Advanced Science
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2025
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IF 14.1
Lei Lei,Wenbin Dai,Jinchao Zhao,Angfeng Jiang,Haisheng Peng,Qiao Jin,Xiaojing Li,Zhe Tang
Photodynamic therapy (PDT) is a promising cancer therapy modality by generating reactive oxygen species (ROS) and triggering immunogenic cell death. However, the therapeutic effect of PDT is strongly limited by tumor hypoxia and immunosuppressive landscape. Herein, a pH-sensitive nanosized covalent–organic polymer (COP), composed of the photosensitizer porphyrin and pyruvate kinase inhibitor vitamin K3 (VK3), is designed to overcome these issues. The signal transducer and activator of transcription 3 (STAT3) inhibitor WP1066 is further encapsulated into COPs to form a WP1066-loaded COP (TVW). As an inhibitor of pyruvate kinase, VK3 can reduce intracellular oxygen consumption by inhibiting the glycolytic pathway, leading to the alleviation of the tumor hypoxic microenvironment. The relief of tumor hypoxia by VK3 enhances photodynamic cytotoxicity by generating more ROS. Meanwhile, STAT3 acts as a major regulator of PD-L1, a key inhibitor that promotes immune escape. WP1066 effectively inhibits the expression of STAT3 and reduces PD-L1 expression, thereby significantly inhibiting tumor immune escape and enhancing antitumor efficacy in a synergistic manner. The antitumor capacity of photodynamic immunotherapy is extensively investigated in a murine subcutaneous hepatocellular carcinoma model. This photo-immunotherapy may provide an effective combination regimen for the efficient treatment of solid tumors such as hepatocellular carcinoma.
研究领域:
肿瘤学
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生物医学工程
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免疫学
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产品关联
DOI
PubMed
高影响因子
Clinical & Translational Oncology
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2022
·Vol. 25
·期 3
·662-672
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IF 3.34
Chen Jing,Huang Shuting,Li Huawen,Li Yun,Zeng Haishan,Hu Jiemei,Lin Yanchun,Cai Huihua,Deng Pengfei,Song Ting,Guan Tian,Zeng Haoyu,Liu Mubiao
Purpose Aberrant activation of STAT3 signal pathway promotes tumor progression in many solid tumor types, including cervical cancer and endometrial cancer. BBI608, the STAT3 inhibitor had been reported in previous studies for restraining cancer stem cells. However, whether BBI608 is available for inhibiting the proliferation of cervical cancer or endometrial cancer remains poorly understood. This study investigated the anti-tumor effect and molecular mechanism of BBI608 on the patient-specific primary cells (PSPC) generated from cervical and endometrial cancer in vitro. Methods PSPCs were obtained from four patients via biopsy. The cell viability was analyzed by the CCK8 assay. The PSPCs were treated with various concentrations of BBI608 or/and paclitaxel; and then, western blot was applied to investigate the expression of phosphorylated STAT3 (pSTAT3). Results The PSPCs cell viability was reduced after treated with BBI608 at a lower concentration. Western blot results showed a reduction trend of pSTAT3 after PSPCs treated with BBI608. Our results demonstrated that BBI608 at the certain concentrations worked well in reducing the cell viability of PSPC from the patients who suffered from cervical cancer and endometrial cancer. Conclusions In this study, the patient-specific primary cell (PSPC) was used as the pre-clinical model for investigating the efficiency of BBI608 in reducing cancer cells viability. BBI608, at a clinical-relevant concentration, had valid efficiency in PSPCs from the patients. The dose of drugs treatment and the measured results were more valuable for further guiding clinical trials.
研究领域:
肿瘤学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
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2022
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IF 5.307
Shuang-Qiang Liu,Zhi-Chen Mao,Yan-Li Xu,Xiao-Man Chen,Hui-Ling Wang,Qi Wang,Jian-Hua Wei,Ri-Zhen Huang,Ye Zhang
Two biotin-polyethylene glycol (PEG)4‑diarylidenyl piperidone (DAP) prodrugs, compounds 3a and 3b , were designed as antineoplastic agents and synthesized by coupling biotin to bifluoro- and binitro-substituted DAP derivatives ( DAP-F and DAP-NO 2 ) through a PEG4 linker, respectively. The results of the MTT (3-(4, 5)-dimethylthiahiazo (-z-y1)-3, 5-di- phenytetrazoliumromide) assay and a SW480 xenograft model identified compounds 3a and 3b as candidate antitumor agents with good efficacy, limited toxicity, and low resistance, as compared to the original drugs ( DAP-F and DAP-NO 2 ), cisplatin, and doxorubicin (dox). The results of a preliminary pharmacokinetic study showed that compounds 3a and 3b slowly released their original drug DAP-F and DAP-NO 2 within 12 h after intraperitoneal injection, respectively. Western blot analysis and computer docking simulations indicated that DAP-F , DAP-NO 2 , and compounds 3a and 3b were indeed inhibitors of signal transducer and activator of transcription 3 (STAT3) and the antitumor effects of compounds 3a and 3b were exerted by sequentially interacting with the SH2-binding domain followed by the DNA-binding domain after releasing the original drugs DAP-F and DAP-NO 2 , respectively. These results suggest that the targeted prodrug model led to good antitumor efficacy with reduced toxicity, while a dual STAT3-binding model may promote antitumor efficacy and resistance.
研究领域:
药理学
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肿瘤学
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药物化学
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产品关联
DOI
PubMed
高影响因子
Small
·
2022
·Vol. 18
·期 18
·2107712
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IF 15.153
Qinjun Chen,Qingbing Wang,Yu Wang,Yongchao Chu,Yifan Luo,Haoyu You,Boyu Su,Chao Li,Qin Guo,Tao Sun,Chen Jiang
Pancreatic ductal adenocarcinoma (PDAC) is on of the most lethal malignant tumors with relatively poor prognosis, characterized with insufficient drug penetration, low immune response and obvious drug resistances. The therapeutic inefficiency is multifactorially related to its specific tumor microenvironment (TME), which is representatively featured as rich stroma and immunosuppression. In this work, a versatile drug delivery system is developed that can coencapsulate two prodrugs modified from gemcitabine (GEM) and a signal transducer and activator of transcription 3 (STAT3) inhibitor (HJC0152), and the gradient pH variation is further sensed in the TME of PDAC to achieve a higher penetration by reversing its surficial charges. The escorted prodrugs can release GEM intracellularly, and respond to the hypoxic condition to yield the parental STAT3 inhibitor HJC0152, respectively. By inhibiting STAT3, the tumor immunosuppression microenvironment can be re-educated through the reversion of M2-like tumor associated macrophages (M2-TAMs), recruitment of cytotoxic T lymphocytes and downregulation of regulatory T cells (T reg s). Furthermore, cytidine deaminase (CDA) and α-smooth muscle actin (α-SMA) expression can be downregulated, plus the lipid modification of GEM, the drug resistance of GEM can be greatly relieved. Based on the above design, a synergetic therapeutic efficacy in PDAC treatment can be achieved to provide more opportunity for clinical applications.
研究领域:
肿瘤学
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药学
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免疫治疗
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药物递送系统
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癌症生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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