Journal of Materials Chemistry B
·
2015
·Vol. 3
·期 8
·1556-1564
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IF 4.726
Xu Li,Cuixia Gao,Yupei Wu,C.-Yan Cheng,Weiliang Xia,Zhiping Zhang
Combination therapy has been regarded as a potent strategy to overcome multidrug resistance (MDR). In this study, we adopt Adjudin (ADD), a mitochondria inhibitor, and Doxorubicin (DOX), a common chemo-drug, to treat drug-resistant cancer cells (MCF-7/ADR) in combination. Given the different physico-chemical properties of ADD and DOX, we develop a novel drug formulation (ADD–DOX (M)) by integrating drug conjugation and nanocarrier approaches to realize the co-delivery of the two drugs. We demonstrate the conjugation of ADD and DOX via formation of an acid-sensitive hydrazone bond, and then the encapsulation of ADD–DOX conjugates by DSPE-PEG2000 micelles with high drug encapsulation efficiency and well-controllable drug loading efficiency. The obtained ADD–DOX (M) micelles are found to be stable under physiological conditions, but can rapidly release drugs within acidic environments. Following cellular experiments confirm that ADD–DOX (M) vehicles can be internalized by MCF-7/ADR cancer cells through an endocytic pathway and exist within the moderate acidic endolysosomes, thus accelerating the hydrolysis of ADD–DOX and the release of free ADD and DOX. As a result, the ADD–DOX (M) formulation exhibits an excellent anti-MDR effect. In summary, we for the first time report the combinational use of ADD and DOX with an effective co-delivery strategy for the treatment of MDR cancer cells.
研究领域:
药理学
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肿瘤学
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纳米技术
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化疗
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF NANOSCIENCE AND NANOTECHNOLOGY
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2017
·Vol. 17
·期 5
·2873-2880
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IF 1.483
Huang Saiyan,Liu Jieying,Zhu Hao,Hussain Abid,Liu Qing,Li Jing,Shen Yuanyuan,Cheng Jiejun,Guo Shengrong
A novel folate-polyethylene glycol-succinic acid-doxorubicin conjugate (FA-PEG-SA-DOX) micelle loaded with curcumin (CUR) is designed and prepared to target tumor cells via folate-folate receptor interactions and co-deliver chemotherapeutic agent DOX and chemosensitizer CUR for treatment
of multidrug resistant human breast cancer MCF-7/ADR cells. The CUR/FA-PEG-SA-DOX micelles are characterized with the average size of 90.64±0.15 nm and the zeta potential of −15.3±0.8 mV. The CUR and DOX contents of the micelles are 12.07 and 15.69% (w/w), respectively.
The cytotoxicity, cellular uptake and effiux of the micelles are investigated by using MCF-7/ADR cells. The results demonstrate that the CUR/FA-PEG-SA-DOX micelles have greater toxicity (IC50 = 3.10 µg/ml) compared to the free DOX (IC50 = 31.99 µg/ml),
moreover, the micelles present increased cellular uptake and reduced cellular effiux. The combination index of CUR/FA-PEG-SA-DOX micelles was 0.17, which indicate a strong synergistic antitumor efficacy against MCF-7/ADR cells. These results suggest that Curcumin-loaded FA-PEG-SA-DOX micelles
may be a promising nanomedicine for co-delivery dual-drug treatment for cancer.
研究领域:
药学
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肿瘤学
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纳米技术
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药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
International Journal of Nanomedicine
·
2023
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IF 8
Lan Tang,Wenhui Jiang,Lan Wu,Xiaolan Yu,Zheng He,Weiguang Shan,Lulu Fu,Zhenhai Zhang,Yunchun Zhao
Background Doxorubicin (DOX) is an anthracycline antibiotic that inhibits the growth of several solid and hematologic malignant tumors. Increasing the targeting ability of DOX and reducing the multi-drug resistance (MDR) of tumor cells to DOX are major aims for researchers.Purpose In this study, to increase therapeutic efficiency, reduce the side effects and the MDR of tumor cells to DOX, D-alpha-tocopheryl polyethylene glycol 2000 succinate monoester (TPGS2000)-DOX prodrug micelles were developed by grafting DOX to TPGS2000 via an amide bond that release DOX in the slightly acidic conditions in tumor tissue.Materials and Methods The TPGS2000-DOX micelles were constructed using polyethylene glycol 12-hydroxy stearate (Solutol HS15) as the carrier. The in vitro drug release profile and dilution stability of the nanomicelles were determined. The in vitro cytotoxicity and distribution of the nanomicelles in the tumor cells were also investigated. Moreover, we explored the therapeutic outcomes using the MCF-7/ADR tumor-bearing murine model.Results The average particle size was approximately 30 nm with a narrow distribution, which was conducive for solid tumor accumulation. The results of in vivo imaging and in vitro cellular uptake assays demonstrated that the TPGS2000-DOX micelles increased the tumor-targeting ability and cellular uptake of DOX. The anticancer potential of TPGS2000-DOX micelles was higher than that of DOX, as revealed by in vitro cytotoxic assays with MCF-7/ADR cells and in vivo antitumor assays with MCF-7 tumor-bearing nude mice.Conclusion TPGS2000-DOX prodrug micelles reverse the MDR of tumor cells, achieve passive targeting by forming nanomicelles, and subsequently enhance the efficacy and reduce the toxicity of DOX.
研究领域:
药学
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肿瘤学
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纳米技术
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
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
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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
✓ 已验证
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2017
·
IF 7.504
Ye Zhang,Congjun Zhang,Jing Chen,Li Liu,Mengyue Hu,Jun Li,Hong Bi
Multidrug resistance (MDR) has been recognized as a major obstacle to successful chemotherapy for cancer in the clinic. In recent years, more and more nanoscaled drug delivery systems (DDS) are constructed to modulate drug efflux protein (P-gp) and deliver chemotherapeutic drugs for overcoming MDR. Among them, d-α-tocopheryl polyethylene glycol succinate (TPGS) has been widely used as a drug carrier due to its capability of inhibiting overexpression of P-gp and good amphiphilicity favorable for improving permeation and long-circulation property of DDS. In the present work, a novel kind of mitochondria-targeting nanomicelles-based DDS is developed to integrate chemotherapeutics delivery with fluorescence imaging functionalities on a comprehensive nanoplatform. The mitochondria-targeting nanomicelles are prepared by self-assembly of triphenylphosphine (TPP)-modified TPGS and fluorescent carbon quantum dots (CQDs) in an n-hexane/H2O mixed solution, named CQDs-TPGS-TPP. Notably, although the drug loading content of doxorubicin (DOX) in the as-prepared nanomicelles is as low as 3.4%, the calculated resistant index (RI) is greatly decreased from 66.23 of free DOX to 7.16 of DOX-loaded nanomicelles while treating both parental MCF-7 cells and drug-resistant MCF-7/ADR cells. Compared with free DOX, the penetration efficiency of DOX-loaded nanomicelles in three-dimensional multicellular spheroids (MCs) of MCF-7/ADR is obviously increased. Moreover, the released DOX from the nanomicelles can cause much more damage to cells of drug-resistant MCs. These results demonstrate that our constructed mitochondria-targeting nanomicelles-based DDS have potential application in overcoming MDR of cancer cells as well as their MCs that mimic in vivo tumor tissues. The MDR-reversal mechanism of the DOX-loaded CQDs-TPGS-TPP nanomicelles is also discussed.
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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2015
·Vol. 5
·期 27
·20890-20899
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IF 3.84
Minghui Xu,Junmin Qian,Aili Suo,Weijun Xu,Rongrong Liu,Hongjie Wang
Combination of chemotherapy and small interfering RNA (siRNA)-based therapy has emerged as a promising approach for cancer treatment with the synergistic effect. In this study, a novel terpolymer methoxy poly(ethylene glycol)-block-poly(N,N-dimethylaminopropyl methacrylamide)-block-poly(acrylhydrazine) (mPEG-b-PDMAPMA-b-PAH) with a disulfide linkage between mPEG and PDMAPMA blocks was developed for the intracellular targeted co-delivery of adriamycin and P-gp siRNA. The terpolymer was synthesized by sequential reversible addition–fragmentation chain transfer (RAFT) polymerization of N,N-dimethylaminopropyl methacrylamide and N-tert-butoxycarbonyl-N′-acryl hydrazine (Boc-acrylhydrazine) in the presence of a PEGylated macro-RAFT agent, followed by Boc-deprotection. The terpolymer could chemically conjugate adriamycin via an acid-cleavable hydrazone bond and simultaneously condense the negatively charged siRNA through electrostatic interactions at an N/P ratio of 2. The resultant adriamycin-conjugated nanoparticles/siRNA complexes (ADR-NPs/siRNA complexes) showed a spherical morphology and had an average diameter of 186 nm. The release profiles of the two payloads from the ADR-NPs/siRNA complexes exhibited a pH/reduction dual-dependent sustained release behavior. The ADR-NPs/siRNA complexes could simultaneously deliver adriamycin and siRNA efficiently into MCF-7/ADR cells and significantly inhibit their growth in a synergistic fashion. All the results indicated that the terpolymer mPEG-b-PDMAPMA-b-PAH could serve as a potential vehicle for the combination of chemotherapy and gene 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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聚合物化学
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药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2017
·
IF 3.649
Tingting Meng,Binbin Lu,Shihong Shao,Ming Yuan,Xuan Liu,Hong Yuan,Xuan Huang,Fuqiang Hu
P-glycoprotein (P-gp) is a major efflux transporter overexpressed on multidrug resistant tumor cells and responsible for pumping drugs out. If anti-tumor drugs are given when P-gp level is low, satisfactory treatment efficiency may be achieved. Thus, a P-gp down-regulating siRNA (siMDR1) and doxorubicin (DOX) were applied to eliminate multidrug resistant breast cancer cells (MCF-7/ADR). A redox-responsive glucolipid conjugate (CSO-ss-SA) was used to condense siRNA (CSO-ss-SA/siRNA) and encapsulate DOX (CSO-ss-SA/DOX) separately. They responded to the high reducing environment of tumor cells and fast released the payload. CSO-ss-SA/siMDR1 silenced MDR1 gene and resulted in a transient decrease of P-gp. Sequentially, DOX formulation (CSO-ss-SA/DOX or DOX·HCl) was delivered when P-gp was reduced to the lowest level. After pretreatment by CSO-ss-SA/siMDR1, cytotoxicity of CSO-ss-SA/DOX and DOX·HCl against MCF-7/ADR cells were 6.4 or 3.4-fold respectively of that treated by DOX·HCl alone, which exhibited increased cytotoxin sensitivity of drug resistant cells and maximized therapeutic outcomes. These results revealed that the sequential treatment strategy of CSO-ss-SA/siRNA and CSO-ss-SA/DOX hold potential in achieving an optimal overcoming multidrug resistance efficiency.
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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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2024
·
IF 10.7
Yufan Guo,Xiuru Yang,Yihong Zhang,Fazhen Luo,Juan Yang,Xupeng Zhang,Jinxia Mi,Yan Xie
Cancer multidrug resistance (MDR) dramatically hindered the efficiency of standard chemotherapy. Mitochondria are highly involved in the occurrence and development of MDR; thus, inducing its malfunction will be an appealing strategy to treat MDR tumors. In this paper, a natural polysaccharides-based nanoplatform (TDTD@UA/HA micelles) with cell and mitochondria dual-targeting ability was facilely fabricated to co-deliver ursolic acid (UA) and doxorubicin (DOX) for combinatorial MDR therapy. TDTD@UA/HA micelles featured a spherical morphology, narrow size distribution (∼140 nm), as well as favorable drug co-loading capacity (DOX: 8.41 %, UA : 9.06 %). After hyaluronic acid (HA)-mediated endocytosis , the lysosomal hyaluronidase promoted the degradation of HA layer and then the positive triphenylphosphine groups were exposed, which significantly enhanced the mitochondria-accumulation of nano micelles . Subsequently, DOX and UA were specifically released into mitochondria under the trigger of endogenous reactive oxygen species (ROS), followed by severe mitochondrial destruction through generating ROS, exhausting mitochondrial membrane potential, and blocking energy supply, etc. ; ultimately contributing to the susceptibility restoration of MCF-7/ADR cells to chemotherapeutic agents. Importantly, TDTD@UA/HA micelles performed potent anticancer efficacy without distinct toxicity on the MDR tumor-bearing nude mice model. Overall, the versatile nanomedicine represented a new therapeutic paradigm and held great promise in overcoming MDR-related cancer.
研究领域:
药学
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纳米技术
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肿瘤学
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2018
·
IF 6.383
Yun Wang,Feihu Wang,Ying Liu,Shaohui Xu,Yuanyuan Shen,Nianping Feng,Shengrong Guo
Effects of nanosized drug delivery systems on cancer are often compromised due to their low drug loadings, premature drug release and multi-drug resistance (MDR). Herein, we reported a glutathione detonated and pH responsive nano-cluster of Au nanorods (AuNRs) with chemotherapeutic doxorubicin (DOX) and pre-chemosensitizer polycurcumin to treat MCF-7/ADR cells. The nano-cluster was prepared by self-assembling of AuNRs conjugated with DOX and amphiphilic poly(curcumin-co-dithiodipropionic acid)-b-biotinylated poly(ethylene glycol) via an emulsion/solvent evaporation technique, termed AuNR Cluster. The AuNR Cluster had a high drug loading (31.5% DOX), presenting much better aqueous solubility and stability at physiological pH than their individual AuNRs. The AuNR Cluster could be detonated to be their individual AuNRs at an intracellular concentration level of glutathione (GSH) (5 mM) and triggered to release DOX at an acidic pH (pH 6.8 or 5.0), which effectively facilitated cellular uptake of DOX (607 vs 356 a.u. for AuNRs at 12 h) and inhibited DOX efflux (471.33 vs 39.17 a.u. for free DOX at 24 h). The IC 50 value of DOX against MCF-7/ADR cells for AuNR Cluster was 4.15 µg/mL, much lower than that for free DOX (90.97 µg/mL). The AuNR Cluster took much more photothermal effects than their corresponding AuNRs and presented enhanced anti-tumor effect (IC 50 : 2.61 µg/mL) under 808 nm laser irradiation. Statement of Significance Nano-sized drug delivery systems for anti-MDR cancer is still a challenging task. Herein, AuNR Cluster was self-assembled by individual AuNRs via emulsion/solvent evaporation technique, having a structure consisting of hydrophobic DOX/PCDA-AuNR core and hydrophilic biotin-PEG chain shell. AuNR Cluster is detonated to disintegrate and yield its individual AuNRs at an intracellular concentration level of glutathione (5 mM) and triggered to release DOX at an acidic pH (6.8 or 5.0). In comparison with its individual AuNRs, AuNR Cluster has better water solubility and stability, greater photothermal effects under NIR irradiation, bigger cytotoxicity against MCF-7/ADR cells. AuNR Cluster is expected to be a potential nanomedicine for treatment of MDR cancer.
研究领域:
纳米医学
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癌症研究
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药物递送系统
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材料科学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2019
·
IF 4.213
Chunlai Feng,Haisheng Zhang,Jiaming Chen,Siqi Wang,Yuanrong Xin,Yang Qu,Qi Zhang,Wei Ji,Fumiyoshi Yamashita,Mengjie Rui,Ximing Xu
Combination therapy is a promising treatment for certain advanced drug-resistant cancers. Although effective inhibition of various tumor cells was reported in vitro , combination treatment requires improvement in vivo due to uncontrolled ratiometric delivery. In this study, a tumor-targeting lipodisk nanoparticle formulation was developed for ratiometric loading and the transportation of two hydrophobic model drugs, doxorubicin (DOX) and paclitaxel (PTX), in one single platform. Furthermore, a slightly acidic pH-sensitive peptide (SAPSP) incorporated into lipodisks effectively enhanced the tumor-targeting and cell internalization. The obtained co-loaded lipodisks were approximately 30 nm with a pH-sensitive property. The ratiometric co-delivery of two drugs via lipodisks was confirmed in both the drug-resistant MCF-7/ADR cell line and its parental MCF-7 cell line in vitro , as well as in a tumor-bearing mouse model in vivo compared with a cocktail solution of free drugs. Co-loaded lipodisks exerted improved cytotoxicity to tumor cells in culture, particularly to drug-resistant tumor cells at synergistic drug ratios. In an in vivo xenograft mouse model, the anti-tumor ability of co-loaded lipodisks was evidenced by the remarkable inhibitory effect on tumor growth of either MCF-7 or MCF-7/ADR tumors, which may be attributed to the increased and ratiometric accumulation of both drugs in the tumor tissues. Therefore, tumor-specific lipodisks were crucial for the combination treatment of DOX and PTX to completely exert a synergistic anti-cancer effect. It is concluded that for co-loaded lipodisks, cytotoxicity data in vitro could be used to predict their inhibitory activity in vivo , potentially enhancing the clinical outcome of synergistic therapy.
研究领域:
癌症治疗
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药学
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纳米技术
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肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Science Bulletin
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2016
·
IF 0
Bo-Ya Liu,Cong Wu,Xiao-Yan He,Ren-Xi Zhuo,Si-Xue Cheng
A facile self-assembly strategy to fabricate vitamin E-tocopheryl polyethylene glycol succinate (TPGS) based nanoparticles with a high drug loading level for co-delivery of multiple drugs was developed. To overcome multi-drug resistance, a chemotherapeutic agent (paclitaxel, PTX) and a drug resistance inhibitor (tariquidar, TQR) were co-loaded in the vitamin E-TPGS based nanoparticle to obtain TPGS/PTX/TQR nanoparticles. The sizes of mono-drug loaded TPGS/PTX nanoparticles and dual-drug loaded TPGS/PTX/TQR nanoparticles were below 150 nm with relatively narrow size distributions. The efficiencies of the drug delivery systems on tumor cells inhibition and reversal of drug resistance were evaluated in drug resistant cancer cells (MCF-7/ADR) as compared with nonresistant cells (HeLa). Due to the effective inhibition of the P-gp efflux by TQR, the dual-drug loaded nanoparticles exhibited significantly improved tumor cell inhibitory efficiency. To study the immunostimulatory effect, the effect of the drug delivery system on the production of IL-10, a cytokine related to tumor development, in the drug resistant cells was determined. After the treatment by the drug delivery systems, the concentration of IL-10 in the cell supernatant decreased. The multi-drug loaded vitamin E-TPGS nanoparticles for synergistic drug delivery have promising applications in reversal of drug resistance in tumor treatments.
研究领域:
药学
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纳米技术
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肿瘤学
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药物递送系统
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生物医学工程
✓ 已验证
产品关联
DOI
RSC Advances
·
2015
·Vol. 5
·期 66
·53835-53845
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IF 3.84
Weihua Jiang,Lei Yang,Lipeng Qiu,Jingwen Xu,Xiuchun Yang,Ju Wang,Hui Zhou,Dongkai Wang
Multifunctional hybrid nanoparticles (NPs) based on sodium carboxymethylcellulose-graft-histidine (CMH) and TPGS were designed for effective delivery and overcoming multidrug resistance (MDR) of docetaxel (DTX). An amphiphilic CMH copolymer with excellent biocompatibility, pH-sensitivity, and solubilizing capacity for poorly soluble drugs was firstly synthesized and characterized. TPGS incorporated into CMH copolymer facilitated lower critical aggregation concentration (CAC) (0.0074 mg mL−1), smaller particle size (147.8 ± 3.14 nm), higher drug encapsulation (88.3 ± 3.33%), and better controlled release rate. The NPs based on CMH copolymer showed a pH-dependent drug release manner. The DTX-loaded CHT-1.5 NPs could significantly enhance cytotoxicity against both MCF-7 and MCF-7/ADR cells when compared to DTX-loaded CMH NPs and free DTX. Furthermore, cellular uptake and P-gp inhibition assays confirmed that the enhanced MDR reversal effect of DTX-loaded CHT-1.5 NPs was caused by the combination of increased drug accumulation and inhibition of P-glycoprotein mediated drug efflux in drug-resistant MCF-7/ADR cells. Consequently, CHT-1.5 NPs can act as an effective nanocarrier for delivering antitumor drugs and overcoming P-gp overexpressing tumor cells.
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
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）