Acta Pharmaceutica Sinica B
·
2019
·
IF 5.808
Fangfang Li,Zongliang Liu,Heyuan Sun,Chunmei Li,Wenyan Wang,Liang Ye,Chunhong Yan,Jingwei Tian,Hongbo Wang
Gliomas are the most common primary intracranial neoplasms among all brain malignancies, and the microtubule affinity regulating kinases (MARKs) have become potential drug targets for glioma. Here, we report a novel dual small-molecule inhibitor of MARK3 and MARK4, designated as PCC0208017. In vitro, PCC0208017 strongly inhibited kinase activity against MARK3 and MARK4, and strongly reduced proliferation in three glioma cell lines. This compound attenuated glioma cell migration, glioma cell invasion, and angiogenesis. Molecular mechanism studies revealed that PCC0208017 decreased the phosphorylation of Tau, disrupted microtubule dynamics, and induced a G2/M phase cell cycle arrest. In an in vivo glioma model, PCC0208017 showed robust anti-tumor activity, blood–brain barrier permeability, and a good oral pharmacokinetic profile. Molecular docking studies showed that PCC0208017 exhibited high binding affinity to MARK3 and MARK4. Taken together, our study describes for the first time that PCC0208017, a novel MARK3/MARK4 inhibitor, might be a promising lead compound for treatment of glioma.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
神经科学
✓ 已验证
DOI
PubMed
高影响因子
Biomaterials Science
·
2019
·Vol. 8
·期 5
·1418-1430
·
IF 5.251
Tiankuan Li,Zhongqian Hu,Chao Wang,Jian Yang,Chuhui Zeng,Rui Fan,Jinhe Guo
Immunotherapy is gradually becoming as important as traditional therapy in the treatment of cancer, but adverse drug reactions limit patient benefits from PD1/PD-L1 checkpoint inhibitor drugs in the treatment of non-small cell lung cancer (NSCLC). As a chemotherapeutic drug for NSCLC, docetaxel (DTX) can synergize with PD1/PD-L1 checkpoint inhibitors but increase haematoxicity and neurotoxicity. Herein, anti-PD-L1 monoclonal antibody (mAb)-conjugated and docetaxel-loaded multifunctional lipid-shelled microbubbles (PDMs), which were designed with biologically safe phospholipids to produce synergistic antitumour effects, reduced the incidence of side effects and promoted therapeutic effects under ultrasound (US) irradiation. The PDMs were prepared by the acoustic-vibration method and then conjugated with an anti-PD-L1 mAb. The material features of the microbubbles and their cytotoxic effects, cellular apoptosis and cell cycle inhibition were studied. A subcutaneous tumour model was established to test the drug concentration-dependent and antitumour effects of the PDMs combined with US irradiation, and an orthotopic lung tumour model simultaneously confirmed the antitumour effect of this synergistic treatment. The PDMs achieved higher cellular uptake than free DTX, especially when combined with US irradiation. The PDMs combined with US irradiation also induced an increased rate of cellular apoptosis and an elevated G2-M arrest rate in cancer cells, which was positively correlated with PD-L1 expression. An in vivo study showed that synergistic treatment had relatively strong effects on tumour growth inhibition, increased survival time and decreased adverse effect rates. Our study possibly provides a well-controlled design for immunotherapy and chemotherapy and has promising potential for clinical application in NSCLC treatment.
研究领域:
肿瘤学
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药学
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生物医学工程
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免疫学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Bioengineering and Biotechnology
·
2022
·
IF 6.064
Zhiguang Fu,Hongqi Li,Peng Xue,Hanying Yu,Shuo Yang,Cheng Tao,Wei Li,Yingjie Wang,Jianjun Zhang,Yu Wang
Breast cancer is one of the most common types of cancer. Patients are often concerned about regional recurrence after breast cancer surgery. Radiotherapy plays a vital role in reducing recurrence and prolonging the survival of patients undergoing breast-conserving surgery and high-risk mastectomy. However, 8–15% of patients still have disease progression due to radiation resistance. Therefore, new strategies for combination radiotherapy sensitization must be investigated. In this study, an implantable drug loading system, sunitinib nanoparticles @ matrix metalloproteinases -response hydrogel (NSMRH), uses enzyme-sensitive hydrogel as a carrier to load sunitinib nanoparticles, was identified. The releasing profile demonstrated that sunitinib nanoparticles may be continuously released from the hydrogels. Functional experiments revealed that, when paired with NSMRH, radiation may significantly inhibit tumor cell proliferation, migration, and invasion in vitro . Further animal experiments showed that NSMRH combined with radiotherapy could more effectively control the recurrence of subcutaneous xenograft tumors, prolong the survival time, and have no obvious toxicity in nude mice. Finally, by studying the molecular mechanism of NSMRH, it was hypothesized that in breast cancer cells, NSMRH cooperated with sensitized radiotherapy, mainly due to significantly blocking the G2/M phase, reducing the DNA repair efficiency, inhibiting tumor angiogenesis, promoting apoptosis, and reversing the abnormal expression of platelet-derived growth factor receptor alpha (PDGFRA) after radiotherapy. These findings suggest that NSMRH’s radiation sensitization and anti-tumor activity may aid in the development of a novel method in future clinical applications.
研究领域:
肿瘤学
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药学
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生物医学工程
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2025
·
IF 16
Lianxue Zhang,Yun Teng,Hai Yang,Jianxiang Huang,Zhaoqi Shi,Cenhao Wu,Zaixing Yang,Liquan Huang,Jun Zou,Ruhong Zhou
Chordoma presents a formidable therapeutic challenge due to its distinct anatomical location, thus complicating its complete surgical resection coupled with marked resistance to both radiotherapy and chemotherapy. Currently, effective systemic therapies remain unavailable, contributing to a poor prognosis for patients. To address this critical unmet need, we have developed a targeted drug delivery system tailored to the tumor biology of chordoma. This system encapsulates the CDK7 inhibitor THZ1 within nanoparticles featuring diselenide bonds as dual-responsive release triggers. Upon exposure to low-dose X-ray irradiation (e.g., 2 Gy) and to the elevated reactive oxygen species (ROS) level in the tumor microenvironment, these diselenide bonds are cleaved and transformed into selenic acid (RSeOOH), which subsequently initiates rapid carrier disassembly and drug release. The synergy between RSeOOH and THZ1 enhances radiotherapy efficacy by modulating p53 signaling, inducing apoptosis, and promoting G2/M phase cell cycle arrest in U-CH1 cells, thereby overcoming the radiotherapy resistance commonly seen in chordoma. To further improve tumor-specificity, we functionalize the carrier with the EGFR-targeting GE11 peptide, which drives selective drug accumulation at tumor sites. In murine models, this delivery system has demonstrated substantial efficacy in combination with radiochemotherapy and yet produces minimal toxicity. Molecular dynamics simulations have further elucidated carrier self-assembly mechanisms, guiding the rational design of this nanoplatform.
研究领域:
纳米医学
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肿瘤学
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放射治疗学
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药理学
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生物化学
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生物物理学
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材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2022
·
IF 15.304
Xiaohui Xiao,Yupeng Wang,Jieyao Chen,Peng Qin,Peiyao Chen,Dongfang Zhou,Yue Pan
Chemoradiotherapy is a widely used treatment for patients with malignancies such as hepatocellular carcinoma (HCC). However, it remains challenging to realize safe and synergistic chemotherapy and radiation sensitization . Herein, we design a self-targeting nano-assembly (STNA) based on platinum(IV)-lactose amphiphilic prodrug for synergistic and safe chemoradiotherapy of HCC. The Pt STNA would improve the tumor accumulation due to the targeting ability of lactose to HCC cells. After receptor-mediated endocytosis , Pt STNA would release cisplatin(II) in cancer cells to form DNA-binding, thus inducing DNA damage and cell apoptosis. Meanwhile, the DNA-binding also causes cell cycle arrest in the radiation-sensitive G2/M phase by the up-regulation of phosphorylated checkpoint kinase 1 (p-Chk1) expression. Furthermore, under X-ray irradiation, Pt STNA as radiosensitizer possesses a strong X-ray attenuation ability to deposit more energy, thus elevating the level of reactive oxygen species (ROS) to amplify the cell-killing effect of radiotherapy in the G2/M phase with increased DNA damage. As a result, Pt STNA exhibits significant synergistic therapeutic effects in chemoradiotherapy with no adverse effects in vitro and in vivo . Overall, we present a novel self-targeting nano-assembly strategy based on widely used Pt drugs for synergistic chemotherapy and radiation sensitization of HCC treatment.
研究领域:
肿瘤学
·
药学
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纳米技术
·
放射生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2023
·
IF 5.8
Dongchao Xu,Ajuan Liu,Qiang Liu,Hongchen Zhang,Mengyao Tian,Ying Bian,Xiaofeng Zhang,Meidan Ying,Hongzhang Shen
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating diseases; it has a considerably poor prognosis and may become the second most lethal malignancy in the next 10 years. Chemotherapeutic resistance is common in PDAC; thus, it is necessary to exploit effective alternative drugs. In recent years, traditional folk medicines and their extracts have shown great potential in cancer treatment. The seed of Lagenaria siceraria (Molina) Standl. is a traditional medicine in Asia. Because of its analgesic effects and ability to reduce swelling, it is often used as an adjuvant treatment for abdominal tumors. Cucurbitacin compounds are extracts abundant in Lagenaria siceraria (Molina) Standl. Here, we found that cucurbitacin C (CuC), a member of the cucurbitacin family, has apparent anti-PDAC therapeutic properties. CuC decreased the viability and suppressed the proliferation of PDAC cells in a time- and dose-dependent manner. Further studies revealed that CuC inhibited cell migration and invasion by inhibiting epithelial-mesenchymal transition (EMT). In addition, G2/M arrest was induced, and the apoptotic pathway was activated. Transcriptomic and bioinformatic analyses showed that CuC inhibited the cGMP-PKG-VASP axis, increasing the content of cGMP to restore tumor characteristics. The antitumor activity of CuC in vivo was verified through animal experiments, and no obvious side effects were observed. Overall, our study indicates a candidate therapeutic compound for PDAC that is worthy of further development.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
传统医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF INORGANIC BIOCHEMISTRY
·
2024
·
IF 3.8
Wujiu Jiang,Qing Luo,Wei Huang,Yuxing Tan,Yiyuan Peng
Diorganotin acylhydrazone complexes with mitochondrial targeting demonstrate significant potential as replacements for platinum-based complexes due to their potent anticancer properties. Twelve methylphenyltin arylformylhydrazone complexes have been synthesized by microwave “one-pot” reaction. The complexes have been characterized by FT-IR, multinuclear NMR ( 1 H, 13 C, and 119 Sn), TGA, and HRMS. Crystal structures were determined for 10 out of the 12 complexes under study. Structures 1 through 8 , 10 and 12 possessed a central symmetric structure of a di-nuclear Sn 2 O 2 tetrahedral ring. All complexes were tested for their inhibitory activity against human cell lines NCI-H460, MCF-7, and HepG2. Complex 8 exhibited the most effective inhibitory effect on HepG2 cells, with an IC 50 value of 1.34 ± 0.04 μM. Preliminary studies on the anticancer mechanism suggest that complex 8 induces apoptosis in HepG2 cells via the mitochondrial pathway, accompanied by G2/M phase cell cycle arrest.
研究领域:
无机化学
·
药物化学
·
癌症研究
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-16
·
IF 10.6
Lan Zhou,Liu Wei-Jia,Yin Wu-Wei,Yang Sheng-Ren,Cui Hao,Zou Ke-Long,Cheng Guo-Wang,Chen Hao,Han Yan-Hua,Rao Lang,Tian Rui,Li Ling-Ling,Zhao Yu-Yue,Yu Guang-Tao
Photothermal therapy is favored by cancer researchers due to its advantages such as controllable initiation, direct killing and immune promotion. However, the low enrichment efficiency of photosensitizer in tumor site and the limited effect of single use limits the further development of photothermal therapy. Herein, a photo-responsive multifunctional nanosystem was designed for cancer therapy, in which myeloid-derived suppressor cell (MDSC) membrane vesicle encapsulated decitabine-loaded black phosphorous (BP) nanosheets (BP@ Decitabine @MDSCs, named BDM). The BDM demonstrated excellent biosafety and biochemical characteristics, providing a suitable microenvironment for cancer cell killing. First, the BDM achieves the ability to be highly enriched at tumor sites by inheriting the ability of MDSCs to actively target tumor microenvironment. And then, BP nanosheets achieves hyperthermia and induces mitochondrial damage by its photothermal and photodynamic properties, which enhancing anti-tumor immunity mediated by immunogenic cell death (ICD). Meanwhile, intra-tumoral release of decitabine induced G2/M cell cycle arrest, further promoting tumor cell apoptosis. In vivo, the BMD showed significant inhibition of tumor growth with down-regulation of PCNA expression and increased expression of high mobility group B1 (HMGB1), calreticulin (CRT) and caspase 3. Flow cytometry revealed significantly decreased infiltration of MDSCs and M2-macrophages along with an increased proportion of CD4+, CD8+ T cells as well as CD103+ DCs, suggesting a potentiated anti-tumor immune response. In summary, BDM realizes photothermal therapy/photodynamic therapy synergized chemotherapy for cancer.
研究领域:
癌症研究
·
纳米技术
·
免疫治疗
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）