CRYSTENGCOMM
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2020
·Vol. 23
·期 3
·653-662
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IF 3.117
Jun-Long Jia,Xia-Lin Dai,Hao-Jie Che,Meng-Ting Li,Xiao-Mei Zhuang,Tong-Bu Lu,Jia-Mei Chen
Regorafenib (REG) is an oral multikinase inhibitor used for the treatment of gastrointestinal stromal tumors, metastatic colorectal cancer and advanced hepatocellular carcinoma. REG exists in various crystal forms and its monohydrate form (REG·H2O) is selected as the commercial form. However, the clinical efficacy of REG is severely limited by low oral bioavailability due to its poor aqueous solubility. With the intention to expand the solid forms and to improve the aqueous solubility at the same time, three cocrystals of REG with malonic acid (REG–MA), glutaric acid (REG–GA) and pimelic acid (REG–PA) were successfully synthesized by liquid-assisted grinding and/or the slurry methods. The obtained cocrystals were fully characterized by X-ray diffraction analysis, thermal analysis, and Fourier transform infrared and proton nuclear magnetic resonance spectroscopy, and were then subjected to powder dissolution, dynamic vapor sorption, stability and tabletability investigations. As compared to REG·H2O, REG–MA exhibits comparable dissolution behavior, while REG–GA and REG–PA demonstrate significantly enhanced apparent solubility and dissolution rates without compromising the hygroscopicity and physicochemical stability of the drug. In addition, the formation of the cocrystals also improves the tabletability of the powdered samples. These results suggest that REG–GA and REG–PA have great potential to be developed as new, more efficient formulations of REG.
研究领域:
药学
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材料科学
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DOI
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2017
·
IF 3.887
Xiurong Hu,Mengying Sun,Yang Li,Guping Tang
Regorafenib (RG) was an oral multi-kinase inhibitor with poor water solubility. In order to enhance the drug’s solubility, dissolution and bioavailability, the binary molecular chaperone drug between RG and β-cyclodetrin (β-CD) had prepared by co-crystallization. The structure of RG-β-CD was characterized by thermal analysis, powder X-ray diffraction, infrared spectroscopy and nuclear magnetic resonance. Phase-solubility study revealed the higher solubility and complexing ability of β-CDwith RG.The solubility and dissolution of RG-β-CD was significantly enhanced in pH 1.2 medium, pH 6.8 PBS buffer solution and distilled water compared to RG. In vivo distribution and antitumor studies revealed that the bioavailability of RG-β-CD was increased when β-CD mated with RG. Therefore, these findings could provide a suitable pharmaceutical dosage to enhanced therapeutic activity.
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DOI
PubMed
高影响因子
TOXICOLOGICAL SCIENCES
·
2024
·
IF 3.4
Xu Bo,Liu Ning,Zhou Taicheng,Chen Jian,Jiang Liyu,Wu Wentong,Fu Huangxi,Chen Xueqin,Yan Hao,Yang Xiaochun,Luo Peihua,Yang Bo,Xu Zhifei,He Qiaojun
Regorafenib, an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases, has been approved for the treatment of metastatic colorectal cancer, gastrointestinal stromal tumors and hepatocellular carcinoma by the US Food and Drug Administration and European Medicines Agency. However, regorafenib-induced cardiotoxicity increases the risk of mortality. Despite reports that regorafenib can cause mitochondrial dysfunction in cardiomyocytes, the molecular mechanism of regorafenib-induced cardiotoxicity is much less known and there is an urgent need for intervention strategies. Here, we treated mice with vehicle or 200 mg/kg regorafenib daily for 42 days by gavage or treated cardiomyocyte lines with 8, 16 or 32 μM regorafenib, and we found that regorafenib could cause apoptosis, mitochondrial injury and DNA damage in cardiomyocytes. Mechanistically, regorafenib can reduce the expression of EPHA2, which inhibits AKT signaling, leading to cardiomyocyte apoptosis and cardiotoxicity. In addition, we showed that recovering EPHA2 expression via plasmid-induced overexpression of EPHA2 or schisandrin C, a natural product, could prevent regorafenib-induced cardiotoxicity. These findings demonstrated that regorafenib causes cardiomyocyte apoptosis and cardiac injury by reducing the expression of EPHA2 and schisandrin C could prevent regorafenib-induced cardiotoxicity by recovering EPHA2 expression, which provides a potential management strategy for regorafenib-induced cardiotoxicity and will benefit the safe application of regorafenib in clinic.
研究领域:
肿瘤学
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心脏病学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
·
2020
·
IF 3.391
Ruobing Wang,Yahui Liu,Xuguang Mi,Qingmin Chen,Peiqiang Jiang,Junjie Hou,Yifan Lin,Siqi Li,Bai Ji,Yanqiu Fang
Regorafenib , a multiple kinase inhibitor, is recently approved for treatment of patients with advanced hepatocellular carcinoma (HCC). Previous studies demonstrated that regorafenib was a mitochondrial toxicant, which associated with the impairment of mitochondria. Sirt3 is involved in the regulation of mitochondrial function in cancers. This study aimed to investigate the mechanism of Sirt3 involved in the mitochondrial dysfunction which associated with regorafenib treatment in liver cancer cells. We found regorafenib inhibited Sirt3 and p-ERK expression in HCC cells in a dose-dependent manner. Bioinformatics analysis showed that Sirt3 expression was down-regulated in liver cancer tissues and its low expression was correlated with worse overall survival (OS) in liver cancer patients. After transfected with Sirt3 overexpression plasmid, we found that Sirt3 sensitized liver cancer cells to regorafenib and resulted in much more apoptosis with a significant increase of ROS level. However, exogenous antioxidant could not weaken the apoptosis. Mitochondrial membrane potential assay indicated that Sirt3 overexpression accelerated the mitochondrial depolarization process induced by regorafenib and aggravated mitochondrial injury. Cellular oxygen consumption assay showed that mitochondrial dysfunction was caused by the damage of the electron transport chain . The results demonstrated that Sirt3 overexpression promoted the increase of ROS and apoptosis induced by regorafenib through the acceleration of mitochondrial dysfunction by impairing function of the electron transport chain in liver cancer cells. Our studies verified the functional role of Sirt3 in regorafenib treatment and suggested that regorafenib accompanied with Sirt3 activator as a novel treatment strategy for HCC.
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
MOLECULAR CARCINOGENESIS
·
2021
·Vol. 60
·期 2
·151-163
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IF 4.784
Nan Zhang,Shaoqin Zhang,Wenda Wu,Wenxian Lu,Mingting Jiang,Ning Zheng,Jing Huang,Long Wang,Hekun Liu,Min Zheng,Jichuang Wang
Regorafenib is approved for patients with unresectable hepatocellular carcinoma (HCC) following sorafenib. However, the effect of regorafenib on HCC metastasis and its mechanism are poorly understood. Here, our data showed that regorafenib significantly restrained the migration, invasion and vasculogenic mimicry (VM) of HCC cells, and downregulated the expression of epithelial-to-mesenchymal transition (EMT)/VM-related molecules. Using RNA-seq and cellular thermal shift assays, we found that inhibitor of differentiation 1 (ID1) was a key target of regorafenib. In HCC tissues, the protein expression of ID1 was positively correlated with EMT and VM formation (CD34 − /PAS + ). Functionally, ID1 knockdown inhibited HCC cell migration, invasion, metastasis, and VM formation in vitro and in vivo, with upregulation of E-cadherin and downregulation of Snail and VE-cadherin. Moreover, Snail overexpression promoted the migration, invasion, and VM formation of ID1 knockdown cells. Snail knockdown reduced the migration, invasion, and VM formation of ID1 overexpression cells. Finally, regorafenib suppressed VM formation and decreased the expression of ID1, VE-cadherin and Snail in HCC PDX model. In conclusion, we manifested that regorafenib distinctly inhibited EMT in HCC cells via targeting ID1, leading to the suppression of cell migration, invasion and VM formation. These findings suggest that regorafenib may be developed as a suitable therapeutic agent for HCC metastasis.
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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DOI
PubMed
高影响因子
Cancer Nanotechnology
·
2023
·Vol. 14
·期 1
·1-21
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IF 5.7
Wang Hongsheng,Jin Xinmeng,Gao Yinghua,He Xin,Xu Yiming,Mu Haoran,Jiang Yafei,Wang Zhuoying,Yu Chen,Zhang Tao,Hua Yingqi,Cai Zhengdong,Xu Jing,Ma Xiaojun,Sun Wei
Background Tumor angiogenesis, immunosuppression, and progression are all closely correlated with the tumor microenvironment (TME). Immune evasion is supported by both M2 phenotype tumor-associated macrophages (TAMs) and vascular aberrations in the TME. TME reprogramming is a promising therapeutic approach for treating tumors. Anti-angiogenesis has the power to control the polarization of macrophages, prevent progression, and increase drug penetration. Additionally, polyamine blocking therapy can increase CD8 + T cell infiltration and decrease immunosuppressive cells. These results led to developing a potential therapeutic regimen that targets TAMs and angiogenesis to reprogram the osteosarcoma TME. Results For the targeted biomimetic co-delivery of regorafenib and alpha-difluoromethylornithine via the mannose receptor, which is overexpressed in both TAMs and osteosarcoma cells, mannosylated poly(lactide-co-glycolide)-polyethylene glycol nanoparticles (Man-NPs) were synthesized. The superior physiological properties and intratumoral accumulation of the Man-NPs efficiently promoted TAMs polarization and inhibited angiogenesis. Macrophage repolarization further activated immune cells, which contributed to remodeling the TME. Conclusion Overall, these findings suggested that using Man-NPs as an immunotherapeutic approach to treat osteosarcoma may be promising. Graphical Abstract
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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纳米技术
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产品关联
DOI
高影响因子
Nature Communications
·
2023
·Vol. 14
·期 1
·1-20
·
IF 16.6
Yan Hao,Wu Wentong,Hu Yuhuai,Li Jinjin,Xu Jiangxin,Chen Xueqin,Xu Zhifei,Yang Xiaochun,Yang Bo,He Qiaojun,Luo Peihua
The hepatotoxicity of regorafenib is one of the most noteworthy concerns for patients, however the mechanism is poorly understood. Hence, there is a lack of effective intervention strategies. Here, by comparing the target with sorafenib, we show that regorafenib-induced liver injury is mainly due to its nontherapeutic target Eph receptor A2 (EphA2). EphA2 deficiency attenuated liver damage and cell apoptosis under regorafenib treatment in male mice. Mechanistically, regorafenib inhibits EphA2 Ser897 phosphorylation and reduces ubiquitination of p53 by altering the intracellular localization of mouse double minute 2 (MDM2) by affecting the extracellular signal-regulated kinase (ERK)/MDM2 axis. Meanwhile, we found that schisandrin C, which can upregulate the phosphorylation of EphA2 at Ser897 also has protective effect against the toxicity in vivo. Collectively, our findings identify the inhibition of EphA2 Ser897 phosphorylation as a key cause of regorafenib-induced hepatotoxicity, and chemical activation of EphA2 Ser897 represents a potential therapeutic strategy to prevent regorafenib-induced hepatotoxicity.
研究领域:
药理学
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毒理学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN POLYMER JOURNAL
·
2022
·
IF 5.546
Hang Hu,Defeng Xu
In the present work, methoxypoly(ethylene glycol)-polycaprolactone (mPEG-Hyd-PCL) and lactobionic acid-grafted poly(ethylene glycol)-polycaprolactone (LA-PEG-Hyd-PCL) mixed nanoparticles were developed for targeted delivery of dimethylcurcumin (DMC) and regorafenib (RGF) for combinational therapy of hepatocellular carcinoma. mPEG-Hyd-PCL and LA-PEG-Hyd-PCL were synthesized and characterized by 1 H nuclear magnetic resonance spectrometry, flourier transform infrared spectrometry, and gel permeation chromatography. The mixed nanoparticles of mPEG-Hyd-PCL and LA-PEG-Hyd-PCL (m/L) were prepared by a dialysis method, in which nile red was loaded to study the effect of the composition of the mixed nanoparticles on the cellular uptake. The results show that the mixed nanoparticles of mPEG-Hyd-PCL and LA-PEG-Hyd-PCL with a weight ratio of 1:0.2 (m/L(1:0.2)) exhibit the highest cellular uptake efficiency on HepG2 cells in the presence 10% fetal bovine serum. In addition, m/L(1:0.2) nanoparticles can be selectively taken up by HepG2 cells. DMC and RGF co-loaded m/L(1:0.2) nanoparticles (DMC/RGF@m/L(1:0.2)) were then prepared and evaluated regarding the in vitro drug release, cellular uptake, and in vitro antitumor effect . The results show that DMC/RGF@m/L(1:0.2) nanoparticles exhibit pH-sensitive drug release, enhanced cellular uptake amount and in vitro antitumor effect on HepG2 cells as compared to DMC/RGF@mPEG-Hyd-PCL and DMC/RGF@LA-PEG-Hyd-PCL nanoparticles. Although the in vitro antitumor effect of DMC/RGF@m/L(1:0.2) nanoparticles is still lower than DMC/RGF mixture, they might achieve selective cytotoxicity against hepatoma cells.
研究领域:
药学
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肿瘤学
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生物医学工程
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DOI
高影响因子
PHYTOTHERAPY RESEARCH
·
2021
·Vol. 35
·期 8
·4567-4578
·
IF 5.882
Tianfeng Yang,Jian Huo,Rui Xu,Yanmin Zhang
Regorafenib (RGF), a second-line multi-kinase inhibitor in the treatment of HCC (hepatocellular carcinoma) after sorafenib failure, exposes to the risk of drug resistance and subsequent progression of HCC patients. Toosendanin (TSN), a triterpenoid has presented excellent inhibition on several tumors. The purpose of this study is to investigate the inhibitory effect of the combination of TSN and RGF on HCC cells. We identified that TSN and RGF combination (TRC) synergistically inhibited the proliferation and migration of MHCC-97L cells. The upregulation of WWOX (WW-domain containing oxidoreductase) played a vital role in the HCC cell growth treated with TRC. TRC suppressed the phosphorylation of Stat3 and expression of DVL2, negatively regulated the activity of β-catenin by promoting the phosphorylation of GSK3β. In addition, the intranuclear proteins, including MMP2, MMP9, and C-MYC were significantly inhibited by TRC. The in vivo xenograft models confirmed that TRC effectually prevented the tumor growth through upregulating WWOX. Therefore, the treatment of TRC may be a potential solution of RGF resistance and promising therapeutic method in malignant HCC.
研究领域:
肿瘤学
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药理学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
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