BIOCHEMICAL PHARMACOLOGY
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2021
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IF 5.858
Xiaohua Lu,Ge Yan,Sabine M. Klauck,Edmond Fleischer,Anette Klinger,Yoshikazu Sugimoto,Letian Shan,Thomas Efferth
After decades of research, multidrug resistance (MDR) remains a huge challenge in cancer treatment. In this study, the cytotoxic of 4-hydroxy-N-(naphthalen-1-yl)-2-oxo-2H-chromene-3-carboxamide (MCC1734) has been investigated towards multidrug-resistant cancer cell lines. MCC1734 exerted cytotoxicity on cell lines expressing different mechanisms of drug resistance (P-glycoprotein, BCRP, ABCB5, EGFR, p53 knockout) to a different extent. Interestingly, sensitive CCRF-CEM cells and multidrug-resistant P-gp-overexpressing CEM/ADR5000 cells represented similar sensitivity towards MCC1734, indicating MCC1734 can bypass P-gp-mediated resistance. Microarray-based mRNA expression revealed that MCC1734 affected cells by multiple pathways, including cell cycle regulation, mitochondrial dysfunction, apoptosis signaling, and EIF2 signaling. MCC1734 stimulated the generation of excessive reactive oxygen species and the collapse of mitochondria membrane potential in CCRF-CEM cells, companied by the arrest of the cell cycle in the G 2 M phase and apoptosis induction as determined by flow cytometry. In addition, our immunoblotting analysis highlighted that MCC1734 triggered endoplasmic reticulum (ER) stress, evidenced by the activation of p-PERK, p-eIF2α, ATF4 and CHOP. The anti-cancer effects of MCC1734 were further observed in vivo using human xenograft tumors transplanted to zebrafish, providing further support for MCC1734 as a promising new candidate for cancer drug development.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2022
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IF 11.467
Chun-Nan Zhu,Mei-Yu Lv,Fei Song,Dong-Yun Zheng,Chao Liu,Xiao-Jun Liu,Dong-Bing Cheng,Zeng-Ying Qiao
The drug efflux by P-glycoprotein (P-gp) is the primary contributor of multidrug resistance (MDR), which eventually generates insufficient nuclear drug accumulation and chemotherapy failure. In this paper, reversible covalent nanoassemblies on the basis of catechol-functionalized methoxy poly (ethylene glycol) (mPEG- dop) and phenylboronic acid-modified cholesterol (Chol-PBA) are successfully synthesized for delivery of both doxorubicin (DOX, anti-cancer drug) and tariquidar (TQR, P-glycoprotein inhibitor), which shows efficient nuclear DOX accumulation for overcoming tumor MDR. Through naturally forming phenylboronate linkage in physiological circumstances, Chol-PBA is able to bond with mPEG- dop. The resulting conjugates ( PC ) could self-assemble into reversible covalent nanoassemblies by dialysis method, and transmission electron microscopy analysis reveals the PC distributes in nano-scaled spherical particles before and after drug encapsulation. Under the assistance of Chol, PC can enter into lysosome of tumor cells via low-density lipoprotein (LDL) receptor-mediated endocytosis. Then the loaded TQR and DOX are released in acidic lysosomal compartments, which inhibit P-gp mediated efflux and elevate nuclear accumulation of DOX, respectively. At last, this drug loaded PC nanoassemblies show significant tumor suppression efficacy in multidrug-resistant tumor models, which suggests great potential for addressing MDR in cancer therapy.
研究领域:
药学
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纳米技术
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癌症研究
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2023
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IF 9.9
Xiaochen Qiu,Liang Zhuang,Jian Yuan,Huizhen Wang,Xiaoyu Dong,Shan He,Shanyue Guan,Zhiyue Chang,Pengtao Bao
Developing an effective strategy to combat multi-drug-resistant (MDR) bacteria and promote wound healing without overuse of antibiotics remains an important and challenging goal. Herein, we established a synergistic reactive oxygen species (ROS) and reactive nitrogen species (RNS)-mediated nanocatalytic therapy, which was consisted of a multifunctional Cu single-atom nanozyme loaded with the l -arginine ( l -Arg@Cu-SAzymes) and a low level of hydrogen peroxide (H 2 O 2 ) as a trigger. l -Arg@Cu-SAzymes can possess excellent dual enzyme-like activities: catalase (CAT)-like activity that decompose H 2 O 2 into O 2 , and subsequent oxidase (OXD)-like activity that convert O 2 to cytotoxic superoxide anion radical (•O 2 − ). Meanwhile, l -Arg@Cu-SAzymes can also be triggered by H 2 O 2 to release nitric oxide (NO), which can continue to react with •O 2 – to generate more lethal peroxynitrite (ONOO − ). Collectively, the synergistic ROS and RNS mediated by l -Arg@Cu-SAzymes endow the treatment system with an outstanding antibacterial ability against MDR bacteria and reduce the inflammation at the wound site. Furthermore, l -Arg@Cu-SAzymes-mediated NO and O 2 release promote the cell proliferation , collagen synthesis, and the angiogenesis , as well as facilitate macrophage polarization to reparative M2 phenotype, thereby accelerating wound closure and tissue remodeling. Therefore, l -Arg@Cu-SAzymes-based synergistic nanocatalytic therapy can be regarded as a promising strategy for MDR bacterial infected wounds treatment, owing to their potent antibacterial efficacy and enhanced tissue remodeling effects.
研究领域:
纳米技术
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生物材料
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生物医学工程
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微生物学
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伤口愈合
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2022
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IF 16.744
Xiaolu Chen,Rongying Ma,Zhaoming Fu,Qianhong Su,Xingyu Luo,Yingchao Han,Yong Yang,Qingchun Deng
Multidrug resistance (MDR) of cancer is the main reason for cancer chemotherapy failure, and the use of anticancer drugs usually brings about adverse side effects to patients. Therefore, the aim of developing new cancer treatments must consider overcoming MDR and abating the toxicity of drugs to normal tissues. In this work, we designed and prepared multifunctional cascade amplification delivery nanoparticles (CADNs) with a core structure composed of glucose oxidase (GOx)-attached Fe 3 O 4 nanoparticles, and a shell layer of PEGylated metal-phenolic networks (MPNs), in which the prodrug of doxorubicin (pDOX) was loaded. In vitro assays showed that the MPNs had dual sensitivities to acidic and reducing conditions, and the CADNs promoted the production of hydroxyl radicals in the presence of H 2 O 2 and glucose. Besides, cellular experiments demonstrated that CADNs could efficiently facilitate the accumulation of pDOX in doxorubicin-resistant MCF-7/Adr cells and enhance cancer cell death under the combined action of ferroptosis and chemotherapy. Furthermore, in vivo assays also showed that CADNs with a PEGylated surface could effectively target tumors, and dramatically suppress the growth of both MCF-7 and MCF-7/Adr tumors, with excellent biosafety. This work presents a novel strategy for overcoming cancer MDR by driving cascade reactions to achieve starvation/chemodynamic/chemo combination therapy.
研究领域:
纳米技术
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药学
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癌症研究
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生物医学工程
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产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2022
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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
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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）