Materials Today Bio
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2026
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IF 11
Jiaqi Liu,Wenting Cheng,Hailong Tian,Zhihan Wang,Canhua Huang,Qifu Li
Glioblastoma (GBM), a highly malignant central nervous system tumor, poses a major therapeutic challenge due to the poor blood-brain barrier (BBB) permeability and an immunosuppressive tumor microenvironment. Notably, silymarin, a natural compound known for its anti-inflammatory and liver-protective properties, has emerged as a promising candidate for GBM immunotherapy through the inhibition of glycolysis and induction of mitochondrial damage. In this study, we developed a silymarin-repurposed, site-specific delivery photo-chemotherapy nanoplatform, designed to synergistically suppress mitochondria for efficient GBM immunotherapy. The platform utilizes a self-assembly strategy incorporating brain-targeted lactoferrin (LF), triphenylphosphine-modified chlorin e6 (TCe6), and silymarin. Mechanistically, LF facilitates targeted binding to low-density lipoprotein receptor-related protein-1 (LRP1), enabling BBB penetration and inducing mitochondrial dysfunction in GBM cells through TCe6-mediated intracellular reactive oxygen species (ROS) generation and silymarin-induced glycolysis suppression. This mitochondrial dysfunction triggers the activation of the AMPK pathway, leading to the degradation of programmed cell death ligand-1 (PD-L1) and the activation of the cGAS-STING pathway, thereby enhancing the anti-tumor immune response. As anticipated, this nanoplatform significantly improves BBB permeability and antitumor immunity, providing an innovative drug repurposing strategy for effective GBM immunotherapy.
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Materials Today Bio
·
2025
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IF 10.2
Long Zhou,Qingyu Zhao,Lijuan Gu,Renfu Tian,Yong Li,Xiaoxing Xiong
Background Glioblastoma multiforme (GBM) is the most common and worst-prognosed primary malignant tumor in the central nervous system. Epithelial mesenchymal transition (EMT) is an important cause of postoperative invasion and recurrence in GBM. Due to the presence of the blood-brain barrier, local therapy may be the preferred route for treatment of GBM after surgery. Methods Our objective is to develop an anti- EMT functional hydrogel for post-GBM surgery tamponade. We fabricated self-assembled luteolin nanoparticles (LU NPs) via the solvent evaporation method, and characterized their morphology and particle size using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and dynamic light scattering (DLS). Furthermore, biological evaluations were conducted through CCK-8 assays, EdU staining, flow cytometry for cell cycle analysis, scratch assays, transwell assays and western blot. Ultimately, we constructed a polyvinyl alcohol (PVA) hydrogel loaded with luteolin nanoparticles and validated its therapeutic efficacy in vivo experiments. Results We successfully synthesized LU NPs, which significantly inhibited GBM cell proliferation, as well as GBM cell invasion and migration in vitro. Furthermore, LU NPs downregulated the EMT signaling pathway. We discovered that the observed anti-tumor effects of LU NPs were dependent on the function of β-catenin. Additionally, we successfully constructed a PVA hydrogel loaded with LU NPs (LU@gel). Finally, in the postoperative model of intracranial GBM xenograft in mice, LU@gel effectively suppressed GBM proliferation and EMT, significantly prolonging the survival time of the mice. Conclusions In summary, we have demonstrated that LU@gel exhibits potent anti-GBM effects, primarily attributed to the inhibition of β-catenin-mediated cell proliferation and EMT.
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JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
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2024
·Vol. 43
·期 1
·1-16
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IF 11.4
Li Xing,Sun Shiyu,Zhang Wansong,Liang Ziwei,Fang Yitong,Sun Tianhu,Wan Yong,Ma Xingcong,Zhang Shuqun,Xu Yang,Tian Ruilin
Background Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a poor prognosis. Current treatment options are limited and often ineffective. CAR T cell therapy has shown success in treating hematologic malignancies, and there is growing interest in its potential application in solid tumors, including GBM. However, current CAR T therapy lacks clinical efficacy against GBM due to tumor-related resistance mechanisms and CAR T cell deficiencies. Therefore, there is a need to improve CAR T cell therapy efficacy in GBM. Methods We conducted large-scale CRISPR interference (CRISPRi) screens in GBM cell line U87 MG cells co-cultured with B7-H3 targeting CAR T cells to identify genetic modifiers that can enhance CAR T cell-mediated tumor killing. Flow cytometry-based tumor killing assay and CAR T cell activation assay were performed to validate screening hits. Bioinformatic analyses on bulk and single-cell RNA sequencing data and the TCGA database were employed to elucidate the mechanism underlying enhanced CAR T efficacy upon knocking down the selected screening hits in U87 MG cells. Results We established B7-H3 as a targetable antigen for CAR T therapy in GBM. Through large-scale CRISPRi screening, we discovered genetic modifiers in GBM cells, including ARPC4 , PI4KA , ATP6V1A , UBA1 , and NDUFV1 , that regulated the efficacy of CAR T cell-mediated tumor killing. Furthermore, we discovered that TNFSF15 was upregulated in both ARPC4 and NDUFV1 knockdown GBM cells and revealed an immunostimulatory role of TNFSF15 in modulating tumor-CAR T interaction to enhance CAR T cell efficacy. Conclusions Our study highlights the power of CRISPR-based genetic screening in investigating tumor-CAR T interaction and identifies potential druggable targets in tumor cells that confer resistance to CAR T cell killing. Furthermore, we devised targeted strategies that synergize with CAR T therapy against GBM. These findings shed light on the development of novel combinatorial strategies for effective immunotherapy of GBM and other solid tumors.
CAS / MDL:
研究领域:
肿瘤学
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免疫学
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基因组学
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细胞生物学
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OncoTargets and Therapy
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2022
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IF 4.345
Rong Wang,Danni Deng,Naiyuan Shao,Yuan Xu,Lian Xue,Ya Peng,Yatian Liu,Feng Zhi
Background Glioblastoma multiforme (GBM) is the most malignant primary tumor of the central nervous system and is associated with a very poor prognosis. No further improvements in outcomes have been reported since radiotherapy-temozolomide therapy was introduced. Therefore, developing new agents to treat GBM is important.Aim This study aimed to evaluate the anti-tumor effect of evodiamine (Evo) on GBM cells, and to determine the underlying mechanisms involved.Results According to MTT assay results, Evo significantly inhibited the cell proliferation in a time- and dose-dependent manner. Fluorescence microscopy and flow cytometry analyses revealed that Evo induced cell apoptosis in a concentration-dependent manner. Moreover, Evo induced reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) disruption. Finally, Evo induced apoptosis in cancer cells by suppressing PI3K/AKT signaling and inducing MAPK phosphorylation (p38 and JNK, but not ERK) to regulate apoptotic proteins (Bax, Bcl-2, Cytochrome c, Caspase-3, and PARP).Conclusion In summary, Evo inhibits cell proliferation by inducing cellular apoptosis via suppressing PI3K/AKT and activating MAPK in GBM; these results indicate that Evo may be regarded as a new approach for GBM treatment.
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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ADVANCED FUNCTIONAL MATERIALS
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2024
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IF 18.5
Bin Gu,Xianyan Zeng,Ming Gong,Xiangyu Li,Qian Yu,Zhengzong Tan,Zheqi Lou,Tinghui Jiang,Yu Che,Yiran Ao,Yong Zhu
Glioblastoma multiforme (GBM) is the most aggressive and common adult brain tumor. Current therapies primarily involve surgical resection, followed by chemotherapy and radiotherapy. However, the low survival rate due to high toxicity, side effects, and poor targeting necessitates novel treatments. Post-transcriptional regulation pathways, particularly the regulation of alternative polyadenylation based on the mRNA 3′UTR, play a critical role in cell growth and development and the progression of tumors. Targeting tumor cells and reprogramming the 3′UTR of tumor suppressor genes to achieve post-transcriptional regulation is expected to be a new channel for GBM therapy. Herein, a novel siRNA delivery system is developed based on mesoporous silica nanoparticles: siRNA composite nanoparticles (siRNA CNP). Encapsulation in MSNs overcomes siRNA degradation and cellular entry issues, while lipid bilayer coating improves biocompatibility and stability. Surface-modified nucleic acid aptamer SL1 (Apt-SL1) significantly enhances GBM targeting, offering therapeutic potential. The findings show that siRNA CNP effectively silences the promoter CFIm25 of distal poly(A) in tumor cells, inducing gene reprogramming, inhibiting tumor growth, and promoting apoptosis in nude mice. The siRNA CNP demonstrates a significant effect in reprogramming tumor suppressor genes and treating GBM. It offers a novel and promising therapeutic avenue for GBM.
研究领域:
肿瘤学
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纳米技术
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分子生物学
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癌症治疗
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ACS Nano
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2024
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IF 15.8
Hao Zhang,Li Yang,Mengxiao Han,Yaobao Han,Zhilin Jiang,Qing Zheng,Jun Dong,Tingting Wang,Zhen Li
The currently available immune checkpoint therapy shows a disappointing therapeutic efficacy for glioblastoma multiforme (GBM), and it is of great importance to discover better immune checkpoints and develop innovative targeting strategies. The discovered metabolic immune checkpoint ecto-5-nucleotidase (CD73) in a tumor contributes to its immune evasion due to the dysregulation of extracellular adenosine (ADO), which significantly inhibits the function of antitumor T cells and increases the activity of immunosuppressive cells. Herein, we drastically inhibit the expression of CD73 to reduce the production of ADO by using versatile Au@Cu2–xSe nanoparticles (ACS NPs). ACS NPs can decrease the expression of CD73 by alleviating the tumor hypoxia through their Fenton-like reaction to weaken the ADO-driven immunosuppression for enhancing antitumor T cell infiltration and activity of GBM. The copper ions (Cu2+) released from ACS NPs can chelate with disulfide, leading to the formation of cytotoxic bis(N,N-diethyldithiocarbamate)-copper complex (CuET), which can be combined with radiotherapy to recruit more antitumor T cells to infiltrate into the tumor site. Based on the inhibition of CD73 to promote the infiltration and activity of antitumor T cells, a cascade of enhancing GBM immunotherapy effects can be achieved. The significant increase in CD8+ T and CD4+ T cells within the tumor and the memory T cells in the spleen effectively reduces tumor size by 92%, which demonstrates the excellent efficacy of immunotherapy achieved by a combination of metabolic immune checkpoint CD73 inhibition with chemoradiotherapy. This work demonstrates that modulation of CD73-mediated tumor immunosuppression is an important strategy of improving the outcome of GBM immunotherapy.
研究领域:
肿瘤学
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免疫治疗
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纳米技术
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癌症研究
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JOURNAL OF NANOBIOTECHNOLOGY
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2024
·Vol. 22
·期 1
·1-19
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IF 10.6
Chen Yang,Tian Hailong,Zhang Xiaodian,Nice Edouard C.,Huang Canhua,Zhang Haiyuan,Zheng Shaojiang
Limited drug accumulation and an immunosuppressive microenvironment are the major bottlenecks in the treatment of glioblastoma multiforme (GBM). Herein, we report a copper-coordination driven brain-targeting nanoassembly (TCe6@Cu/TP5 NPs) for site-specific delivery of therapeutic agents and efficient immunotherapy by activating the cGAS-STING pathway and downregulating the expression of PD-L1. To achieve this, the mitochondria-targeting triphenylphosphorus (TPP) was linked to photosensitizer Chlorin e6 (Ce6) to form TPP-Ce6 (TCe6), which was then self-assembled with copper ions and thymopentin (TP5) to obtain TCe6@Cu/TP5 NPs. This nanoassembly effectively accumulated in tumor sites through the copper transport mechanism. Meanwhile, TCe6@Cu/TP5 could induce mitochondrial impairment by photodynamic therapy (PDT) mediated reactive oxygen species (ROS) accumulation and Cu 2+ triggered cuproptosis, resulting in evoking the AMP-activated protein kinase (AMPK) pathway to degrade PD-L1, and activating the cGAS-STING pathway to enhance anti-tumor immunity. Moreover, TP5 significantly promoted the proliferation and differentiation of dendritic cells (DCs) and T lymphocytes to further amplify the cancer immunity cycle. Collectively, our TCe6@Cu/TP5 NPs effectively facilitate drug accumulation and activate systemic antitumor immunity in vitro and in vivo, providing an innovative solution across the BBB that potentiates GBM immunotherapy. Graphical
研究领域:
癌症研究
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纳米技术
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免疫学
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神经科学
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BIOCHEMICAL PHARMACOLOGY
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2023
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IF 5.8
Lin Zhao,Bingling Zhong,Yanyan Zhu,Haoyi Zheng,Xumei Wang,Ying Hou,Jin-Jian Lu,Nana Ai,Xiuli Guo,Wei Ge,Yan-Yan Ma,Xiuping Chen
Glioblastoma multiforme (GBM) is one of the most lethal malignant tumors in the human brain, with only a few chemotherapeutic drugs available after surgery. Nitrovin (difurazone) is widely used as an antibacterial growth promoter in livestock. Here, we reported that nitrovin might be a potential anticancer lead. Nitrovin showed significant cytotoxicity to a panel of cancer cell lines. Nitrovin induced cytoplasmic vacuolation, reactive oxygen species (ROS) generation, MAPK activation, and Alix inhibition but had no effect on caspase-3 cleavage and activity, suggesting paraptosis activation. Nitrovin-induced cell death of GBM cells was significantly reversed by cycloheximide (CHX), N-acetyl-l-cysteine (NAC), glutathione (GSH), and thioredoxin reductase 1 (TrxR1) overexpression. Vitamins C and E, inhibitors of pan-caspase, MAPKs, and endoplasmic reticulum (ER) stress failed to do so. Nitrovin-triggered cytoplasmic vacuolation was reversed by CHX, NAC, GSH, and TrxR1 overexpression but not by Alix overexpression. Furthermore, nitrovin interacted with TrxR1 and significantly inhibited its activity. In addition, nitrovin showed a significant anticancer effect in a zebrafish xenograft model, which was reversed by NAC. In conclusion, our results showed that nitrovin induced non-apoptotic and paraptosis-like cell death mediated by ROS through targeting TrxR1. Nitrovin might be a promising anticancer lead for further development.
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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分子生物学
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