Journal of Materials Chemistry B
·
2024
·
IF 6.1
Mengxia Xu,Yuyang Yun,Changjun Li,Yiling Ruan,Osamu Muraoka,Weijia Xie,Xiaolian Sun
Proteolysis targeting chimeras (PROTACs) is a promising strategy for cancer therapy. However, the always-on bioactivity of PROTACs may lead to non-target toxicity, which restricts their antitumor performance. Here, we developed an X-ray radiation responsive PROTAC nanomicelle (RCNprotac) by covalently conjugating a reported small molecule PROTAC (MZ1) to hydrophilic PEG via a diselenide bond-containing carbon chain, which then self-assembled into a 141.80 ± 5.66 nm nanomicelle. The RCNprotac displayed no bioactivity during circulation due to the occupation of the hydroxyl group on the E3 ubiquitin ligand component and could effectively accumulate at the tumor site owing to the enhanced permeability and retention effect. Upon exposure to X-ray radiation, the radiation-sensitive diselenide bonds were broken to specifically release MZ1 for tumor BRD4 protein degradation. Furthermore, the reduction in the BRD4 protein level could increase the tumor's sensitivity to radiation. RCNprotac showed a synergistic enhancement of antitumor effects both in vitro and in vivo. We believe that this X-ray-responsive PROTAC nanomicelle could provide a new strategy for the X-ray-activated spatiotemporally controlled protein degradation and for the BRD4 proteolysis enhanced tumor radiosensitivity.
研究领域:
癌症治疗
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纳米技术
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放射肿瘤学
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药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Reports Medicine
·
2025
·
IF 10.6
Wenhua Wang,Xin Li,Rui Hu,Liang Dong,Shiyao Pei,Liping Jin,Qian Gao,Xiang Chen,Mingzhu Yin
Immunotherapy shows remarkable benefits in treating melanoma, yet existing approaches achieve limited overall responses. Here, we show that a combination of bromodomain and extra-terminal protein family inhibitor, NHWD-870, and Bacillus Calmette-Guérin vaccine is a promising therapeutic strategy for melanomas. Single-cell transcriptome analyses and functional experiments show that the combination therapy significantly inhibited tumor growth by reprogramming T cells toward an immune-activated state, enhancing their cytotoxicity, preventing their exhaustion, and increasing the recruitment of them into the tumor microenvironment. We identify the molecule, MT1, as a direct downstream target of BRD4, which is effectively suppressed by NHWD-870. Furthermore, our findings are reinforced by a humanized patient-derived xenograft (PDX) model, which exhibits notable antitumor effects in humanized tumor-bearing mice treated with the combination therapy. Our study underscores the immense potential of this therapeutic approach for clinical practice, offering promising prospects in overcoming the limitations of current treatments.
研究领域:
肿瘤学
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免疫学
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分子生物学
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癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TISSUE & CELL
·
2024
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IF 2.7
Lei Zhu,Qingxin Cai,Gang Li,Xiaoming Zou
Objective Gastric precancerous lesions (GPL), characterized by intestinal metaplasia and dysplasia, marks a pivotal juncture in the transformation from gastritis to gastric cancer. Research on GPL could offer fresh perspectives on preventing cancer occurrence. Methods This study employed 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) to establish GPL rat models and knocked BRD4 down in vivo to assess its impact on the lesions and macrophage morphology. Following that, the impacts of BRD4 knockdown on the malignant phenotypes of human gastric epithelial GES-1 cells were determined. Moreover, conditioned medium from macrophage was gathered and used for GES-1 cell culture. The involvement of macrophage polarization in the BRD4 regulatory mechanism in GES-1 cells was assessed. Results This study elucidated that MNNG induced an increase level of BRD4 in the rat models. BRD4 knockdown reduced lesions based on pathological sections and immunohistochemistry to detect proliferative antigens. Western blotting and immunofluorescence showed that BRD4 knockdown suppressed epithelial-mesenchymal transition and macrophage M2 polarization. In in vitro experiments, BRD4 knockdown inhibited the malignant phenotype of GES-1 cells and the differentiation of THP-1 cells into M2 macrophages, respectively. The conditioned medium from M2 macrophages with BRD4 knockdown was co-incubated with GES-1 cells, which attenuated the malignant phenotypes compared with the medium from M2 macrophages. Conclusion: Through in vivo and in vitro experiments, BRD4 upregulation was found to already occur during GPL, affecting macrophage polarization and epithelial cell cancerization. This finding provides an experimental basis for strategies targeting BRD4 inhibition at this critical stage.
研究领域:
肿瘤学
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免疫学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2021
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IF 11.614
Jiao Xue,Yining Zhu,Shuting Bai,Chunting He,Guangsheng Du,Yuandong Zhang,Yao Zhong,Wenfei Chen,Hairui Wang,Xun Sun
Photothermal therapy has been intensively investigated for treating cancer in recent years. However, the long-term therapeutic outcome remains unsatisfying due to the frequently occurred metastasis and recurrence. To address this challenge, immunotherapy has been combined with photothermal therapy to activate anti-tumor immunity and relieve the immunosuppressive microenvironment within tumor sites. Here, we engineered silica-based core‒shell nanoparticles ( [email protected] ), in which silica cores were coated with the photothermal agent polydopamine, and a bromodomain-containing protein 4 (BRD4) inhibitor JQ-1 was loaded in the polydopamine layer to combine photothermal and immune therapy for tumor elimination. Importantly, to improve the therapeutic effect, we increased the surface roughness of the nanoparticles by hydrofluoric acid (HF) etching during the fabrication process, and found that the internalization of [email protected] was significantly improved, leading to a strengthened photothermal killing effect as well as the increased intracellular delivery of JQ-1. In the animal studies, the multifunctional nanoparticles with rough surfaces effectively eradicated melanoma via photothermal therapy, successfully activated tumor-specific immune responses against residual tumor cells, and further prevented tumor metastasis and recurrence. Our results indicated that [email protected] could serve as an innovative and effective strategy for combined cancer therapy.
研究领域:
癌症治疗
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纳米技术
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免疫学
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材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2022
·Vol. 13
·期 1
·1-12
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IF 17.694
Zhai Yansheng,Huang Xiaoyan,Zhang Keren,Huang Yuchen,Jiang Yanlong,Cui Jingwei,Zhang Zhe,Chiu Cookson K. C.,Zhong Weiye,Li Gang
Enzymatic-based proximity labeling approaches based on activated esters or phenoxy radicals have been widely used for mapping subcellular proteome and protein interactors in living cells. However, activated esters are poorly reactive which leads to a wide labeling radius and phenoxy radicals generated by peroxide treatment may disturb redox-sensitive pathways. Herein, we report a photoactivation-dependent proximity labeling (PDPL) method designed by genetically attaching photosensitizer protein miniSOG to a protein of interest. Triggered by blue light and tunned by irradiation time, singlet oxygen is generated, thereafter enabling spatiotemporally-resolved aniline probe labeling of histidine residues. We demonstrate its high-fidelity through mapping of organelle-specific proteomes. Side-by-side comparison of PDPL with TurboID reveals more specific and deeper proteomic coverage by PDPL. We further apply PDPL to the disease-related transcriptional coactivator BRD4 and E3 ligase Parkin, and discover previously unknown interactors. Through over-expression screening, two unreported substrates Ssu72 and SNW1 are identified for Parkin, whose degradation processes are mediated by the ubiquitination-proteosome pathway.
研究领域:
蛋白质组学
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细胞生物学
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分子生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2022
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IF 16.744
Hao Liu,Chao Chen,Haolin Chen,Luoqi Mo,Zhouyi Guo,Binggang Ye,Zhiming Liu
Proteolytic targeting chimeras (PROTACs) are a strategy for protein degradation through proteasome degradation pathway, which has great potential in nano therapy. However, its degradation efficiency of target protein is low, which could not achieve the expected effect, leading to the failure of this tumor treatment. Herein, Two-dimensional (2D) nanosystems (2D-PROTACs: T-ARV) constructed from tantalum telluride (TaTe 2 ) nanosheets loaded with PROTACs (ARV-825) in order to increase the contact probability between the target protein and E3 ligase and enhance the protein degradation performance. It can realize the efficient degradation of Bromodomain Containing 4 (BRD4) and C-MYC, so as to enhance the photothermal and photodynamic therapy of tumors. Importantly, as a photothermal optical coherence tomography (PT-OCT) contrast agent, T-ARV is able to provide micron-resolution three-dimensional images of tumor tissue, guided multimodal tumor therapy. Therefore, the construction of therapeutic strategies for 2D-PROTACs enables effectively improve the degradation efficiency of protacs to target proteins and enhance the therapeutic effect of nano preparations on tumors.
研究领域:
纳米技术
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癌症治疗
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生物医学工程
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光学成像
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分子生物学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Shunzhe Zheng,Meng Li,Wenqian Xu,Jiaxin Zhang,Guanting Li,Hongying Xiao,Xinying Liu,Jianbin Shi,Fengli Xia,Chutong Tian,Ken-ichiro Kamei
The efficacy of DNA-damaging agents, such as the topoisomerase I inhibitor SN38, is often compromised by the robust DNA repair mechanisms in tumor cells, notably homologous recombination (HR) repair. Addressing this challenge, we introduce a novel nano-strategy utilizing binary tumor-killing mechanisms to enhance the therapeutic impact of DNA damage and mitochondrial dysfunction in cancer treatment. Our approach employs a synergistic drug pair comprising SN38 and the BET inhibitor JQ-1. We synthesized two prodrugs by conjugating linoleic acid (LA) to SN38 and JQ-1 via a cinnamaldehyde thioacetal (CT) bond, facilitating co-delivery. These prodrugs co-assemble into a nanostructure, referred to as SJNP, in an optimal synergistic ratio. SJNP was validated for its efficacy at both the cellular and tissue levels, where it primarily disrupts the transcription factor protein BRD4. This disruption leads to downregulation of BRCA1 and RAD51, impairing the HR process and exacerbating DNA damage. Additionally, SJNP releases cinnamaldehyde (CA) upon CT linkage cleavage, elevating intracellular ROS levels in a self-amplifying manner and inducing ROS-mediated mitochondrial dysfunction. Our results indicate that SJNP effectively targets murine triple-negative breast cancer (TNBC) with minimal adverse toxicity, showcasing its potential as a formidable opponent in the fight against cancer.
研究领域:
癌症研究
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药学
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纳米技术
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分子生物学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Jing Huang,Zhuo Yao,Bowen Li,Yuan Ping
Proteolysis-targeting chimera (PROTAC) is emerging as a new strategy to degrade target proteins in a precise way by taking advantage of the cellular ubiquitin-proteasome system. However, the potential cytotoxicity of PROTAC should be avoided to mitigate the off-target degradation of proteins in healthy tissues or cells. To address this issue, we herein present a strategy to cage a PROTAC with 4-(vinyloxy) benzyl carbonate ( MZ1-O ), which can be eliminated through a 3,6-dimethyl-1,2,4,5-tetrazine ( Tz )-mediated inverse electron-demand Diels-Alder (iEDDA) reaction to generate a BRD4 (bromodomain-containing protein 4) degrader, MZ1 . We further propose a dissolvable microneedle-assisted strategy for site-specific activation of MZ1-O that is delivered by a targeted delivery vector through systemic route in vivo , and demonstrate such a bioorthogonal strategy is efficient and precise for tumor treatment. Our study suggests that the bioorthogonal activation of PROTAC-based prodrug offers a highly specific and precise approach for cancer therapy.
研究领域:
药理学
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癌症研究
·
化学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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