Journal of Materials Chemistry B
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2017
·Vol. 5
·期 42
·8399-8407
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IF 4.543
Dan Zhao,Shujie Ma,Xiaoqing Yi,Sixue Cheng,Renxi Zhuo,Feng Li
Herein, a pH and redox dual-sensitive core-crosslinked targeting nanocarrier was prepared and used for co-delivery of doxorubicin (DOX) and tariquidar (TQR). The nanocarrier not only had excellent stability but also prevented the leakage of the drug in the normal physiological environment efficiently. Meanwhile, the targeting function of nanocarriers could also be suppressed in the normal physiological environment, protecting nanocarriers from being captured by RAW264.7 cells. Under mild acidic conditions, the targeting function was regained, leading to an effective tumor cell uptake of the nanocarrier. Furthermore, reduction-responsive drug release would occur in the cytoplasm due to the collapse of the reduction-sensitive crosslinked structure in the nanocarrier. By means of ligand–receptor mediated endocytosis and TQR-mediated glycoprotein (P-gp) inhibition, the IC50 value of DOX to MCF-7/ADR cells reduced from more than 100 μg mL−1 to 8.55 μg mL−1, exhibiting great potential in overcoming drug resistance.
研究领域:
纳米技术
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药学科学
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癌症研究
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Polymer Chemistry
·
2015
·Vol. 6
·期 13
·2445-2456
·
IF 5.52
Minghui Xu,Junmin Qian,Aili Suo,Ting Liu,Xuefeng Liu,Hongjie Wang
To enhance the therapeutic efficacy of doxorubicin (DOX) to breast cancer cells, a multifunctional triblock copolymer, poly(ethylene glycol)-block-poly(L-glutamic acid γ-hydrazide)-block-polyethylenimine (PEG-b-PGAH-b-PEI) having a cleavable disulfide linkage between blocks, was developed as a vehicle for targeted co-delivery of DOX and P-glycoprotein (P-gp) siRNA into MCF-7/ADR cells. The PGAH blocks were used to chemically conjugate DOX molecules via hydrazone bonds, while the PEI blocks could complex siRNA through electrostatic interactions. A tumor-targeting agent, folic acid (FA), was attached to the distal ends of the PEG blocks to specifically bind to the folate receptors overexpressed in MCF-7/ADR cells. The DOX-conjugated copolymer would self-assemble in aqueous solutions into cationic nanomicelles, which could condense siRNA to form nanomicelleplexes with an average particle size of ∼194 nm and a positive zeta potential of >+10 mV. The nanomicelleplexes exhibited sustained drug release profiles, and the release rates of DOX and siRNA from the nanomicelleplexes in a reductive acidic environment (pH 5.0 + 10 mM glutathione) were much faster than those under physiological conditions (pH 7.4). FA-decorated nanomicelleplexes were more efficiently internalized by MCF-7/ADR cells via folate-receptor-mediated endocytosis and exhibited a higher cytotoxic effect on MCF-7/ADR cells in comparison with FA-undecorated nanomicelleplexes. Furthermore, the synergistic effects of DOX and P-gp siRNA in inhibiting cell proliferation and inducing apoptosis in MCF-7/ADR cells were achieved by the FA-targeted co-delivery system. The triblock copolymer itself had a low cytotoxicity. These results indicate that the triblock copolymer could serve as an ideal tumor-targeting vehicle for simultaneous delivery of drugs and siRNA in breast cancer therapy.
研究领域:
药学
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纳米技术
·
癌症治疗
·
药物递送系统
·
生物医学工程
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2015
·
IF 3.65
Lejiao Jia,Zhenyu Li,Jingyi Shen,Dandan Zheng,Xiaona Tian,Hejian Guo,Ping Chang
The objective of the study is to fabricate multifunctional mesoporous silica nanoparticles for achieving co-delivery of conventional antitumor drug paclitaxel (PTX) and the multidrug resistance reversal agent tetrandrine (TET) expecting to overcome multidrug resistance of MCF-7/ADR cells. The nanoparticles were facile to prepare by self-assemble in situ drug loading approach. Namely, PTX and TET were solubilized in the cetyltrimethylammonium bromide (CTAB) micelles and simultaneously silica resources hydrolyze and condense to form nanoparticles. The obtained nanoparticles, denoted as PTX/TET-CTAB@MSN, exhibited pH-responsive release property with more easily released in the weak acidic environment. Studies on cellular uptake of nanoparticles demonstrated TET could markedly increase intracellular accumulation of nanoparticles. Furthermore, the PTX/TET-CTAB@MSN suppressed tumor cells growth more efficiently than only delivery of PTX (PTX-CTAB@MSN) or the free PTX. Moreover, the nanoparticle loading drugs with a PTX/TET molar ratio of 4.4:1 completely reversed the resistance of MCF-7/ADR cells to PTX and the resistance reversion index was 72.3. Mechanism research showed that both TET and CTAB could arrest MCF-7/ADR cells at G1 phase; and besides PTX arrested cells at G2 phase. This nanocarrier might have important potential in clinical implications for co-delivery of multiple drugs to overcome MDR.
研究领域:
纳米技术
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药物科学
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癌症研究
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药物递送系统
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Oncology
·
2024
·
IF 3.5
Qianqian Gao,Tingting Liu,Li Sun,Yongliang Yao,Fang Li,Lingxiang Mao
Ferroptosis is considered an effective method to overcome drug-resistant tumors. This study aims to use three FDA-approved biological materials, human serum albumin, D-α-tocopherol succinate, and indocyanine green, to construct a novel biocompatible nanomaterial named HTI-NPs, exploring its effect in drug-resistant breast cancer (MCF-7/ADR cells). The research results indicate that HTI-NPs can selectively inhibit the proliferation of MCF-7/ADR cells in vitro , accompanied by upregulating transferrin receptor, generating reactive oxygen species, and downregulating glutathione peroxidase 4. Under laser irradiation, HTI-NPs can promote ferroptosis by inhibiting glutathione expression through photodynamic therapy. Notably, HTI-NPs exhibit good inhibitory effects on MCF-7/ADR xenograft tumors in vivo . In conclusion, HTI-NPs represent a biocompatible nanomaterial that induces ferroptosis, providing new insights and options for treating drug-resistant breast cancer.
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
ACS Applied Bio Materials
·
2019
·
IF 0
Xiaomin Zhi,Yuqian Jiang,Linlin Xie,Yanbo Li,Chen-Jie Fang
Multidrug resistance (MDR) and adverse effects of chemotherapeutic agents are severe issues in clinical cancer treatment. Due to the dysregulation of enzymes in the cancer cells, enzyme-responsive drug delivery systems (DDSs) have been considered as a viable technology for cancer chemotherapy. In the present work, doxorubicin (DOX) is visible after leaving from AuNR–LAX. After treatment with AuNR–LAX, the drug resistance index of DOX-resistant MCF-7/ADR cells was reduced from extremely high 955.0 to 1.7, implying high potential of AuNR–LAX in the MDR phenotype cancer treatment. In addition, the cellular viability of both MCF-7 and MCF-7/ADR cells decreased from 50% to 80% after treatment with AuNR–LAX along (equivalent DOX concentration = 2.3 μg/mL, Au concentration = 30 μg/mL) to below 10% after AuNR–LAX treatment plus radiation of 808 nm, due to the NIR photothermal effect of AuNRs. Human bronchial epithelial cell line 16HBE was chosen to evaluate the adverse effect of AuNR–LAX on the normal cells. At the low concentration, the cytotoxicity of LAX and AuNR–LAX is comparable for breast cancer cell MCF-7 and normal cell 16HBE. It is noted that, at high concentration (with equivalent DOX concentration = 13.1 μg/mL, Au concentration = 167.7 μg/mL), the cellular viability of 16HBE cells is over 50%, whereas that of MCF-7 cancer cells is close to 0, implying the potential of AuNR–LAX in reducing the adverse effects of DOX against normal cells/tissues. Overall, AuNR–LAX showed high potential in overcoming MDR and alleviating adverse effect on normal cells.
研究领域:
纳米技术
·
药学
·
癌症研究
·
生物医学工程
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2016
·
IF 3.994
Yuan Sheng,Yiwen You,Yun Chen
The extended use of doxorubicin (DOX) could be limited due to the emergence of drug resistance associated with its treatment. In addition to the overexpression of ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), other mechanisms including apoptosis evasion and tumor cell survival may also be important contributor to drug resistance. Within this context, targeting extracellular signal-regulated kinases (ERK), one of the principle protein molecules in cell apoptosis has emerged as an attractive therapeutic concept. In this study, a dual-targeting hybrid peptide HAIYPRHGGCGMPKKKPTPIQLNP (T10-ERK), which is composed of ERK peptide inhibitor MPKKKPTPIQLNP, a thiol spacer ( i.e ., GGCG) and transferrin receptor (TfR)-binding peptide HAIYPRH, was designed. Then, this thiol-modified hybrid peptide was conjugated to DOXO-EMCH (6-maleimidocaproyl) hydrazone of DOX), forming a novel peptide-DOX conjugate T10-ERK-DOX. The structure and properties of this conjugate were characterized using 1 H NMR, mass spectrometry and HPLC. Using MCF-7/ADR cells as an in vitro model system and nude mice bearing MCF-7/ADR xenografts as an in vivo model, the ability of T10-ERK-DOX to reverse drug resistance was accessed as compared with free DOX and T10-DOX. As a result, T10-ERK-DOX demonstrated a much lower in vitro IC 50 (20.8 ± 1.1 μM) and its in vivo extent of inhibition in mice was more evident (72.2 ± 4.6%). Induction of various apoptosis pathways was also observed. Furthermore, the potency of ERK peptide inhibitor to reverse drug resistance was individually assessed, given the pronounced efficacy of T10-DOX indicated by our previous work. The results provided evidence of its additive effect with T10-DOX, which leads to greater efficacy and less susceptibility to drug resistance. Finally, the success of multi-targeting strategy in the present study implied that multi-target drugs with rational design could be more promising in cancer therapy.
研究领域:
药理学
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肿瘤学
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分子生物学
·
化疗
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2018
·Vol. 8
·期 28
·15831-15841
·
IF 2.936
Li Zong,Zifeng Pi,Shu Liu,Zhiqiang Liu,Fengrui Song
The comprehensive characterization of metabolome and lipidome to reveal unknown pathological conditions, are being used to investigate the molecular mechanisms of cancer, especially in the field of early diagnosis, treatment, and prognosis. The multidrug resistance (MDR) of tumor cells limits the therapeutic effect of anti-cancer drugs and is the main obstacle for chemotherapy. Here, we adopted a methyl-tert-butyl ether (MTBE)-based extraction method to simultaneously extract small polar molecules and lipophilic metabolites for nontargeted metabolomics of multidrug-resistant breast cancer cell line MCF-7/ADR and its parental cell line MCF-7/S by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Distinctly different metabolic features were shown between MCF-7/ADR cells and MCF-7/S on the basis of multivariate analyses. 17 potential biomarkers were identified. And these potential biomarkers were mainly correlated with cell membrane lipids composition, cell signaling regulated by lipids, and anti-oxidation ability. The studies of cellular ultrastructure and morphology by in situ atomic force microscopy (AFM) also demonstrated the cellular membrane changed along with the MDR. We expect that this study could provide a new method for monitoring drug resistance during clinical chemotherapy and be useful for the development of drugs to overcome the MDR.
研究领域:
癌症生物学
·
药理学
·
分析化学
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细胞生物学
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生物信息学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2018
·
IF 7.877
Chenfeng Xu,Yu Sun,Yan Qi,Yulin Yu,Yangzhou He,Mei Hu,Qian Hu,Tingting Wu,Dan Zhang,Lihuan Shang,Huan Deng,Zhiping Zhang
Tumor heterogeneity is considered as one of main obstacles to limit the clinical application of stimuli-responsive nanocarriers . Multidrug resistance (MDR) is also a major challenge in cancer chemotherapy . Here, we developed a tumor redox heterogeneity-responsive prodrug with self-induced reactive oxygen species (ROS) amplification property for facilitating rapid drug release and overcoming MDR and lung metastasis . The prodrug can self-assemble into polymer micelles (PMs) with high drug loading content (~30%), good physiological stability, prolonged systemic circulation and enhanced tumor distribution. Moreover, the prodrug PMs can stimulate tumor-specific ROS signal amplification, which provided a replenishment of consumed ROS necessary for rapid and complete drug release. The elevated ROS could not only evoke the mitochondria-dependent apoptosis by caspase-9/3 activation, but also inhibit inherent and acquired drug resistance by altering expression of Bcl-2 protein family and by reducing mitochondria membrane potential (ΔΨm) and ATP level in cancer cells. As a result, the prodrug PMs showed enhanced efficacy for inhibiting tumor growth in S180 sarcoma tumor model and in drug-resistant tumor model MCF-7/ADR and preventing lung metastasis in 4T1 in situ breast cancer model. This novel approach reported here may provide a promising strategy in the design of stimuli-responsive nanocarriers for efficient therapy of multidrug resistant and metastatic tumor.
研究领域:
癌症治疗
·
药学
·
纳米技术
·
生物医学工程
✓ 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）