CYTOTECHNOLOGY
·
2019
·Vol. 71
·期 4
·785-795
·
IF 1.672
Zhou Leilei,Weng Qi,Zheng Yixin,Zhou Yuqin,Li Qingyong,Li Fengzhi
Drug uptake and efflux are two of the critical factors required in order to be able to define drug efficacy. This study aims to investigate cytotoxicity and uptake mechanisms of two FL118 analogues (7-Q20 and val-FL118) in parallel with FL118 in three-dimensional multi-cellular spheroids model. The influence of compound concentration, time, temperature, cell lines, and the inhibitors of P-gp, BCRP and LAT1 on drug uptake and efflux were investigated. In vitro cytotoxicity studies revealed that FL118, 7-Q20 and val-FL118 exhibited sensitive cytotoxicity to the HCT-116 cell line and the water-soluble compound 7-Q20 showed the lowest IC 50 . Cellular uptake and efflux of FL118 was independent of efflux pump proteins. Uptake and efflux of 7-Q20 were affected by P-gp, which was one of reasons that caused a lower uptake at 37 °C than at 4 °C. The carrier protein LAT1 played a role in the cellular intakes of val-FL118. These findings provided basic information for FL118 and the two novel FL118 derivatives for further development.
研究领域:
药理学
·
肿瘤学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICAL CHROMATOGRAPHY
·
2014
·Vol. 28
·期 10
·1393-1401
·
IF 1.662
Bin Deng,Zhi-Ming Wang,Zi-Hao Zhou,Yi-Meng Liu,Xi-Liang Yang,Jian Song,Yu-Xiu Xiao
Cellular heterogeneity in doxorubicin (DOX) uptake and its relationship with pharmacological effect on cancer cells were quantitatively investigated for the first time. An in vitro experimental model was established by treating human leukemia K562 and breast cancer MCF-7 cells with different schedules of DOX with or without surface P-glycoprotein (P-gp) inhibitor verapamil (VER). The cellular heterogeneity in DOX uptake was quantitatively examined by single-cell analysis using capillary electrophoresis coupled with laser-induced fluorescence detection. The corresponding cytotoxic effect was tested by cellular morphology, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium and flow cytometry assays. The expression of cellular membrane surface P-gp was determined by flow cytometry. Results showed that the cellular heterogeneity exists in DOX uptake. The single-high DOX schedule leads to lower uptake heterogeneity and higher mean drug uptake. The cellular heterogeneity in DOX uptake was found to be negatively correlated with drug cytotoxicity and surface P-gp expression, with r = −0.7680 to ~ −0.9587. VER reduces the cellular variation in DOX uptake, suggesting that surface P-gp may be one of the causes of the cellular heterogeneity in DOX uptake. This research demonstrates the importance of quantitative study of cellular heterogeneity in drug uptake and its potential application in drug schedule design, response prediction and therapy modulation. Copyright © 2014 John Wiley & Sons, Ltd.
研究领域:
药理学
·
肿瘤学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Molecular Biosciences
·
2020
·
IF 4.188
Han Xiao,Xu Xiaoquan,Tang Yuxia,Zhu Feipeng,Tian Ying,Liu Wei,He Doudou,Lu Guangming,Gu Yunfei,Wang Shouju
Anaplastic thyroid cancer (ATC) is a highly aggressive and the most lethal type of thyroid cancer. The standard-of-care for unresectable ATC is radiotherapy and chemotherapy, usually based on doxorubicin (Dox). However, most patients develop resistance shortly after treatment. To overcome the drug resistance, we synthesized the mesoporous organosilica nanoparticles (MONPs) loaded with Dox and stabilized the nanocomposites by bovine serum albumin (BSA). The surface area and pore volume of MONPs were 612.653 m2/g and 0.589 cm3/g. The loading capacity of Dox-MONPs reached 47.02%. Compared to Dox-MONPs and free Dox, BSA-Dox-MONPs had more durable tumor-killing power on both drug-sensitive cell line HTh74 and drug-resistant cell line HTh74R. The cellular uptake of BSA-Dox-MONPs was 28.14 and 65.53% higher than that of Dox-MONP in HTh74 and HTh74R. Furthermore, the BSA coating decreased the efflux rate of nanocomposites in HTh74 (from 38.95 to 33.05%) and HTh74R (from 43.03 to 32.07%). In summary, BSA-Dox-MONPs reversed the chemotherapy resistance of ATC cells via increased drug uptake and inhibited drug efflux, offering a promising platform for the treatment of chemo-resistant ATC.
研究领域:
肿瘤学
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纳米技术
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药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2020
·Vol. 8
·期 7
·1496-1506
·
IF 5.344
Jianhua He,Yun Yang,Xiaoju Zhou,Wenli Zhang,Jianping Liu
Targeting drug delivery to macrophage/foam cells is challenged owing to the poor cell permeability and fluidity resulting from the massive accumulation of intracellular cholesterol in atherosclerosis (AS). Discoidal reconstituted high-density lipoprotein (d-rHDL) has been well regarded as a potential drug delivery system for AS by virtue of its plaque-targeting and cholesterol removal abilities, while the latter is compromised by the high activation energy of cholesterol efflux. It is reported that a low concentration of β-cyclodextrin (β-CD) can function as a cholesterol shuttle to promote cholesterol efflux from cells to the extracellular acceptors (cholesterol sink, such as HDL particles), but it is still unknown whether the combination of β-CD with a drug-loaded d-rHDL can function as a shuttle/sink model to promote the remodeling and drug release of the d-rHDL carrier after accelerating the cholesterol efflux. Furthermore, it is interesting to investigate whether enhanced cholesterol efflux can improve the cellular drug uptake by restoring the permeability and fluidity of the cell membrane. Here, simvastatin-loaded d-rHDL (ST-d-rHDL) was combined with different concentrations of β-CD. Compared with ST-d-rHDL alone, the cholesterol removal ability of ST-d-rHDL combined with 0.5 mM of β-CD increased by 31-fold after incubation for 6 h and the cumulative drug release of ST-d-rHDL increased by two-fold during the initial 1 h in an acellular mimetic system. In macrophage/foam cells, 0.5 mM of β-CD showed superior promoting effects in the cholesterol removal ability and remodeling of ST-d-rHDL compared to 0.1 mM of β-CD. The high concentration of β-CD at 2 mM displayed a low efficiency for accelerating cholesterol efflux, which might function as a cholesterol sink rather than a cholesterol shuttle. Moreover, the permeability and fluidity of the cell membrane were improved by combining 0.5 mM of β-CD with ST-d-rHDL, which exhibited an enhanced cellular drug uptake and inhibiting effect on the intracellular lipid deposition and secretion of inflammatory cytokine. Collectively, combination of β-CD and ST-d-rHDL as a shuttle/sink model could enhance cholesterol efflux and drug uptake to suppress inflammation in macrophage/foam cells.
研究领域:
药学
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心血管疾病
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2016
·
IF 8.387
Zi-Wei Jing,Yi-Yang Jia,Ning Wan,Min Luo,Meng-Lei Huan,Tai-Bin Kang,Si-Yuan Zhou,Bang-Le Zhang
The covalently modified ureido-conjugated chitosan/TPP multifunctional nanoparticles have been developed as targeted nanomedicine delivery system for eradication of Helicobacter pylori . H. pylori can specifically express the urea transport protein on its membrane to transport urea into cytoplasm for urease to produce ammonia, which protects the bacterium in the acid milieu of stomach. The clinical applicability of topical antimicrobial agent is needed to eradicate H. pylori in the infected fundal area. In this study, we designed and synthesized two ureido-conjugated chitosan derivatives UCCs-1 and UCCs-2 for preparation of multifunctional nanoparticles. The process was optimized in order to prepare UCCs/TPP nanoparticles for encapsulation of amoxicillin. The results showed that the amoxicillin-UCCs/TPP nanoparticles exhibited favorable pH-sensitive characteristics, which could procrastinate the release of amoxicillin at gastric acids and enable the drug to deliver and target to H. pylori at its survival region effectively. Compared with unmodified amoxicillin-chitosan/TPP nanoparticles, a more specific and effective H. pylori growth inhibition was observed for amoxicillin-UCCs/TPP nanoparticles. Drug uptake analysis tested by flow cytometry and confocal laser scanning microscopy verified that the uptake of FITC-UCCs-2/TPP nanoparticles was associated with urea transport protein on the membrane of H. pylori and reduced with the addition of urea as competitive transport substrate. These findings suggest that the multifunctional amoxicillin-loaded nanoparticles have great potential for effective therapy of H. pylori infection. They may also serve as pharmacologically effective nanocarriers for oral targeted delivery of other therapeutic drugs to treat H. pylori .
研究领域:
药学
·
纳米技术
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微生物学
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
XENOBIOTICA
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2020
·
IF 1.902
Ruicong Ma,Gentao Li,Xue Wang,Yajuan Bi,Youcai Zhang
To date, relatively little is known about the interactions of pharmaceutical excipients with hepatic and renal drug uptake transporters. The present study was designed to systematically evaluate the effects of 16 commonly consumed excipients on human organic cation transporter 1 and 2 (hOCT1 and hOCT2), human organic anion transporter 1 and 3 (hOAT1 and hOAT3) and human organic anion transporting polypeptide 1B1 and 1B3 (hOATP1B1 and hOATP1B3).The inhibitory effects and mechanisms of excipients on transporters were investigated using in vitro uptake studies, cell viability assays, concentration-dependent studies, and the Lineweaver–Burk plot method.Triton X-100 is a non-competitive inhibitor for all six transporters. Tween 20 inhibits hOCT2, hOAT1, hOAT3, and hOATP1B3 in a mixed way, whereas it competitively inhibits hOATP1B1. The inhibition of Tween 80 is competitive for hOCT2, non-competitive for hOATP1B1 and hOATP1B3, and mixed for hOAT1 and hOAT3. Concentration-dependent studies identify Triton X-100 as a strong inhibitor of hOCT1 and hOCT2 with IC50 values of 20.1 and 4.54 μg/mL, respectively. Additionally, Triton X-100, Tween 20, and Tween 80 strongly inhibit hOAT3 with IC50 values ≤31.0 μg/mL.The present study is significant in understanding the excipient–drug interactions and provides valuable information for excipient selection in drug development.
研究领域:
药理学
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药物开发
·
制药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2022
·
IF 6.51
Yan Liang,Ping-Yu Wang,You-Jie Li,Ze-Yun Liu,Ran-Ran Wang,Guang-Bin Sun,Hong-Fang Sun,Shu-Yang Xie
Reduced drug uptake and elevated drug efflux are two major mechanisms in cancer multidrug resistance (MDR). In the present study, a new multistage O 2 -producing liposome with NAG/R8-dual-ligand and stimuli-responsive dePEGylation was developed to address the abovementioned issues simultaneously. The designed C-NAG-R8-PTXL/MnO 2 -lip could also achieve magnetic resonance imaging (MRI)-guided synergistic chemodynamic/chemotherapy (CDT/CT). In vitro and in vivo studies showed that C-NAG-R8-PTXL/MnO 2 -lip enhanced circulation time by PEG and targeted the tumor site. After tumor accumulation, endogenous l -cysteine was administered, and the PEG-attached disulfide bond was broken, resulting in the dissociation of PEG shells. The previously hidden positively charged R8 by different lengths of PEG chains was exposed and mediated efficient internalization. In addition, the oxygen (O 2 ) generated by C-NAG-R8-PTXL/MnO 2 -lip relieved the hypoxic environment within the tumor, thus reducing the efflux of chemotherapeutic drug. O 2 was able to burst liposomes and triggered the release of PTXL . The toxic hydroxyl radical (·OH), which was produced by H 2 O 2 and Mn 2+ , strengthened CDT/CT. C-NAG-R8-PTXL/MnO 2 -lip was also used as MRI contrast agent , which blazed the trail to rationally design theranostic agents for tumor imaging.
研究领域:
药学
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生物医学工程
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癌症研究
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纳米技术
·
分子生物学
✓ 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）