FITOTERAPIA
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2024
·
IF 2.5
Ye-Fang Lu,Chuang Liu,Juan Ma,Hu-Ri Piao,Changhao Zhang,Xuejun Jin,Cheng-Hua Jin
Hypoxia-inducing factor-1α (HIF-1α) is overexpressed in variety of tumor patients and plays an important role in the regulation of hypoxia response in tumor cells. Therefore, its inhibitors have become one of the targets for the treatment of a variety of cancers. Two series of panaxadiol (PD) ester derivatives containing pyrazole ( 18a–j ) and pyrrole ( 19a–n ) moiety were synthesized and their HIF-1α inhibitory activities were evaluated. Among all the target compouds, compounds 18c , 19d , and 19n (IC 50 = 8.70 – 10.44 μM) showed better HIF-1α inhibitory activity than PD (IC 50 = 13.35 μM). None of these compounds showed cytotoxicity above 100 μM and inhibited HIF-1α transcription in a dose-dependent manner. These compounds showed good antitumor activity and provide lead compounds for further design and activity study of PD ester derivatives.
研究领域:
药理学
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肿瘤学
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药物化学
✓ 已验证
DOI
PubMed
高影响因子
CHEMISTRY & BIODIVERSITY
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2024
·
IF 2.3
Hu-Ri Piao,Xin-Yu Ma,Ming-Yue Li,Kai-Han Jin,Zhen-Yuan Han,Yuan-Liang Gao,Yu-Qing Zhao,Xue-jun Jin
The hypoxia-inducible factor-1α (HIF-1α) pathway has been implicated in tumor angiogenesis, growth, and metastasis. Therefore, the inhibition of this pathway is an important therapeutic target for cancer. Here, three series of panaxadiol derivatives containing a thiazole moiety (5a-l, 7a-i, and 9a-i) were synthesized and evaluated for HIF-1α inhibitory activity using a Hep3B cell-based luciferase reporter assay. Compounds 5d and 7b showed the strongest inhibitory activity with IC50 values of 17.37 and 6.42 μM, respectively, and did not show any significant cytotoxicity. Western blot assay results indicated that these two compounds exhibited more potent inhibition, compared with panaxadiol, of the expression of HIF-1α protein in Hep3B cells at a concentration of 50 µM. Molecular docking experiments were also performed to investigate the structure–activity relationship.
研究领域:
药理学
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肿瘤学
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药物化学
✓ 已验证
DOI
PubMed
高影响因子
Pharmaceutics
·
2024
·Vol. 16
·期 9
·1130
·
IF 4.9
Xiao Li,Zhiyin Li,Yue Su,Jia Zhou,Yuxiang Li,Qianqian Zhao,Xia Yang,Leilei Shi,Lingyue Shen
In the present work, we pioneered a coordinated self-assembly approach aimed at fabricating carrier-free hybrid nanoparticles to address the inherent challenges of the anaerobic microenvironment and the oxidative resistance induced by reductive glutathione (GSH) in photodynamic therapy (PDT). In these nanoparticles, protoporphyrin IX (PP), HIF-1α inhibitor ofN, Nʹ-(2,5-Dichlorosulfonyl) cystamine KC7F2 (KC), and the cofactor Fe3+present hydrogen bond and coordination interaction. The nanoparticles exhibited efficient cellular uptake by CAL-27 cells, facilitating their accumulation in tumors by enhanced permeability and retention (EPR) effect. Under irradiation at 650 nm, the formation of cytotoxic singlet oxygen (1O2) would be enhanced by the synergy effect on the Fenton reaction of Fe3+ion and the downregulation of the HIF-1α, leading to the improved PDT efficacy both in vitro and in vivo biological studies. Our work opens a new supramolecular approach to prepare hybrid nanoparticles for effective synergy therapy with PDT against cancer cells.
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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药学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Nano Materials
·
2024
·
IF 5.3
Zhi-Hang He,Han-Xiao Tang,Yan-Zheng Pan,Min Cen,Zhi-Juan Zhang
The oxygen consumption during chemodynamic therapy (CDT) can lead to severe cellular hypoxia, resulting in an increase in the hypoxia inducible factor-1α (HIF-1α) level, which hinders the effectiveness of CDT and induces tumor metastasis. Here, we propose a strategy of synergistic therapy between CDT and the HIF-1α inhibitor to avoid the limitations of CDT and reduce the risk of metastasis. Herein, based on the coordination between Fe3+ and apigenin (API, HIF-1α inhibitor), we constructed a hyaluronic acid (HA)-modified API-Fe nanoparticles (AF@HA NPs) for synergetic chemotherapy and glutathione (GSH)-activated self-enhancing CDT. AF@HA NPs have high drug loading capacity, stability, and biocompatibility. Furthermore, the overexpressed GSH in cancer cells can reduce Fe3+ to Fe2+, weakened the coordination between API and Fe, and promoted the release of API for chemotherapy. Fe2+ could react with endogenous H2O2 to generate hydroxyl groups for CDT. In addition, the released API could inhibit the expression of HIF-1α and increase the sensitivity of cells to reactive oxygen species (ROS), thereby achieving a synergistic effect between self-enhancing CDT and chemotherapy. The results of in vitro and in vivo experiments indicated that AF@HA NPs could effectively inhibit tumor growth and suppress the lung metastasis of tumor cells.
研究领域:
纳米技术
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癌症治疗
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药理学
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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
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2021
·
IF 9.776
Mengshi Jiang,Bing Qin,Lihua Luo,Xiang Li,Yingying Shi,Junlei Zhang,Zhenyu Luo,Chunqi Zhu,Guannan Guan,Yongzhong Du,Jian You
The hypoxic tumor microenvironment (TME) hinders the effectiveness of immunotherapy . Alleviating tumor hypoxia to improve the efficacy of immune checkpoint inhibitors (ICIs) represented by programmed cell death protein 1 (PD-1) antibody has become a meaningful strategy. In this study, we adopted three methods to alleviate hypoxia, including direct oxygen delivery using two different carriers and an indirect way involving HIF-1α inhibition. Both in vivo and in vitro experiments showed that liposomes modified with perfluorocarbon or hemoglobin ( [email protected] or [email protected] ) were able to efficiently load and release oxygen, relieving tumor hypoxia. However, the gas release behavior of [email protected] was uncontrollable, which might induce acute hyperoxia side effects during intravenous injection and reduce its biosafety. In contrast, whether administered locally or systemically, [email protected] revealed high animal tolerance, and was much safer than commercial HIF-1α inhibitor (PX-478), displaying prospects as a promising oxygen carrier for clinical practice. Pharmacodynamic experiments suggested that [email protected] helped PD-1 antibody break the therapeutic bottleneck and significantly inhibited the progression of 4 T1 breast cancer. But in CT26 colon cancer , the combination therapy failed to suppress tumor growth. After in-depth analysis and comparison, we found that the ratio of M1/M2 tumor associated macrophages (TAMs) between these two tumor models were dramatically different. And the lower M1/M2 ratio in CT26 tumors limited the anti-tumor effect of combination therapy. In this study, three methods for alleviating tumor hypoxia were compared from the perspectives of biosafety, efficacy and clinical applicability. Among them, [email protected] stood out, and its combined use with PD-1 antibody exhibit a distinct synergistic suppression effect on tumors with more M1 macrophages presented in the microenvironment. Our work provided a good reference for improving the efficacy of PD-1 antibody by alleviating tumor hypoxia.
研究领域:
肿瘤学
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免疫疗法
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药理学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2023
·
IF 17.1
Qiqi Zhang,Xuan Wang,Yuanyuan Zhao,Zhuo Cheng,De Fang,Yingqi Liu,Gan Tian,Menghuan Li,Zhong Luo
Low-dose radiotherapy (LDR) has shown significant implications for inflaming the immunosuppressive tumor microenvironment (TME). Surprisingly, we identify that FABP-dependent lipid droplet biogenesis in tumor cells is a key determinant of LDR-evoked cytotoxic and immunostimulatory effects and developed a nanointegrated strategy to promote the antitumor efficacy of LDR through cooperative ferroptosis immunotherapy. Specifically, TCPP-TK-PEG-PAMAM-FA, a nanoscale multicomponent functional polymer with self-assembly capability, was synthesized for cooperatively entrapping hafnium ions (Hf4+) and HIF-1α-inhibiting siRNAs (siHIF-1α). The TCPP@Hf-TK-PEG-PAMAM-FA@siHIF-1α nanoassemblies are specifically taken in by folate receptor-overexpressing tumor cells and activated by the elevated cellular ROS stress. siHIF-1α could readily inhibit the FABP3/7 expression in tumor cells via HIF-1α-FABP3/7 signaling and abolish lipid droplet biogenesis for enhancing the peroxidation susceptibility of membrane lipids, which synergizes with the elevated ROS stress in the context of Hf4+-enhanced radiation exposure and evokes pronounced ferroptotic damage in vital membrane structures. Interestingly, TCPP@Hf-TK-PEG-PAMAM-FA@siHIF-1α-enhanced ferroptotic biomembrane damage also facilitates the exposure of tumor-associated antigens (TAAs) to promote post-LDR immunotherapeutic effects, leading to robust tumor regression in vivo. This study offers a nanointegrative approach to boost the antitumor effects of LDR through the utilization of tumor-intrinsic lipid metabolism.
研究领域:
肿瘤学
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放射肿瘤学
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纳米技术
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免疫疗法
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2024
·Vol. 16
·期 5
·619
·
IF 4.9
Huaying Xie,Xuhua Xiao,Xiaoyuan Yi,Kunzhao Huang,Liyan Wang
Chemodynamic therapy (CDT) employs hydrogen peroxide (H2O2) within the tumor microenvironment (TME) to initiate the Fenton reaction and catalyze the generation of hydroxyl radicals (·OH) for targeted therapy. Metal ion-based nanomaterials have garnered significant attention as catalysts due to their potent anti-tumor effects. Hypoxia in the TME is often associated with cancer cell development and metastasis, with HIF-1α being a pivotal factor in hypoxia adaptation. In this study, an organic framework called MIL-101 (Fe) was designed and synthesized to facilitate H2O2-induced ·OH production while also serving as a carrier for the HIF-1α inhibitor Acriflavine (ACF). A biomimetic nanomedical drug delivery system named MIL-101/ACF@CCM was constructed by encapsulating liver cancer cell membranes onto the framework. This delivery system utilized the homologous targeting of tumor cell membranes to transport ACF, inhibiting HIF-1α expression, alleviating tumor hypoxia, and catalyzing ·OH production for effective tumor eradication. Both in vivo and in vitro experiments confirmed that combining ACF with chemotherapy achieved remarkable tumor inhibition by enhancing ROS production and suppressing HIF-1α expression.
研究领域:
肿瘤学
·
纳米医学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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