INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2014
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IF 3.785
Yan Yang,Xiaomin Zhang,Xiaofen Wang,Xiaomei Zhao,Tianrui Ren,Feng Wang,Bo Yu
Artemisinin (ART) and its analogues, such as dihydroartesunate (DHA) and artesunate (ATS), are sesquiterpene lactones with anticancer activities. Transferrin (Tf) receptor is frequently overexpressed in cancer cells. In order to improve the delivery and the anticancer activity of ART and its analogues, adducts of Tf with ART, DHA or ATS were fabricated by simply combining ART, DHA or ATS with Tf. Increased antitumor effects of these adducts were observed on human liver hepatocellular carcinoma (HepG2) and lung adenocarcinoma (A549) cells. Meanwhile, only a low level of toxic effect was observed on normal human liver cells (HL-7702). Improved cellular uptake of ATS-Tf adduct compared to ATS alone was confirmed by HPLC analysis. UV–vis, fluorescence spectroscopy and docking study further confirmed the formation of the adducts with relatively high binding constants at neutral pH (7.4 × 10 4 , 4.2 × 10 5 and 3.4 × 10 5 M −1 , for ART-Tf, DHA-Tf and ATS-Tf, respectively, at pH 7.4). However, the adducts became less stable with reduced binding constants under an acidic condition (2.6 × 10 4 , 1.9 × 10 4 and 1.7 × 10 4 M −1 , for ART-Tf, DHA-Tf and ATS-Tf, respectively, at pH 5.5). A possible mechanism of the anticancer effect by these adducts was proposed. The short term and long term stability of ART-Tf in the presence of human serum albumin (HSA) was also studied. Our results showed that adducts of ART and its analogues with Tf, especially ATS-Tf and DHA-Tf, have significant anticancer effects to cancer cells, with minimal side effects on normal cells, therefore, are promising as potential novel anticancer agents.
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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产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE RESEARCH
·
2014
·
IF 1.966
Rui-jian Jiang,Yu-lin Zhao,Yun-jian Chen,Dan Xiao,Fen Wang,Bin Han,Jian Yang,Xia-li Liao,Li-Juan Yang,Chuan-zhu Gao,Bo Yang
A novel series of artesunate-β-cyclodextrin (ATS-β-CD) conjugates, in which artesunate (ATS) was coupled covalently to one of the primary hydroxyl groups of β-cyclodextrin (β-CD) through amino bond formation, were synthesized and characterized by 1 H NMR, HRMS, 2D NMR (ROESY), X-ray diffraction (XRD), and thermogravimetric analysis (TGA). The results showed that the aqueous solubility of ATS-β-CD conjugates was 26–45 times better than that of free ATS. The cytotoxicity of the ATS-β-CD conjugates was evaluated on human colon cancer cell lines HCT116, LOVO, SW480, and HT-29, and the results indicated that ATS-2NβCD exhibited a very high cytotoxicity against HCT116, LOVO, and HT-29 with IC 50 values of 0.58, 1.62, and 5.18 μmol/L, respectively. In addition, the supposition of better cytotoxicity was further supported by the control experiment of fluorescent cyclodextrin .
研究领域:
药物化学
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肿瘤学
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生物化学
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DOI
PubMed
高影响因子
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
·
2022
·Vol. 66
·期 5
·
IF 5.938
Yawei Du,Carlo Giannangelo,Wei He,Gerald J. Shami,Wenya Zhou,Tuo Yang,Darren J. Creek,Con Dogovski,Xinsong Li,Leann Tilley
Current best practice for the treatment of malaria relies on short half-life artemisinins that are failing against emerging Kelch 13 mutant parasite strains. Here, we introduce a liposome-like self-assembly of a dimeric artesunate glycerophosphocholine conjugate (dAPC-S) as an amphiphilic prodrug for the short-lived antimalarial drug, dihydroartemisinin (DHA), with enhanced killing of Kelch 13 mutant artemisinin-resistant parasites. Cryo-electron microscopy (cryoEM) images and the dynamic light scattering (DLS) technique show that dAPC-S typically exhibits a multilamellar liposomal structure with a size distribution similar to that of the liposomes generated using thin-film dispersion (dAPC-L). Liquid chromatography-mass spectrometry (LCMS) was used to monitor the release of DHA. Sustainable release of DHA from dAPC-S and dAPC-L assemblies increased the effective dose and thus efficacy against Kelch 13 mutant artemisinin-resistant parasites in an in vitro assay. To better understand the enhanced killing effect, we investigated processes for deactivation of both the assemblies and DHA, including the roles of serum components and trace levels of iron. Analysis of parasite proteostasis pathways revealed that dAPC assemblies exert their activity via the same mechanism as DHA. We conclude that this easily prepared multilamellar liposome-like dAPC-S with long-acting efficacy shows potential for the treatment of severe and artemisinin-resistant malaria.
研究领域:
药理学
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寄生虫学
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生物化学
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DOI
高影响因子
ACS Applied Nano Materials
·
2024
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IF 5.3
Lirong Zhang,Beibei Yu,Zijian Zhuang,Zhengzou Fang,Mengke Lu,Huijun Yu,Xiao Xu,Xin Sun,Fengyi Du,Miaomiao Zhang
Artesunate (Art) with a unique peroxy-bridging bond can react with a ferrous ion and produce excess carbon-centered radicals, which cause irreversible damage to tumor cells. However, the antitumor effect of artesunate still faces challenges due to its poor water solubility and insufficient amount of ferrous ions in tumor cells. Herein, we constructed artesunate coordinated zeolite imidazole framework nanoplatforms (Art/ZIF NPs) coated with ferric ion-rutin network (Ru–Fe@Art/ZIF NPs) for synergy therapy. In virtue of zinc-ion-mediated coordination, Art was efficiently loaded into ZIF-8 NPs (loading capacity and rate are 29.58 and 30.73%) and responsively released under an acidic environment. Meanwhile, the introduction of rutin (a type of plant flavonoid) not only enabled tumor targeting via GLUT receptors but also reduced Fe3+ to Fe2+ under acidic conditions. Subsequently, these ferrous ions loading with Art enhance the tumor killing effect via radical-dependent cell cycle arrest. This “core–shell” autocatalytic nanoplatform provides a novel strategy for developing Art-based chemodynamic therapy.
研究领域:
纳米医学
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肿瘤学
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药剂学
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产品关联
DOI
高影响因子
INORGANIC CHEMISTRY
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2024
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IF 4.3
Chuanxun Zhang,Bo Hu,Jiajia Ren,Wanqi Du,Minjia Meng
The selective separation and purification of artesunate (ARU) and artemisinin (ART) using zirconium-based metal–organic frameworks (MOF), especially UiO-66 MOF, are receiving increasing attention. In this study, tunable “hydrophobic” sites of thiol (–SH) were introduced to amino-functionalized MOFs (UiO-66-NH2) to fabricate a thiol-amino bifunctional UiO-66/polyvinylidene fluoride (PVDF)-blended membrane (S1-UiO/PVDF-DPIM) via the delayed-phase-inversion method for selective separation of ARU/ART. The adsorption results indicated that the modification of UiO-66-NH2 with thiol can indeed increase the ARU adsorption. The thiol-functional MOF (S1-UiO-66-NH2) was chosen as the optimal thiol-amino bifunctional MOF, as it possessed the maximum ARU adsorption capacity (111.14 mg g–1) and the highest selective-separation factor (α = 51.84). The ATR FT-IR dynamic spectrum disclosed the recognition mechanism, indicating that incorporating thiol groups into a hydrophilic MOF as hydrophobic sites can boost adsorption efficiency. Moreover, the static-selective permeation results showed that the S1-UiO/PVDF-DPIM preferentially transfers ARU when mixed with ART, even achieving complete ARU/ART separation. The most crucial aspect was the introduction of a hydrophobic core of –SH and new spontaneously formed disulfide bonds to S1-UiO/PVDF-DPIM, creating alternated hydrogen bonds and hydrophobic interactions. This work provides an alternative strategy to prepare hydrophobic–hydrophilic MOF-based membranes for the highly efficient and selective separation of complex analogue systems.
研究领域:
材料科学
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药物化学
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分离技术
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产品关联
DOI
PubMed
高影响因子
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
·
2025
·Vol. 66
·期 11
·19-19
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IF 4.7
Yuchen Liu,Xue Tian,Cui Li,Jing Lin,Lina Zhang,Qian Wang,Hong Li,Yuqi Li,Xiangzhi Liu,Guiqiu Zhao
Purpose:The purpose of this study was to investigate the therapeutic effect of artesunate (ART) on fungal keratitis (FK).Methods:The antifungal properties of ART againstAspergillus fumigatus(A. fumigatus) were confirmed by minimum inhibitory concentration (MIC), biofilm formation inhibition test, propidium iodide fluorescence, and calcium fluorescence white test. The levels of HSP90, BrlA, AbaA, WetA, CnaA, and CrzA were detected by quantitative reverse transcription PCR (qRT-PCR). Cell counting kit 8 (CCK-8) was used to detect the cytotoxicity of ART on RAW 264.7 cells and human corneal epithelial cells (HCECs). Clinical corneal score, hematoxylin and eosin (H&E) staining, and corneal fungal plate counts were used to evaluate the therapeutic effect of ART on FK in mice. The qRT-PCR, ELISA, and Western blot were used to investigate the effect of ART on inflammatory mediator expression during fungal infection.Results:ART inhibited the growth ofA fumigatus, biofilm formation, and conidium adhesion in vitro, and destroyed fungal cell walls and cytomembrane. In vivo, ART effectively reduced corneal fungal load. ART could reduce the inflammation of the cornea by reducing the accumulation of inflammatory cells and down-regulating the expression of TNF-α, IL-1β, and IL-6. ART could activate the autophagy pathway to play an anti-inflammatory role in FK by increasing the expression of Beclin-1 and LC3B.Conclusions:ART inhibits fungal growth by inhibiting biofilm formation, destroying fungal cell walls and membranes, and reducing the expression of HSP90 and calcineurin-related factors, and activates the autophagy pathway to reduce the expression of TNF-α, IL-1β, and IL-6 in FK by upregulating the protein expression of Beclin-1 and LC3B. ART has therapeutic potential for FK.
研究领域:
医学真菌学
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药理学
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免疫学
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微生物学
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眼科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY
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2016
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IF 3.035
Jie-hua Shi,Dong-qi Pan,Xiou-xiou Wang,Ting-Ting Liu,Min Jiang,Qi Wang
Artemether (AMT), a peroxide sesquiterpenoides, has been widely used as an antimalarial for the treatment of multiple drug-resistant strains of plasmodium falciparum malaria . In this work, the binding interaction of AMT with bovine serum albumin (BSA) under the imitated physiological conditions (pH 7.4) was investigated by UV spectroscopy , fluorescence emission spectroscopy , synchronous fluorescence spectroscopy, Fourier transform infrared spectroscopy (FT-IR), circular dichroism (CD), three-dimensional fluorescence spectroscopy and molecular docking methods. The experimental results indicated that there was a change in UV absorption of BSA along with a slight red shift of absorption wavelength, indicating that the interaction of AMT with BSA occurred. The intrinsic fluorescence of BSA was quenched by AMT due to the formation of AMT–BSA complex. The number of binding sites ( n ) and binding constant of AMT–BSA complex were about 1 and 2.63 × 10 3 M − 1 at 298 K, respectively, suggesting that there was stronger binding interaction of AMT with BSA. Based on the analysis of the signs and magnitudes of the free energy change (Δ G 0 ), enthalpic change (Δ H 0 ) and entropic change (Δ S 0 ) in the binding process, it can be concluded that the binding of AMT with BSA was enthalpy-driven process due to | Δ H °| > | T Δ S °|. The results of experiment and molecular docking confirmed the main interaction forces between AMT and BSA were van der Waals force . And, there was a slight change in the BSA conformation after binding AMT but BSA still retains its secondary structure α-helicity. However, it had been confirmed that AMT binds on the interface between sub-domain IIA and IIB of BSA.
研究领域:
药理学
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生物化学
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分子生物学
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DOI
PubMed
高影响因子
Exploration
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2024
·
IF 0
JunJie Tang,Yadong Liu,Yifan Xue,Zhaozhong Jiang,Baizhu Chen,Jie Liu
Prodrug-based self-assembled nanoparticles (PSNs) with tailored responses to tumor microenvironments show a significant promise for chemodynamic therapy (CDT) by generating highly toxic reactive oxygen species (ROS). However, the insufficient level of intracellular ROS and the limited drug accumulation remain major challenges for further clinical transformation. In this study, the PSNs for the delivery of artesunate (ARS) are demonstrated by designing the pH-responsive ARS-4-hydroxybenzoyl hydrazide (HBZ)-5-amino levulinic acid (ALA) nanoparticles (AHA NPs) with self-supplied ROS for excellent chemotherapy and CDT. The PSNs greatly improved the loading capacity of artesunate and the ROS generation from endoperoxide bridge using the electron withdrawing group attached directly to C10 site of artesunate. The ALA and ARS-HBZ could be released from AHA NPs under the cleavage of hydrazone bonds triggered by the acidic surroundings. Besides, the ALA increased the intracellular level of heme in mitochondria, further promoting the ROS generation and lipid peroxidation with ARS-HBZ for excellent anti-tumor effects. Our study improved the chemotherapy of ARS through the chemical modification, pointing out the potential applications in the clinical fields.
研究领域:
药理学
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生物医学工程
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肿瘤学
✓ 已验证
DOI
Materials Science & Engineering C-Materials for Biological Applications
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2018
·
IF 5.08
Dongjing Zhang,Cheng Zhou,Pin Lv,Yulin Zhao,Jing Liang,Xiali Liao,Bo Yang
The purpose of this study was to develop a novel folate-modified host-guest complex to enhance antitumor activity of the artesunate and improve the solubility and stability by encapsulated in β-cyclodextrin and linked with folate. In this work, we designed and prepared the inclusion complex of adamantanamine conjugated artesunate (AD-ATS) with folic acid-ethylenediamine-β-cyclodextrin (FA-EN-β-CD). This material was characterized by 1D and 2D NMR, XRD, TG and SEM. The results suggested that AD-ATS was encapsulated within the FA-EN-β-CD cavity to form host-guest inclusion complex, and the water solubility of AD-ATS was improved in the form of inclusion complex with FA-EN-β-CD. The assessment of antitumor activity showed that cytotoxicity of AD-ATS/FA-EN-β-CD complex was significantly enhanced in comparison to free AD-ATS, ATS/β-CD inclusion complex and ATS/FA-EN-β-CD inclusion complex.
研究领域:
药学
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肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Advanced Research
·
2025
·
IF 13
Jia Xu,Bingxin Huangfu,Teng Wang,Xinxin Ren,Feng Zhang,Kunlun Huang,Xiaoyun He
Introduction The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is rising, while current pharmacological treatments are often limited by adverse effects. Artemether (Art), a derivative of artemisinin, has demonstrated therapeutic potential against MAFLD, but its direct molecular targets remain unclear. Objectives This work focuses on Art’s therapeutic effects and molecular targets in MAFLD. Methods In this study, MAFLD was induced in C57BL/6J male mice via high-fat diets, followed by treatment with Art at 10 or 50 mg/kg·bw/d; obeticholic acid served as a positive control. Glucose tolerance, serum biochemistry, and liver histology were assessed. Fatty acid-induced MAFLD models in HepG2 and primary mouse hepatocytes were treated with Art (5 µM or 25 µM), and lipid accumulation was evaluated. Protein target identification involved drug affinity responsive target stability (DARTS), cellular thermal shift assay (CESTA), chemical proteomics, and molecular docking etc. Heat shock protein 90 (HSP90) and epidermal growth factor receptor (EGFR) were confirmed as direct targets of Art through over-expression, inhibition, and knockdown techniques in cells and mice. Results Art dose-dependently reduced hepatic lipid accumulation in MAFLD mice and suppressed oleic-palmitic acid–induced lipid droplet formation in vitro . HSP90 and EGFR were identified as direct binding targets of Art, which disrupted the HSP90–EGFR complex, reducing EGFR stability and expression. The therapeutic efficacy of Art was not further enhanced when administered following HSP90 or EGFR knockdown, confirming that HSP90 and EGFR function as key molecular targets of Art. Conclusion These findings identify EGFR as a key target of Art, modulated directly or via HSP90, thereby offering new insights into Art’s multi-target therapeutic mechanism in MAFLD.
研究领域:
药理学
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分子生物学
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肝病学
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生物化学
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药物研发
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOSCIENCE REPORTS
·
2020
·Vol. 40
·期 7
·
IF 2.942
Huang Ming-Zhi,Zhuang Yong,Ning Xu,Zhang Hao,Shen Zhi-Min,Shang Xian-Wen
Osteoporosis is a metabolic bone disease that is characterized by decreased bone density and strength due to excessive loss of bone protein and mineral content, which can be induced by increased osteoclast activity. Developing agents targeting osteoclast activation is considered to be the most effective method to reverse bone destruction and alleviate the pain caused by osteoporosis. MTT assay was conducted to detect the cell viability after artesunate treatment of RAW264.7 cells. TRACP staining and pit formation assays were performed to examine the TRACP-positive cells and pit-forming activity of osteoclasts. qRT-PCR and Western blot analysis were performed to assess the mRNA and protein expression levels of the osteoclastogenesis-related genes NFATc1, TRAP, and cathepsin k. The protein levels of RANK, p-Akt, p-p38, and p-ERK were examined by Western blotting. Luciferase reporter assay was conducted to determine whether miR-503 targeted RANK directly. Artesunate inhibited TRACP-positive cells and the pit-forming activity of osteoclasts. However, artesunate increased the expression of miR-503. Artesunate suppressed osteoclastogenesis-related gene expression and RANKL-induced activation of MAPKs and the AKT pathway. In addition, miR-503 inhibited RANK expression by directly targeting RANK during osteoclast differentiation. Artesunate inhibited osteoclastogenesis and osteoclast functions in vitro by regulating the miR-503/RANK axis and suppressing the MAPK and AKT pathways, which resulted in decreased expression of osteoclastogenesis-related markers.
研究领域:
药理学
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骨骼生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2013
·
IF 2.947
Guangzhao He,Huixin Qi,Meiyu Wang,Jingjing Yang,Fengjiao Wen,Weipeng Wang,Chunhua Qiao,Hongjian Zhang
Schistosomiasis is an infectious disease that has been recognized as a severe health burden for some regions of the world. While praziquantel is the drug of choice, there is an unmet medical need for novel therapies with greater efficacy and resistant profile. DW-3-15 is a novel and promising prodrug possessing both adult and juvenile schistosomes killing capability. Its proposed hydrolytic products, artesunate (ARS), dihydroartemisinin (DHA) and 10-hydroxypraziquantel (10-OHPZQ), are all active in preventing schistosomal infection in relevant disease models. To support pharmacokinetic and PK-PD studies of DW-3-15, a simple, specific and rapid liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed and validated for the simultaneous determination of the three active components in rat plasma. Using a short C 18 column (2.1 mm × 50 mm, 5 μm) with linear gradient, a baseline resolution of the three analytes and corresponding internal standards was achieved with a total run time of 6 min. Mass detection was carried out by electrospray ionization in positive MRM mode with ion transitions of m / z 402.2 → m / z 267.3 for ARS, m / z 302.2 → m / z 163.1 for DHA, and m / z 329.2 → m / z 219.4 for 10-OHPZQ. The method was linear over concentration ranges of 1.0–500 ng/mL for ARS, 5.0–2500 ng/mL for DHA, and 1.0–500 ng/mL for 10-OHPZQ. The accuracy was within ±10.0% for ARS, ±6.4% for DHA, and ±13.0% for 10-OHPZQ. The within-run and between-run precision of all three analytes at four concentrations tested were less than 15%, except at the LLOQ for DHA which was between 15 and 20%. The method was successfully applied to pharmacokinetic evaluation of DW-3-15 in rats following intravenous administration.
研究领域:
药理学
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分析化学
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传染病学
✓ 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）