Drug Design Development and Therapy
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2025
·
IF 5.1
Wei-Chong Dong,Shuai-Shuai Gao,Bo Shi,Hao-Ran Li,Ye Jiang,Jia-Liang Guo,Zhi-Qing Zhang,Ying-Ze Zhang
Background High-dose methotrexate (HD-MTX) is seen as an effective therapy for acute lymphoblastic leukemia (ALL); however, it is extremely toxic. Monitoring the plasma concentrations of methotrexate (MTX) and its important metabolite, 7-hydroxy-methotrexate (7-OH-MTX), on a routine basis aids in dose modification of rescue medications and in avoiding toxicity. The pharmacologically active and toxic effects of drugs are due to the unbound portion, as most drugs are bound to plasma proteins to some degree. However, the simultaneous measurement of unbound plasma concentrations of MTX and 7-OH-MTX has not been reported.Methods We developed and validated a hollow fiber centrifugal ultrafiltration (HFCF-UF) technology to simultaneously analyze unbound MTX and 7-OH-MTX concentrations in human plasma. In total, 234 plasma samples from 58 children diagnosed with ALL who were administered HD-MTX were used in our study. We investigated the connection between unbound and total plasma concentrations of MTX and 7-OH-MTX, as well as how these concentrations relate to liver and renal function.Results The method that was developed is both simple and accurate. A weak linear relationship was observed between the concentrations of unbound and total 7-OH-MTX (r2 = 0.732). The concentration of total MTX and unbound 7-OH-MTX were both positively correlated with creatinine (Cr) levels and negatively correlated with Creatinine clearance (CCr). There was a wide variation in the concentration ratios of 7-OH-MTX to MTX, both total and unbound, and these ratios were significantly lower in individuals with impaired liver function.Conclusion The total concentration of 7-OH-MTX is an unreliable predictor of unbound concentration, necessitating the monitoring of unbound levels. The concentration ratios of 7-OH-MTX to MTX (both total and unbound) could be more accurate and sensitive biomarkers for predicting hepatotoxicity.
研究领域:
药理学
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肿瘤学
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临床医学
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DOI
PubMed
高影响因子
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
·
2022
·
IF 3.712
Sa-sa Zhang,Yi-jin Wu,Shu Pan,Qi-hai Wang,Wen-gang Chen,Zhong-fang Wang,Jin-ying Xu,Jian Zuo,Qin Yin
Background The first-line anti-rheumatic drug methotrexate (MTX) is used in the combination. Because of the unpredictable adverse reactions, optimization of relevant regimens is necessary and meaningful. This study aimed to study the possible interaction between Securidaca inappendiculate Hassk. Derived xanthones and MTX.Methods We established adjuvant-induced arthritis (AIA) model, which was treated with MTX and MTX + xanthone-rich fraction (XRF). The clinical efficacy was evaluated by histopathological examination, and LC-MS was used to monitor the blood concentration of MTX. Western blotting and immunohistochemistry were used to detect protein expression. In vitro, we assessed the activity of related transporters by cellular uptake assay based on HEK-293T cells.Results Compared with MTX-treated rats, inflammation in the immunized rats in the MTX + XRF group was obvious, indicating that XRF antagonized the anti-rheumatic effect of MTX. Meanwhile, XRF reduced liver and kidney injuries caused by MTX in addition to MTX. Results from immunohistochemical and nappendiculat assays suggested that XRF may reduce uptake of MTX by down-regulating reduced folate carrier 1 (RFC1).Conclusion This study indicated that XRF could reduce the plasma concentration of MTX by inhibiting the expression of RFC1, antagonize the therapeutic effect of MTX on AIA rats, and reduce its oral bioavailability. The combination of S. inappendiculate and MTX should be further optimized to achieve the goal of increasing efficiency and reducing toxicity.
研究领域:
药理学
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风湿病学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2024
·
IF 4.3
Shulin Shen,Xi Zheng,Xu Dong,Min Fang,Aiqun Wan,Tong Zhu,Qingliang Yang,Jing Xie,Qinying Yan
Methotrexate (MTX) is a first-line drug in treating psoriasis because of its strong anti-proliferation and anti-inflammatory effects. However, systemic administration of MTX will lead to many side effects, such as gastrointestinal irritation, liver and kidney toxicity, etc. Herein, we developed liposome-loaded microneedles (MNs) system to improve transdermal efficiency, which was used to overcome the problems of low transdermal efficiency and poor therapeutic effect of traditional transdermal drug delivery methods. Hyaluronic acid (HA) was modified on the surface of MTX-loaded liposomes. The interaction of HA and CD44 could increase the adhesion of HA-MTX-Lipo to HaCaT cells, thereby promoting the apoptosis or death of HaCaT cells. Results indicated HA-MTX-Lipo MNs could inhibit the development of psoriasis and reduce the degree of skin erythema, scaling, and thickening. The mRNA levels of proinflammatory cytokines such as IL-17A, IL-23, and TNF-α were decreased. The epidermal thickness and proliferative cell-associated antigen Ki67 expression were also reduced. Specifically, the expression of mRNA levels of proinflammatory cytokines was down-regulated. The MNs transdermal delivery of HA-modified-MTX liposomes provided a promising method for treating psoriasis.
研究领域:
药剂学
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皮肤病学
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生物医学工程
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DOI
PubMed
高影响因子
JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A
·
2018
·Vol. 107
·期 2
·319-329
·
IF 3.231
Jianhui Chen,Xiaofeng Chen,Zhengyu Yang,Xiaojun Tan,Jiachen Wang,Yao Chen
We have successfully prepared a novel targeted drug delivery system, composed of folic acid (FA) as targeting molecule, methotrexate (MTX) as anticancer drug, and bioactive glass (BG) as carrier. The BG nanoparticles were synthesized by sol-gel method with the dodecylamine as template. The surface of BG nanoparticles was grafted with amino groups by (3-aminopropyl) triethoxysilane, then, FA and MTX were covalently conjugated to the surface of modified BG through amidation reaction, so FA functionalized BG (BG-FA) and targeted drug delivery system (MTX-BG-FA) were prepared. The physicochemical properties of BG, BG-NH 2 , and BG-FA were characterized by various methods, such as X-ray diffraction, scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, ultraviolet–visible, and so on. Moreover, the drug release results showed that the MTX-BG-FA had sustained release property because of the peptide bond between MTX and BG-FA. And the cytocompatibility evaluation demonstrated that the BG and BG-FA were biocompatible and BG-FA even could promote cell proliferation, while the MTX-BG-FA had high cytotoxicity owning to the sustained release of anticancer drug. From the above, it could be concluded that MTX-BG-FA could kill tumor cells targetedly and sustainedly, which made it a good cancer targeted therapy material. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 319–329, 2019.
研究领域:
生物材料学
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肿瘤学
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药剂学
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产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2025
·
IF 4.7
Nan Li,Feng-xiang Pang,Yu-wan Zhou,Shou-chang Ding,Chuan-jian Shi,Rui-jia Wen,Yong-xin Mai,Xian-lin Wu,Jin-fang Zhang
Background Osteosarcoma (OS) is a malignant primary tumor in bone tissues, and Methotrexate (MTX) is widely used as a chemotherapeutic drug for OS in clinical treatment. However, MTX resistance is a major challenge for OS patients. Polydatin (PD) is an extract derived from Reynoutria japonica Houtt and has been identified as a potential agent for reversing chemotherapy resistance in cancer. We therefore wondered whether PD could alleviate MTX resistance in OS. Methods The effect of PD on MTX resistance was investigated. And H19 expression was examined in the PD-treated OS cells. The association between H19 and MTX resistance in osteosarcoma was investigated.The effects of H19 on MTX resistance in osteosarcoma were evaluated by cell proliferation, colony formation, ChIP and western blotting assays. In order to investigate the molecular mechanism of PD underlying methotrexate resistance in OS, the cell proliferation, colony formation, q-PCR and western blotting were examined. Results In the present study, PD was found to act as a novel MTX sensitizer, and significantly enhanced the suppressive effects of MTX on OS in vitro and in vivo . Mechanically, PD was demonstrated to suppress the expression of long non-coding RNA H19 as well as its binding protein histone methyltransferase Enhancer of zeste homolog 2 (EZH2), and thus reduced the trimethylation of histone H3K9 (H3K9me3) and K27 (H3K27me3). Furthermore, H19 knowndown increased the binding ability of H3K9me3 and H3K27me3 with the folate metabolism-related genes RFC-1 and PCFT's promoter, and influenced folate metabolism and MTX resistance. Conclusion In conclusion, our results indicated that PD alleviated MTX resistance in OS via the H19/H3K27me3/H3K9me3 mediated folate metabolism regulatory axis. The translational potential of this article The findings of this study validate the function of PD in alleviating MTX resistance, and provide the new insight into developing PD as a promising drug candidate for the MTX resistant OS patients.
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
Materials Science & Engineering C-Materials for Biological Applications
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2019
·
IF 4.959
Chengqiang Ding,Hongwei Wu,Zheng-Zhi Yin,Jun Gao,Datong Wu,Yong Qin,Yong Kong
Hydrophilic poly (acrylic acid) (PAA) and hydrophobic α-tocopherol succinate (TOS) were integrated via a two-step amidation with cystamine (Cys) as the linkage, and then the self-assembly of amphiphilic PAA-cys-TOS occurred in the aqueous solution of methotrexate (MTX), an anti-cancer drug, resulting a vesicle structured drug carrier. Since the disulfide (–S–S–) bridge of Cys is sensitive to glutathione (GSH) and the amide bonds in PAA-cys-TOS are sensitive to pH, disulfide-cleavage- and pH-triggered drug delivery was achieved with the amphiphilic self-assembly. Of particular interest was that the topography of the self-assembly varied remarkably during the triggered delivery, which was indicated by TEM results.
研究领域:
药剂学
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生物化学
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肿瘤学
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DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2020
·
IF 5.115
Yun-Chun Zhao,Hai-Li Zheng,Xiao-Rong Wang,Xiao-Ling Zheng,Yue Chen,Wei-Dong Fei,Yong-Quan Zheng,Wen-Xi Wang,Cai-Hong Zheng
Background Methotrexate (MTX) is an antiproliferative drug widely used to treat inflammatory diseases and autoimmune diseases. The application of percutaneous administration is hindered due to its poor transdermal penetration. To reduce side effects and enhanced percutaneous delivery of MTX, novel methotrexate (MTX)-loaded micelles prepared with a amphiphilic cationic material, N,N-dimethyl-(N′,N′-di-stearoyl-1-ethyl)1,3-diaminopropane (DMSAP), was designed.Materials and Methods DMSAP was synthesized via three steps using simple chemical agents. H nuclear magnetic resonance and mass spectroscopy were used to confirm the successful synthesis of DMSAP. A safe and non-toxic phosphatidylcholine, soybean phosphatidylcholine (SPC), was added to DMSAP at different ratios to form P/D-micelles. Then, MTX-entrapped micelles (M/P/D-micelles) were prepared by electrostatic adsorption. The physicochemical properties and blood stability of micelles were examined thoroughly. In addition, the transdermal potential of the micelles was evaluated by permeation experiments.Results In aqueous environments, DMSAP conjugates could self-assemble spontaneously into micelles with a low critical micelle concentration (CMC) of 0.056 mg/mL. Stable, spherical MTX-entrapped micelles (M/P/D-micelles) with a size of 100–120 nm and high zeta potential of +36.26 mV were prepared. In vitro permeation studies showed that M/P/D-micelles exhibited superior skin permeability and deposition of MTX in the epidermis and dermis compared with that of free MTX.Conclusion These special novel cationic M/P/D-micelles can enhance the permeability of MTX and are expected to be a promising percutaneous delivery system for therapy skin diseases.
研究领域:
药剂学
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皮肤病学
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生物材料
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产品关联
DOI
PubMed
高影响因子
Nanomaterials
·
2019
·Vol. 9
·期 6
·860
·
IF 4.034
Ji Chen,Guotao Li,Qihong Liu,Yan Liang,Miaochang Liu,Huayue Wu,Wenxia Gao
Accelerating degradation of prodrug is an effective strategy for improving the pharmacological action. A photocleavable amphiphilic prodrug of methotrexate-coumarin derivative-PEG conjugates (MTX-AMC-PEG) with photo-triggered breakage to release clinical drug under laser irradiation was fabricated and self-assembled into nanoparticles for chemotherapy. The nanoparticles exhibited good intracellular uptake and excellent photolysis release of MTX, which resulted in efficient anticancer activity in vitro with laser irradiation. This research provides a way to fabricate photocleavable prodrug nanoparticles with stimuli-triggered drug release behavior.Keywords:prodrug;photocleavable;stimuli-responsive release;methotrexate;chemotherapy
研究领域:
药学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
Materials Science & Engineering C-Materials for Biological Applications
·
2017
·
IF 4.164
Xin Ji,Huilong Guo,Qiao Tang,Dong Ma,Wei Xue
Antitumor efficacy of methotrexate (MTX) is seriously limited due to its poor water solubility, nonspecific tumor distribution and low bioavailability. To overcome these obstacles, polyspermine (PSP) conjugated with MTX and folic acid (FA) as a novel targeted prodrug was designed and has been successfully synthesized using the amidation reaction. The strong hydrophilic properties of PSP made MTX well dispersed in water and the cellular uptake study indicated that the presence of FA enhanced uptake of the FA-PSP-MTX in folate receptor (FR) over-expressing human nasopharyngeal carcinoma HNE-1 cells. 1 H NMR spectra and UV–Vis spectral analysis were carried out to confirm the MTX and FA content in FA-PSP-MTX, respectively. In CCK-8 assay and apoptosis analysis, the prodrug showed significantly enhanced anticancer efficacy than free MTX in HNE-1 cells. These results suggested that the prodrug has the potential for targeted delivery of MTX into cancer cells to improve its anti-tumor efficacy.
研究领域:
药理学
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肿瘤学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
CERAMICS INTERNATIONAL
·
2018
·
IF 3.057
Jingwei Wang,Yong Kong,Feng Liu,Dan Shou,Yongxin Tao,Yong Qin
Construction of simple and convenient platforms for controlled delivery of anti-cancer drugs is of great importance for medical science and pharmaceutics. Here, chitosan (CS) gels were used to induce the growth of calcium carbonate (CaCO 3 ) microspheres , and the resulting CaCO 3 microspheres were well dispersed within the three-dimensional (3D) network framework of the CS gels. The synthesized CaCO 3 /CS composites were then examined by field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), Fourier transform infrared spectrometry (FT-IR) and X-ray diffractometry (XRD). Finally, the designed CaCO 3 /CS composites were used for loading and controlled delivery of methotrexate (MTX), an anti-cancer drug. The encapsulation ratio of MTX calculated by UV–vis spectroscopy was approximately 78.8%. In addition, pH-responsive delivery of MTX from the CaCO 3 /CS composites was successfully achieved due to the pH-sensitive property of CS, and the cumulative release of MTX could reach 93.3%, 86.6% and 77.6% at pH 8.5, 7.4 and 5.8, respectively.
研究领域:
医学
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药剂学
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材料科学
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DOI
高影响因子
ANALYTICA CHIMICA ACTA
·
2018
·
IF 5.123
Yanan Zhao,Shiying Zou,Danqun Huo,Changjun Hou,Mei Yang,Junjie Li,Minghong Bian
Reliable and simple detection methods for chemotherapeutic agent contaminants, such as methotrexate , are required to minimize their possible toxic threat. However, detecting them remains a challenging in environmental and biological analysis. Here, we developed a fluorescent N, S co-doped carbon quantum dots (N, S co-doped CQDs) probe to detect methotrexate on the basis of the inner filter effect of fluorescence. Under optimized conditions, the fluorescent probe exhibits high sensitivity and specific selectivity with a linear detection range from 0.4 μg/mL to 41.3 μg/mL and a low detection limit of 12 ng/mL (S/N = 3). Further, this N, S co-doped CQDs fluorescent probe can be used to analyze extracellular fluids and wastewater samples satisfactorily, thereby showing a remarkable potential for broad applications in biological molecule determination and environmental analysis .
研究领域:
生物医学
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环境科学
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分析化学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Wen Tang,Huiwen Hou,Hanlin Wang,Xinqing Gao,Feiyan Zhao,Yuhan Di,Shengli Ji,Peixue Ling,Fengshan Wang,Feng Sun,Haining Tan
Cancer presents a significant health threat, necessitating the development of more precise, efficient, and less damaging treatment approaches. To address this challenge, we employed the 1-ethyl-(3-dimethyl aminopropyl) carbodiimide/N-hydroxy succinimide (EDC/NHS) catalytic system and utilized quaternized chitosan oligosaccharide (HTCOSC) as a drug carrier to construct a nanoparticle delivery system termed HTCOSC-cRGD-ES2-MTX (CREM). This system specifically targets integrin αvβ3 on tumor cell surfaces and enables simultaneous loading of the antiangiogenic agent ES2 (IVRRADRAAVP) and the chemotherapy drug methotrexate (MTX). Due to its amphiphilic properties, CREM self-assembles into nanoparticles in aqueous solution, exhibiting an average diameter of 179.47 nm. Comparative studies demonstrated that CREM, in contrast to free ES2 and MTX-free nanoparticles (CRE), significantly suppressed the proliferation of EAhy926 endothelial cells and B16 melanoma cells in vitro, resulting in inhibition rates of 71.18 and 82.25%, respectively. Furthermore, CREM exhibited a hemolysis rate below 2%, indicating excellent in vitro antiangiogenic and antitumor activity as well as favorable blood compatibility. Additionally, both CRE and CREM demonstrated favorable tumor targeting capabilities through the specific binding action of cyclic RGD (cRGD) to integrin αvβ3. Further in vivo investigations revealed that CREM induced apoptosis in tumor cells via the mitochondrial apoptotic pathway and reduced the expression of angiogenic factors such as vascular endothelial growth factor (VEGF), thereby inhibiting tumor angiogenesis. This potent antitumor effect was evident through a tumor suppression rate of 80.19%. Importantly, histopathological staining (HE staining) demonstrated the absence of significant toxic side effects of CREM on various organs compared to MTX. In conclusion, the CREM nano drug delivery system synergistically enhances the therapeutic efficacy of antiangiogenic drugs and chemotherapeutic agents, thus offering a novel targeted approach for cancer treatment.
研究领域:
药学
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肿瘤学
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纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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