JOURNAL OF MOLECULAR LIQUIDS
·
2022
·
IF 6.633
Danfeng Wang,Min Liu,Yushu Wu,Tianxin Weng,Lu Wang,Yongfang Zhang,Yanna Zhao,Jun Han
The co-loading of chemotherapy-phototherapy (CTPT) combination drugs by aptamer-targeted DNA nanostructures has significant advantages in improving anticancer effects and overcoming the multidrug resistance of cancer cells. The different binding modes of drugs to DNA nanostructures may impact CTPT therapy. Here, the anti-drug resistance effects of idarubicin (IDA) or acridine orange (AO) as single drug, as well as IDA/mithramycin (MTR) dimers ((MTR) 2 Zn 2+ ) + AO combination drugs loaded by AS1411-tethered DNA nanotrains (AS1411NTrs), were studied. The intercalative binding mode between IDA/AO and AS1411NTrs was verified through measurements of viscosity, changes in melting temperature, and potassium iodide quenching. A series of thermodynamic parameters such as the binding constant and the number of binding sites were obtained through fluorescence spectroscopy, isothermal titration calorimetry, and differential scanning calorimetry. The high binding constants and the number of binding sites indicated that AS1411NTrs had a high loading capacity for IDA and AO. An in vitro release study showed that the release rate and release model of IDA/(MTR) 2 Zn 2+ /AO in the binary and ternary systems with or without deoxyribonuclease I were related to their binding mode and order of addition. An in vitro cytotoxicity study proved that the cytotoxicity and synergistic effects of the three drugs to human breast cancer MCF-7 cells and multidrug-resistant MCF-7/ADR cells were enhanced due to loading of AS1411NTrs. The IDA/(MTR) 2 Zn 2+ + AO combination drugs could more obviously enhance apoptosis of MCF-7/ADR cells as confirmed by cell apoptosis assays. The cell uptake study demonstrated that IDA/(MTR) 2 Zn 2+ /AO loaded by AS1411NTrs was mainly concentrated in the nucleus of MCF-7/ADR cells. This work will provide theoretical information for combination therapy of IDA/(MTR) 2 Zn 2+ and AO based on DNA nanostructures.
研究领域:
药学
·
纳米技术
·
癌症研究
·
生物物理学
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
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
·
肿瘤学
·
分子生物学
·
化疗
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DRUG DELIVERY
·
2023
·
IF 6
Lan Tang,Kaijuan Huang,Wenhui Jiang,Lulu Fu,Ran Zhang,Liting Shen,Zhimin Ou,Ye Huang,Zhenhai Zhang
D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) is a commonly used nonionic surfactant used as a pharmaceutical carrier in different drug delivery systems. TPGS can reverse P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) and also has anticancer activities. It suggests that when designing antitumor drug preparation, it’s necessary to take into account the antitumor activity of TPGS. Our in vivo studies showed that TPGS exerted the strongest cytotoxicity in MCF-7-ADR cells when compared with seven other tumor cell lines. The further study revealed TPGS caused apoptosis and blocked MCF-7 cell growth in G2/M phase. Mechanistic insights suggested that TPGS increased intracellular calcium ion concentrations, leading to apoptosis via the mitochondrial pathway. Furthermore, two in vivo experiments were performed. One was TPGS, and DOX solution was administered by tail vein injection on MCF-7-ADR tumor bearing nude mice. The other was temperature sensitive TPGS gel (TPGS-TG) was administered by intratumoral injection on MCF-7-ADR tumor bearing nude mice combined with paclitaxel albumin nanoparticles (Abraxane®) administered by tail vein injection. The findings confirmed that TPGS could play its role in anti-tumor to reduce the toxicity of chemotherapeutic drugs and improve the efficiency of drug-resistant tumors, thereby enhancing the development of safe oncology therapeutics.
研究领域:
药理学
·
肿瘤学
·
药物递送系统
·
癌症研究
✓ 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
·
细胞生物学
·
生物信息学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2022
·
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
·
药学
·
癌症研究
·
生物医学工程
✓ 已验证
产品关联
DOI
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）