CANCER LETTERS
·
2023
·
IF 9.7
Ruikun Lin,Lei Zhang,Biwei Ye,Yanan Wang,Yi-Dong Li,Hsu Jason,Wenzhen Liu,Ping Hu,Jincan Chen,Zhe-Sheng Chen,Zhuo Chen
P-glycoprotein (P-gp/ABCB1)-mediated multidrug resistance (MDR) in cancers severely limit chemotherapeutic efficacy. We recently reported that phosphatidylinositol-3-kinase (PI3K) 110α and 110β subunits can be novel targets for reversal of P-gp mediated MDR in cancers, and BAY-1082439 as an inhibitor specific for PI3K 110α and 110β subunits could reverse P-gp-mediated MDR by downregulating P-gp expression in cancer cells. However, BAY-1082439 has very low solubility, short half-life and high in-vivo clearance rate. Till now, nano-system with the functions to target PI3K P110α and P110β and reverse P-gp mediated MDR in cancers has not been reported. In our study, a tumor targeting drug delivery nano-system PBDF was established, which comprised doxorubicin (DOX) and BAY-1082439 respectively encapsulated by biodegradable PLGA-SH nanoparticles (NPs) that were grafted to gold nanorods (Au NRs) modified with FA-PEG-SH, to enhance the efficacy to reverse P-gp mediated MDR and to target tumor cells, further, to enhance the efficiency to inhibit MDR tumors overexpressing P-gp. In-vitro experiments indicated that PBDF NPs greatly enhanced uptake of DOX, improved the activity to reverse MDR, inhibited the cell proliferation, and induced S-phase arrest and apoptosis in KB-C2 cells, as compared with free DOX combining free BAY-1082439. In-vivo experiments further demonstrated that PBDF NPs improved the anti-tumor ability of DOX and inhibited development of KB-C2 tumors. Notably, the metastasis of KB-C2 cells in livers and lungs of nude mice were inhibited by treatment with PBDF NPs, which showed no obvious in-vitro or in-vivo toxicity.
研究领域:
肿瘤学
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药理学
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纳米技术
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癌症研究
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DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2021
·
IF 6.025
Yajing Fang,Fuqiang Liang,Mengmeng Xia,Weiwei Cao,Siyi Pan,Ting Wu,Xiaoyun Xu
This study was aimed to investigate the inhibitory activity of flavonoids on P-glycoprotein (P-gp). Effects of 39 flavonoids on the cellular uptake (CU) of rhodamine123 (Rho) and daunomycin (DNR) were investigated in both parental KB and P-gp overexpressed KB/MDR cells. The inhibition mechanism of selected flavonoids was further investigated by measuring the ATPase activity and expression level of P-gp. Twelve flavonoids improved the uptake of Rho (↑Rho F ) and nineteen flavonoids increased the uptake of DNR (↑DNR F ) in KB/MDR cells with nine flavonoids overlapped. Structure-activity relationship (SAR) indicated that 8-OCH 3 , and 2′-OH have a negative effect on Rho and DNR transport. Whereas 5-OH, 5-OCH 3 , 6-OH, 7-OCH 3 , 3′-OH, and 4′-OH, are essential for inhibition of flavonoids on P-gp and reversing the resistance of Rho and DNR. Eleven selected flavonoids significantly induced the basal P-gp-ATPase activity but much lower than that induced by verapamil . Tangeretin , galangin , kaempferol , quercetin , and morin significantly reversed the ATPase activity stimulated by verapamil. Six of eleven flavonoids significantly decreased P-gp expression, whereas three flavonoids slightly increased P-gp expression. These results provide valuable information that flavonoids can effectively reverse multidrug resistance of P-gp-mediated transport of nutraceutical and drugs by co-administration.
研究领域:
药理学
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肿瘤学
·
分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2016
·
IF 5.589
Jianyong Zhu,Ruimin Wang,Lanlan Lou,Wei Li,Guihua Tang,Xianzhang Bu,Sheng Yin
The phytochemical study of Pedilanthus tithymaloides led to the isolation of 13 jatrophane diterpenoids (1–13), of which eight (1–8) are new. Subsequent structural modification of the major components by esterification, hydrolysis, hydrogenation, or epoxidation yielded 22 new derivatives (14–35). Thus, a jatrophane library containing two series of compounds was established to screen for P-glycoprotein (Pgp)-dependent MDR modulators. The activity was evaluated through a combination of Rho123 efflux and chemoreversal assays on adriamycin resistant human hepatocellular carcinoma cell line HepG2 (HepG2/ADR) and adriamycin resistant human breast adenocarcinoma cell line MCF-7 (MCF-7/ADR). Compounds 19, 25, and 26 were identified as potent MDR modulators with greater chemoreversal ability and less cytotoxicity than the third-generation drug tariquidar. The structure–activity relationship (SAR) was discussed, which showed that modifications beyond just increasing the lipophilicity of this class of Pgp inhibitors are beneficial to the activity. Compound 26, which exhibited a remarkable metabolic stability in vitro and a favorable antitumor effect in vivo, would serve as a promising lead for the development of new MDR reversal agents.
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PubMed
高影响因子
Microbial Drug Resistance
·
2020
·Vol. 26
·期 2
·100-109
·
IF 2.519
Chong-Fa Lai,Wei-Bin Xiao,Hua-Cheng Yan,Hui Yang,Lu-Xia Wang,Hui Guan,Qiu-ju Peng,Zhi-Rong Deng,Jian-Wen Chen,Lin-Kun An,Lei Shi
ZTW-41, an indolizinoquinoline-5,12-dione derivative, was investigated for antibacterial activity against Gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA). In our study, the MIC90s (minimum inhibitory concentrations) of ZTW-41 against MRSA (MRSA, n = 200), methicillin-sensitive S. aureus (MSSA, n = 100), Enterococcus faecalis (E. faecalis, n = 32), and Enterococcus faecium (E. faecium n = 32) were 0.25, 0.25, 0.125, and 8 μg/mL, respectively, whereas the MBC90s (minimum bactericidal concentrations) were 2, 1, 1, and >32 μg/mL, respectively. ZTW-41 maintained its potency at different pH levels (range 5–9) and in starting inoculum size up to 107 CFU/mL. The presence of human serum (25–75%) increased ZTW-41 MICs by two- to eightfold. Time-kill curves showed that ZTW-41 had bactericidal activity against MRSA, MSSA, and E. faecalis strains within 8 hours, and rebound growth occurred after 8 hours except at higher multiples of the MIC (4 × and 8 × ). In the acute toxicity study, no mortality or signs of toxicity was noted in mice after 14 days of observation at doses <50 mg/kg. ZTW-41 exhibited good selectivity indices (SIs) (SI = IC50/MIC90) ranging from 1.12 to 71.76 against clinical isolates, demonstrating excellent therapeutic selectivity in MRSA, MSSA, and E. faecalis strains. Moreover, the in vivo efficacy (effective dose [ED]50 = 6.59 mg/kg) of ZTW-41 was found comparable with vancomycin. Collectively, our favorable results supported ZTW-41 as a promising investigational candidate for treating drug-resistant bacteria infection.
研究领域:
微生物学
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药理学
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感染病学
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DOI
PubMed
高影响因子
Microbial Drug Resistance
·
2021
·Vol. 27
·期 3
·337-341
·
IF 3.431
Mingzhi Wang,Bo Ma,Yunfeng Ni,Xiaoyan Xue,Mingkai Li,Jingru Meng,Xiaoxing Luo,Chao Fang,Zheng Hou
Multidrug resistance poses a severe threat to public health and urgently requires new solutions. The natural product chelerythrine (CHE) is a benzophenanthridine alkaloid with antimicrobial potential. In this study, CHE was effective against seven gram-positive bacterial strains, and the minimum inhibitory concentrations (MICs) ranged from 2 to 4 μg/mL. By contrast, CHE showed inferior antibacterial activities against 11 gram-negative strains, and the MICs varied from 16 to 256 μg/mL. We also determined the synergistic/additive effects of combining CHE with nine currently used antibiotics. CHE restored the antibacterial efficacy of the antibiotics against methicillin-resistant Staphylococcus aureus and extended-spectrum β-lactamases producing Escherichia coli. This study suggests that the combination of CHE with conventional antibiotics may be a promising strategy to combat infections caused by multidrug-resistant organisms.
研究领域:
微生物学
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药理学
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感染病学
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DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2024
·
IF 5.4
Juan Wang,Xinchen Zhao,Liyan Qiu
Multidrug resistance (MDR) is an incidental trouble post-chemotherapy, necessitating innovative therapeutic strategies. This study explores the potential of chloroquine (CQ) as a sensitizer for mitoxantrone hydrochloride (MitH) in drug-resistant tumors and introduces a novel pH-responsive drug-induced self-assembly nanovesicle (DIV) based on an amphiphilic polyphosphonitrile (PPAP) for the co-delivery of MitH and CQ. PPAP cannot self-assemble into nanovesicles alone, but when a certain amount of MitH was added, the multiple non-covalent interactions between PPAP and MitH contributed to the formation of DIV, which exactly improved the co-loading content of MitH and CQ to a large extent. CQ prevents MitH efflux and autophagy to reverse MitH resistance. Given the synergy between MitH and CQ at a 1:2 mass ratio with a combination index of 0.40 in K562/ADR cells, MitH and CQ co-loaded DIV (MC-DIV) is constructed and demonstrates a sensitivity index of 7.1 on cytotoxicity compared to free MitH. Furthermore, MC-DIV achieves extended circulation time, synchronous dual-drug delivery, and improved tumor targeting following systemic administration, resulting in exceptional antitumor efficacy in K562/ADR xenograft models with a tumor inhibition rate of 83.0 %. Overall, MC-DIV provides a viable method to maximize the loading capacity of nanocarriers, and potentially serves as a promising formulation for various MitH-resistant tumors.
研究领域:
药学
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肿瘤学
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纳米医学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2021
·
IF 5.875
Lanlan Zong,Haiyan Wang,Xianqiao Hou,Like Fu,Peirong Wang,Hongliang Xu,Wenjie Yu,Yuxin Dai,Yonghui Qiao,Xuefeng Wang,Qi Yuan,Xiaobin Pang,Guang Han,Xiaohui Pu
Tumor multidrug resistance (MDR) is one of the main reasons for the failure of clinical chemotherapy. Here, a bio-responsive anti-drug-resistant polymer micelle that can respond to the reductive GSH in the tumor microenvironment (TME) for delivery of HCPT was designed. A new type of polymer with anti-drug resistance and anti-tumor effect was synthesized and used to encapsulated HCPT to form reduction-sensitive micelles (PDSAH) by a thin-film dispersion method. It is demonstrated that the micelle formulation improves the anti-tumor activity and biosafety of HCPT, and also plays a significant role in reversing the drug resistance, which contributes to inhibiting the tumor growth and prolonging the survival time of H22 tumor-bearing mice. The results indicate that this nanoplatform can serve as a flexible and powerful system for delivery of other drugs that are tolerated by tumors or bacteria.
研究领域:
药学
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癌症研究
·
纳米技术
·
药物递送系统
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DOI
PubMed
高影响因子
RSC Advances
·
2020
·Vol. 10
·期 23
·13687-13695
·
IF 3.119
Wenhua Zhan,Xiaoxia Cai,Hairui Li,Getao Du,Hao Hu,Yayan Wu,Lin Wang
Multidrug resistance (MDR) is a huge challenge for gastric cancer chemotherapy. Therefore, MDR accurate monitoring is of great significance for the treatment of gastric cancer. GMBP1, an extracellular internalization peptide, can target MDR gastric cancer cells through specific binding to GRP78, which is an MDR-related protein that is overexpressed in gastric cancer cells. Herein, we constructed GMBP1 conjugated Mn3O4 nanoplates (Mn3O4@PEG-GMBP1 NPs) for in vivo monitoring of MDR gastric cancer through magnetic resonance imaging (MRI). The generated Mn3O4@PEG-GMBP1 NPs had a size of about 11 nm and exhibited a good colloidal stability in PBS and in 10% FBS medium. Serial in vivo MRI studies in mice demonstrated that the magnetic resonance signal intensity, at the tumor site, reached a peak at 3 h after tail vein injection of Mn3O4@PEG-GMBP1 NPs. The specific targeting ability of MDR gastric cancer cells (SGC7901/ADR) by Mn3O4@PEG-GMBP1 NPs was authenticated in vitro, in vivo and by immunofluorescence analysis experiments. The systematic safety evaluation indicated that the toxicity of Mn3O4@PEG-GMBP1 NPs in mice was negligible. Therefore, the GMBP1 conjugated Mn3O4 nanoplates can be clinically used for accurate imaging and monitoring of MDR gastric cancer.
研究领域:
生物医学工程
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肿瘤学
·
分子影像学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·
IF 7.3
Taoran Wang,Long Tian,Jiangmin Zeng,Ziyao Ning,Li Zhang,Chunhui Zhao,Shuyuan Jiang,Chunlan Zeng,Jiaqi Han,Liang Luan,Weifeng Ye,Qingbin Meng
The rational design of proteolytically stable antimicrobial peptides (AMPs) is crucial for combating antibiotic resistance. Although cyclization has been extensively applied to stabilize α-helical and random-coiled AMPs, its impact on the structure–activity relationship of β-turn AMPs remains underexplored. Here, we engineered cyclized derivatives of P-07─a linear β-turn AMP developed by our group─via disulfide/lactam bond cyclization and d-amino acid substitution. The lead candidate, PT-17, exhibited remarkably enhanced stability, retaining potent broad-spectrum activity against MDR pathogens and a high therapeutic index. Additionally, PT-17 exhibited rapid membrane disruption ability, low potential to induce bacterial resistance, and synergy with conventional antibiotics. In a murine infection model, PT-17 achieved a significant reduction of Escherichia coli (MDR) loads in the main organs with undetectable toxicity. This study provides comprehensive evidence that cyclization and d-amino acid substitution confer synergistic stability to β-turn AMPs without compromising activity, offering a viable strategy for developing novel AMPs with clinical potential.
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PubMed
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
·
2023
·
IF 3.5
Yan-Yan Zhu,Zhao-Jie Wang,Meng Zhu,Zhong-Shun Zhou,Bin-Yuan Hu,Mei-Zhen Wei,Yun-Li Zhao,Zhi Dai,Xiao-Dong Luo
It’s urgent to discover new antibiotics along with the increasing emergence and dissemination of multidrug resistant (MDR) bacterial pathogens. In the present investigation, morusin exhibited rapid bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) by targeting the phospholipid of bacterial inner membrane, increasing membrane rigidity and disrupting bacterial homeostasis together with the membrane permeability, which caused fundamental metabolic disorders. Furthermore, morusin can also accumulate ROS, suppress H 2 S production, and aggravate oxidative damage in bacteria. Importantly, morusin also inhibited the spread of wounds and reduced the bacterial burden in the mouse model of skin infection caused by MRSA. It’s a chance to meet the challenge of existing antibiotic resistance and avoid the development of bacterial resistance, given the multiple targets of morusin.
研究领域:
微生物学
·
药理学
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传染病学
·
分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2025
·
IF 4.9
Xinxin Liu,Zhengfei Hong,Rongrong Li,Shuxian Hou,Xuechao Shi,Guoqiang Yang,Yuxuan Wang,Yimei Wang,Zhiru Tao,Jun Ge,Fei Ge,Yiyan Song,Jun Wang
Wound infections caused by surgery, chronic ulcers, or trauma have been a challenge for clinicians, especially multiple resistant bacteria induced by the misuse of antibiotics, which has increased the risk of bacterial infection. It is very urgent to design and develop antimicrobial materials with potential for clinical application against drug-resistant bacterial infections. In this study, a photothermal montmorillonite-chitosan hydrogel system (MNT-CS Gel) was fabricated as a photothermal antimicrobial dressing. This study found for the first time that montmorillonite (MNT) has good photothermal properties and photothermal conversion efficiency under near-infrared (NIR) light, and on this basis, its application research was carried out. The MNT possesses broad-spectrum antibacterial activity with significant inhibitory effects against E. coli and S. aureus, excellent photothermal stability under NIR light. And all the performances were improved after combining with CS-Gel, especially in bacterial adsorption capacity and photothermal performance. Notably, MNT-CS Gel was used as a photothermal antibacterial agent for the first time, and the antibacterial effects in vitro and their mechanisms have been systematically investigated. It was found that the MNT-CS Gel had significant inhibitory and destructive effects on bacteria in an in vitro pigskin model. The MNT-CS Gel could adsorb the bacteria strongly, inhibit bacterial biofilm formation, induced the generation of ROS, destroy the structure of bacteria, and cause the leakage of nucleic acids. The MNT-CS Gel demonstrated good photothermal antimicrobial properties, suggesting that the MNT-CS Gel has potential for clinical hygiene applications.
研究领域:
生物医学工程
·
材料科学
·
微生物学
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产品关联
DOI
高影响因子
Asian Journal of Pharmaceutical Sciences
·
2021
·
IF 6.598
Yong Xu,Shi Wang,Longshun Yang,Yuhang Dong,Yafang Zhang,Guoqing Yan,Rupei Tang
TPGS approved by FDA can be used as a P-gp inhibitor to effectively reverse multi-drug resistance (MDR) and as an anticancer agent for synergistic antitumor effects. However, the comparatively high critical micelle concentration (CMC), low drug loading (DL) and poor tumor target limit its further clinical application. To overcome these drawbacks, the pH-sensitive star-shaped TPGS copolymers were successfully constructed via using pentaerythritol as the initial materials, ortho esters as the pH-triggered linkages and TPGS active-ester as the terminated MDR material. The amphiphilic star-shaped TPGS copolymers could self-assemble into free and doxorubicin (DOX)-loaded micelles at neutral aqueous solutions. The micelles exhibited the lower CMC (8.2 × 10 −5 mg/ml), higher DL (10.8%) and long-term storage and circulation stability, and showed enhanced cellular uptake, apoptosis, cytotoxicity, and growth inhibition for in vitro MCF-7/ADR and/or MCF-7/ADR multicellular spheroids and in vivo MCF-7/ADR tumors via efficiently targeted drug release at tumoral intracellular pH (5.0), MDR reversal of TPGS, and synergistic effect of DOX and TPGS. Therefore, the pH-sensitive micelles self-assembled from star-shaped TPGS copolymers with ortho ester linkages are potentially useful to clinically transform for enhanced MDR cancer treatment.
研究领域:
药学
·
纳米技术
·
癌症研究
·
药物递送系统
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）