MOLECULAR PHARMACEUTICS
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2016
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IF 4.342
Meirong Huo,Yao Liu,Lei Wang,Tingjie Yin,Chen Qin,Yanyu Xiao,Lifang Yin,Jiyong Liu,Jianping Zhou
A redox-sensitive micellar system constructed from an O,N-hydroxyethyl chitosan–octylamine (HECS-ss-OA) conjugate with disulfide linkages between the hydrophobic alkyl chains and hydrophilic chitosan backbone was synthesized for triggered intracellular delivery of hydrophobic paclitaxel (PTX). In aqueous environments, conjugates formed micelles with high PTX loading (>30%). Mechanistically, the sensitivity of HECS-ss-OA micelles to reducing environments was investigated using the parameters of in vitro release and particle size. Intracellular release of nile red fluorescence alongside cytotoxicity studies further confirmed the potency of redox-sensitive micelles for intracellular drug delivery compared with redox-insensitive micelles. Additionally, an in vivo study confirmed the efficacy of PTX-loaded micelles in tumor-bearing mice with superior antitumor efficacy and diminished systemic toxicity when compared with the redox-insensitive micelles and a PTX solution. These results demonstrate the potential of redox-sensitive HECS-ss-OA micelles for intracellular trafficking of lipophilic anticancer drugs.
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PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY
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2017
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IF 1.86
Shengyu Zhang,Liuwan Zhao,Nanqin Qiu,Yanjun Liu,Bohui Xu,Hongyan Zhu
Hypoxia, an outstanding characteristic of various solid tumors, has been considered a critical factor of aggressive tumor phenotypes, poor clinical prognosis, and increased expression of the multidrug-resistant gene. Therefore, it is critical to develop a drug delivery system to enhance the delivery effect of the antitumor drug in the hypoxic tumor. We constructed two types of tumor targeting micelles based on chitosan and evaluated their properties in targeting hypoxic tumors. Chitosan-based micelles consisted of a hydrophobic group octyl group, a hydrophilic polyethylene glycol, tumor targeting ligands glucosamine or folic acid, and a transmembrane peptide 9-d-arginine. The molecular structure, morphology, size distribution, zeta potential, and biosafety of two micelles were characterized. Oil-soluble CdSe quantum dots were used as a fluorescent probe to evaluate the hypoxic tumor cell targeting properties of the micelles. Moreover, HepG2 human hepatocellular carcinoma cells and HeLa human cervical carcinoma cells were used as in vitro models. We demonstrated that, under hypoxic conditions, two chitosan micelles showed better targeting ability to HepG2 and HeLa cells, which enhanced the effect of antitumor drugs by specifically targeting transport in hypoxic tumors. Therefore, chitosan micelles may be a potential drug delivery system that can be used to deliver antitumor drugs to hypoxic tumors.
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ACS Applied Materials & Interfaces
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2016
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IF 7.145
Yangjun Chen,Zuhong Li,Haibo Wang,Yin Wang,Haijie Han,Qiao Jin,Jian Ji
IR-780 iodide, a near-infrared (near-IR) fluorescent dye, can be utilized as an effective theranostic agent for both imaging and photothermal therapy. However, its lipophilicity limits its further biomedical applications. Herein, we synthesized a phospholipid mimicking amphiphilic homopolymer poly(12-(methacryloyloxy)dodecyl phosphorylcholine) (PMDPC) via reversible addition–fragmentation chain transfer (RAFT) polymerization. The amphiphilic homopolymer PMDPC can be self-assembled into micelles and used for the encapsulation of IR-780. The IR-780 loaded micelles (PMDPC-IR-780) exhibited low cytotoxicity in the dark, whereas remarkable photothermal cytotoxicity to pancreatic cancer cells (BxPC-3) was observed upon near-IR laser irradiation. We further investigated in vivo biodistribution of PMDPC-IR-780 micelles. Higher accumulation of PMDPC-IR-780 than that of free IR-780 in tumor tissue was verified, which might be ascribed to the enhanced permeability and retention (EPR) effect and long circulation time benefiting from the zwitterionic phosphorylcholine surface. Therefore, the IR-780 loaded phospholipid mimicking homopolymeric micelles could have great potential for cancer theranostics.
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MOLECULAR PHARMACEUTICS
·
2016
·
IF 4.342
Haijun Zhao,Qian Li,Zehui Hong
Although PEGylation allows a drug delivery vehicle to have prolonged blood circulation time, it faces the problem of reduced cellular uptake. Removal of the polyethylene glycol (PEG)-shell at the appropriate time through tumor-microenvironment triggers could be a feasible solution to this problem. Here, paclitaxel (PTX)-loaded mixed micelles (PTX-mM) self-assembled from stearate-modified hyaluronic acid (SHA), mPEG-b-poly(β-amino ester) (mPEG-b-PAE), and ethylene acetyl-b-poly(β-amino ester) (EA-b-PAE) were developed. In the preparation of PTX-mM, SHA micelles were coated with EA-b-PAE followed by coloading of PTX and mPEG-b-PAE. PTX-mM were capable of extracellular pH-triggered PEG-detachment and poly(β-amino ester) (PAE)-mediated endosomal escape. When the pH was changed from pH 7.4 to pH 6.8, the particle size of PTX-mM significantly decreased from 97.5 ± 4.4 to 71.5 ± 2.3 nm. It also resulted in rapid and complete release of mPEG-b-PAE from PTX-mM as monitored using quartz crystal microbalance (QCM) technology. PTX-mM capable of PEG detachment provided significant enhancement of PTX accumulation in SKOV-3 cells compared to PEG nondetachable PTX-mM. Interestingly, intracellular transport studies using confocal laser scanning microscopy (CLSM) showed that EA-b-PAE could promote the escape of micelles from endolysosomes. The half-maximal inhibitory concentration (IC50) of PTX-mM against SKOV-3 cells was 5.7 μg/mL, and PTX-mM containing 20 μg/mL of PTX induced apoptosis in 53.0% of the cell population. PTX-mM exhibited a highly prolonged elimination half-life (t1/2, 2.83 ± 0.37 h) and improved area under the curve (AUC, 7724.82 ± 1190.75 ng/mL/h) than the PTX-loaded SHA micelles (PTX-M). Furthermore, PTX-mM showed the highest tumor inhibition rate (64.9%) and the longest survival time (53 days) against the SKOV-3 ovarian cancer xenograft models among all formulations. Taken together, the results suggested that PTX-mM have potential as an efficient anticancer formulation in treatment of ovarian cancer.
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JOURNAL OF INDUSTRIAL AND ENGINEERING CHEMISTRY
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2016
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IF 4.179
Peizhu Zheng,Handi Yin,Jihua Zhao,Weiguo Shen
In order to clarify the nature of the inter-micellar interactions, we developed an approach to obtain the intermicellar interaction enthalpy through measuring the mixing heats of dodecyltrimethylammonium bromide (DTAB)/1-dodecyl-3-methylimidazolium bromide (C 12 mimBr) mixed micelles by using flow-mixing calorimetry . It was found that the inter-micellar interaction enthalpies for this system were negative, representing the attractive enthalpy interactions between the mixed micelle droplets. These results are contradictory to those reported in the literature and interpreted by the predominant attractive dehydration effect of counterion. Static light scattering experiment revealed that the repulsive nature of the interaction characterized by the Gibss free energy should be dominated by the entropy interaction.
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International Journal of Nanomedicine
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2017
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IF 4.3
Wen-Ting Zhu,Sheng-Yao Liu,Lei Wu,Hua-Li Xu,Jun Wang,Guo-Xin Ni,Qing-Bing Zeng
Background It has been widely reported that curcumin (CUR) exhibits anticancer activity and triggers the apoptosis of human A549 non-small-cell lung cancer (NSCLC) cells. However, its application is limited owing to its poor solubility and bioavailability. Therefore, there is an urgent need to develop a new CUR formulation with higher water solubility and better biocompatibility for clinical application in the future. Materials and methods In this study, CUR-loaded methoxy polyethylene glycol–polylactide (CUR/mPEG–PLA) polymeric micelles were prepared by a thin-film hydration method. Their characteristics and antitumor effects were evaluated subsequently. Results The average size of CUR/mPEG–PLA micelles was 34.9±2.1 nm with its polydispersity index (PDI) in the range of 0.067–0.168. The encapsulation efficiency and drug loading were 90.2%±0.78% and 9.1%±0.07%, respectively. CUR was constantly released from the CUR/mPEG–PLA micelles, and its cellular uptake in A549 cells was significantly increased. It was also found that CUR/mPEG–PLA micelles inhibited A549 cell proliferation, increased the cell cytotoxicity, induced G2/M stage arrest and promoted cell apoptosis. Moreover, the CUR/mPEG–PLA micelles suppressed the migration and invasion of A549 cells more obviously than free CUR. Additionally, CUR/mPEG–PLA micelles inhibited human umbilical vein endothelial cells migration, invasion and corresponding tube formation, implying the antiangiogenesis ability. Its enhanced antitumor mechanism may be related to the reduced expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, MMP-9 and Bcl-2 as well as the increased expression of Bax. Conclusion The mPEG–PLA copolymer micelles can serve as an efficient carrier for CUR. The CUR/mPEG–PLA micelles have promising clinical potential in treating NSCLC.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2016
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IF 3.994
Dujuan Zhao,Huiyuan Zhang,Shengfeng Yang,Wenxiu He,Yuxia Luan
The main cause of multidrug resistance (MDR) is overexpression of active efflux transporters, such as P-glycoprotein (P-gp). To reverse MDR and improve the chemotherapy effect of paclitaxel (PTX), we propose a new drug delivery system based on mixed micelles constructed with d -α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS) and the mPEG-SS-PTX conjugate with consideration that TPGS is a P-gp inhibitor that can block the cancer cell action of pumping drugs outside of cells and can enhance the anticancer effect. mPEG-SS-PTX is synthesized by conjugating hydrophilic mPEG with a hydrophobic drug, PTX, via a redox-sensitive disulfide bond. The mPEG-SS-PTX conjugate is amphiphilic and can self-assemble in water. Mixed micelles formed by the mPEG-SS-PTX conjugate and TPGS have a low critical micelle concentration (CMC, ∼1.05 × 10 −3 mg/mL) and high drug loading content (∼19.6%). The disulfide bond in the mPEG-SS-PTX conjugate can be broken in cancer cells (a reductive environment) and release PTX to kill cancer cells. In vitro cytotoxicity and cell uptake suggest that mixed micelles can effectively improve the accumulation of PTX in multidrug-resistant MCF-7 cells. Therefore, the present as-prepared mixed micelles very effectively reverse the MDR and enhance the therapeutic effect.
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RSC Advances
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2016
·Vol. 6
·期 100
·97684-97693
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IF 3.289
Yongchao Yao,Deqiu Xu,Chang Liu,Yayuan Guan,Jiya Zhang,Yuling Su,Lili Zhao,Fancui Meng,Jianbin Luo
Biodegradable multi-blocked polyurethane (PU) based micelles with a hydrophilic PEG corona were extensively studied for anti-cancer drug delivery systems. The hydrophilic PEG segment usually incorporated as a soft segment or as an end capping reagent, which has difficulty forming a dense PEG coating with a brush like conformation due to the low mobility of the PEG domains at the soft segment and the low amount of the PEG at the end of PU chains. In the present study, biodegradable pH sensitive polyurethane micelles with a dense brush like coating of PEG were prepared by a new kind of PEG grafted polyurethanes (PEG-g-PU) which were synthesized using PEGylated diethanolamine (MPEG-DEAM) as a chain extender. The high mobility of pendant MPEG in PEG-g-PU results in the formation of a dense and brush like PEG corona on the PEG-g-PU micelles. Meanwhile the MPEG attached on the hard segment will transfer the diethanolamine (DEAM) to the surface of nanoparticles during the self-assembly process and the DEAM render the particles with positive charges which potentially enhances cellular uptake and endosomal escape. DLS, TEM and AFM showed that a dense PEG domain was formed on the surface of PEG-g-PU micelles while no obvious PEG microdomain was observed for the other two kinds of micelles. FTIR and DSC results demonstrated the enhanced microphase separation of PEG-g-PU micelles compared with PEG-g-PU bulk materials and the other two contrast PU micelles, i.e. PEG-b-PU and PEG-c-PU. Paclitaxel (PTX) was chosen as a model hydrophobic drug to evaluate the loading and pH-triggered release of the PU micelles. The enhanced cytotoxicity of PTX-loaded PEG-g-PU-3 micelles against H460 cancer cells reveals that they are more potent for intracellular delivery of PTX as compared to PEG-b-PU-3 and PEG-c-PU-3 micelles.
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BIOMEDICINE & PHARMACOTHERAPY
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2017
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IF 2.759
Fangfang Teng,Peizong Deng,Zhimei Song,Feilong Zhou,Runliang Feng
In order to enhance water-solubility and realize controlled release while keeping synergistic effects of ketoconazole and curcumin , drug-loaded methoxy poly (ethylene glycol)-b-poly (ε-caprolactone) micelles were prepared through thin membrane hydration method. Transmission electric microscopy and dynamitic light scattering characterization revealed the formation of ketoconazole- and curcumin-loaded micelles with an average size of 44.70 nm and 39.56 nm, respectively. The drug-loaded micelles endowed the two drugs’ slow controlled release with water-solubility enhanced to 85 and 82000 folds higher than the corresponding raw drugs, respectively. In vitro antifungal activity test, chequerboard test and inhibition zone test indicated that efficacy of ketoconazole-loaded micelles was improved by introduction of curcumin-loaded micelles with a low fractional inhibitory concentration index (0.073). Biofilm formation inhibition assay also demonstrated that participation of curcumin-loaded micelles obviously strengthened the inhibition of fungal biofilms formation induced by ketoconazole-loaded micelles. The high synergistic activity of combinations is encouraging and the MPEG-PCL micelle is a potential drug delivery system for the combination of ketoconazole and curcumin.
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BIOMATERIALS
·
2017
·
IF 8.402
Qin Wang,Hao Jiang,Yan Li,Wenfei Chen,Hanmei Li,Ke Peng,Zhirong Zhang,Xun Sun
The transcription factor NF-kB plays a pivotal role in the pathogenesis of rheumatoid arthritis. Here we attempt to slow arthritis progression by co-delivering the glucocorticoid dexamethasone (Dex) and small-interfering RNA targeting NF-kB p65 using our previously developed polymeric hybrid micelle system. These micelles contain two similar amphiphilic copolymers : polycaprolactone-polyethylenimine (PCL-PEI) and polycaprolactone-polyethyleneglycol (PCL-PEG). The hybrid micelles loaded with Dex and siRNA effectively inhibited NF-kB signaling in murine macrophages more efficiently than micelles containing either Dex or siRNA on their own. In addition, the co-delivery system was able to switch macrophages from the M1 to M2 state. Injecting hybrid micelles containing Dex and siRNA into mice with collagen-induced arthritis led the therapeutic agents to accumulate in inflamed joints and reduce inflammation, without damaging renal or liver function. Thus, blocking NF-kB activation in inflammatory tissue using micelle-based co-delivery may provide a new approach for treating inflammatory disease.
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BIOMEDICINE & PHARMACOTHERAPY
·
2024
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IF 6.9
Jingmou Yu,Yifei Zhang,Meilin Xu,Dengzhao Jiang,Wenbo Liu,Hongguang Jin,Pu Chen,Jing Xu,Lei Zhang
Herein, we constructed innovative reduction-sensitive and targeted gelatin-based micelles for doxorubicin (DOX) delivery in tumor therapy. AS1411 aptamer-modified gelatin-ss-tocopherol succinate (AGSST) and the control GSST without AS1411 modification were synthesized and characterized. Antitumor drug DOX-containing AGSST (AGSST-D) and GSST-D nanoparticles were prepared, and their shapes were almost spherical. Reduction-responsive characteristics of DOX release in vitro were revealed in AGSST-D and GSST-D. Compared with non-targeted GSST-D, AGSST-D demonstrated better intracellular uptake and stronger cytotoxicity against nucleolin-overexpressed A549 cells. Importantly, AGSST-D micelles showed more effective killing activity in A549-bearing mice than GSST-D and DOX⋅HCl. It was revealed that AGSST-D micelles had no obvious systemic toxicity. Overall, AGSST micelles would have the potential to be an effective drug carrier for targeted tumor therapy.
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Soft Matter
·
2017
·Vol. 14
·期 4
·499-507
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IF 3.889
Zhaolan Zhai,Xinyan Yan,Zhanqian Song,Shibin Shang,Xiaoping Rao
A novel bio-based anionic surfactant containing a large rigid group and a flexible alkyl chain, namely, sodium N-dodecyl-maleimidepimaric carboxylate (C12-MPA-Na), was synthesized from rosin. The molecular structure of C12-MPA-Na was identified using 1H NMR, FT-IR spectroscopy and MS. Despite containing 36 carbon atoms, C12-MPA-Na showed good water solubility at room temperature. Large spherical aggregates with diameters of 100–200 nm were formed by C12-MPA-Na when its concentration was above 0.1 mM, which was slightly higher than the critical micelle concentration (0.078 mM). Annular wormlike micelles were discovered with increasing C12-MPA-Na concentration, and began to change into extremely long threadlike wormlike micelles when the C12-MPA-Na concentration reached approximately 58 mM. The viscoelastic properties of the wormlike micelle solutions were investigated using steady state and oscillatory shear sweep rheological measurements. The zero-shear viscosity (η0) strongly depended on the concentration of C12-MPA-Na, and the scaling exponent was 34.1. Cryo-TEM confirmed the formation of large spherical aggregates and wormlike micelles. 1H–1H 2D nuclear Overhauser effect spectroscopy (NOESY) was used to detect the molecular interactions of C12-MPA-Na. The results indicated that the alkyl chain of C12-MPA-Na was partially overlapped with its non-planar rigid structure in aqueous solution, and the possible aggregation process for C12-MPA-Na was proposed.
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