PARP/CDK6 inhibitor 11, which was identified through SAR studies. Compound 11 effectively induces excessive DNA damage and apoptosis in MDA-MB-231 cells, while maintaining robust inhibitory activity against both PARP and CDK6. Additionally, 11 demonstrates excellent antitumor efficacy and antimetastatic properties, with no evident toxicity or side effects observed. Further investigations revealed that 11 could inhibit tumor cell proliferation by modulating the Wnt/β-catenin signaling pathway. In summary, these findings highlight the potential therapeutic advantages of 11, coded with KWZY-11, in treating BRCA wild-type tumors.
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高影响因子
Advanced Science
·
2022
·Vol. 9
·期 32
·2203523
·
IF 17.521
Ming Shen,Chuanrong Chen,Qianqian Guo,Quan Wang,Jinghan Liao,Liting Wang,Jian Yu,Man Xue,Yourong Duan,Jiali Zhang
T-cell engagers (TCEs) represent a breakthrough in hematological malignancy treatment but are vulnerable to antigen escape and lack a vaccination effect. The “immunologically cold” solid tumor presents substantial challenges due to intratumor heterogeneity and an immunosuppressive tumor microenvironment (TME). Here, a methoxy poly(ethylene glycol) (mPEG)-masked CD44×PD-L1/CD3 trispecific T-cell nanoengager loaded with the STING agonist c-di-AMP (CDA) (PmTriTNE@CDA) for the treatment of triple-negative breast cancer (TNBC) is rationally designed. PmTriTNE@CDA shows tumor-specific accumulation and is preferentially unmasked in response to a weakly acidic TME to prevent on-target off-tumor toxicity. The unmasked CD44×PD-L1/CD3 trispecific T-cell nanoengager (TriTNE) targets dual tumor-associated antigens (TAAs) to redirect CD8+ T cells for heterogeneous TNBC lysis while achieving PD-L1 blockade. PmTriTNE synergized with CDA to transform the cold tumor into a hot tumor, eradicate the large established TNBC tumor, and induce protective immune memory in a 4T1 orthotopic tumor model without causing obvious toxicity. PmTriTNE@CDA shows potent efficacy in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. This study serves as a proof-of-concept demonstration of a nanobased TCEs strategy to expand therapeutic combinations that previously could not be achieved due to systemic toxicity with the aim of overcoming TNBC heterogeneity and immunotherapy resistance.
研究领域:
肿瘤学
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免疫学
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纳米医学
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DOI
PubMed
高影响因子
International Journal of Medical Sciences
·
2020
·
IF 2.523
Zhao Qu,Yushan Lin,Daniel Kam-Wah Mok,Qingya Bian,William Chi-Shing Tai,Sibao Chen
Triple-Negative Breast Cancer (TNBC) is a most dangerous breast cancer subtype. The naturally occurring sesquiterpene lactone, arnicolide D (AD), has proven effective against a variety of tumors, however, the inhibitory effects of AD against TNBC and the underlying mechanisms remain unclear. In the present study, two TNBC cell lines (MDA-MB-231 and MDA-MB-468) and an MDA-MB-231 xenograft mouse model were employed to investigate the anti-TNBC effects of AD in vitro and in vivo . Cell viability was assessed by MTT assay. Cell cycle arrest and apoptosis were analyzed by flow cytometry. Protein levels were determined by immunoblotting. In vitro studies demonstrated that AD significantly decreased cell viability, and induced G2/M cell cycle arrest and apoptosis. In vivo assays showed that oral administration of 25 or 50 mg/kg AD for 22 days led to a reduction of tumor weights by 24.7% or 41.0%, without appreciable side effects. Mechanistically, AD inhibited the activation of Akt/mTOR and STAT3 signaling pathways. Based on our findings, AD is a promising candidate for development as an adjunctive therapeutic drug for TNBC.
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
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