Biomaterials Science
·
2018
·Vol. 6
·期 11
·2998-3008
·
IF 5.831
Jieming Li,Yan Liu,Huilan Li,Wei Shi,Xinzhou Bi,Qianqian Qiu,Bo Zhang,Wenlong Huang,Hai Qian
Subcellular organelle-specific reagents for simultaneous tumor targeting, imaging, and treatment are of enormous interest in cancer therapy. Herein, we present a mitochondria targeting micelle (PEG-AIE-TPP) by conjugating a triphenylphosphonium (TPP) with a fluorogen which can undergo aggregation-induced emission (AIE). At first, the in vitro and in vivo properties of the PEG-AIE-TPP micelle were characterized in detail. It was found that the micelle was reasonably stable at physiological pH and highly sensitive to mildly acidic pH stimuli. Importantly, this micelle could selectively localize and accumulate in the mitochondria, thus generating an aggregation-induced emission (AIE) effect as confirmed by the green fluorescence. Additionally, the micelle exhibited selective cytotoxicity to cancer cells and negligible toxicity to normal cells in vitro. The in vivo imaging and ex vivo imaging results showed that the accumulation tendency of the micelle at the tumor region was obvious. We also further proved the biocompatible, tumor targeting ability and antitumor activity of the PEG-AIE-TPP micelle in MCF-7 tumor-bearing mice. Accordingly, this mitochondria-targeted therapeutic micelle with good stability, biocompatibility, and tumor-targeting and antitumor activity provides a potentially unique tumor-targeted system for cancer therapy.
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高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2019
·
IF 8.355
Yang Xiang,Xiaohui Duan,Longbao Feng,Shuqi Jiang,Li Deng,Jun Shen,Yijun Yang,Rui Guo
The successful treatment of gliomas relies on two important factors, namely therapeutic genes/drugs and efficient delivery vehicles to cross the blood-brain barrier. In this work, a new gene vector was constructed based on polycaprolactone (PCL), glutathione (reduced; GSH)-sensitive polyethylenimine (PEI-SS) and polyethylene glycol (PEG), and modified with a cell-penetrating peptide (tLyp-1); this yielded tLyp-1-conjugated GSH-sensitive biodegradable micelles (PPPt) that mediated enhanced tumour necrosis factor (TNF)-related apoptosis-inducing ligand (pUNO1-hTRAILa) and curcumin (CUR) co-delivery to gliomas. The sensitisation function of CUR was used to explore whether CUR and genes have a synergistic antitumour effect. The results showed that the drug loading efficiency of PPPt was about 8.6%. The PPPt possessed good cytocompatibility and blood compatibility when the concentration was less than 0.06 mg/mL. PPPt strongly condensed pUNO1-hTRAILa to form a nanocomplex and efficiently transfected C6 cells. The drug-release behaviour of PPPt/CUR/pUNO1-hTRAILa was reduction-sensitive and the cellular uptake results indicate that modification of tLyp-1 promoted the internalisation of micelles. The PPPt/CUR/pUNO1-hTRAILa complexes exhibited much better in vitro and in vivo antitumour effects than micelles loaded with CUR or pUNO1-hTRAILa alone. We also used magnetic resonance imaging for in vivo monitoring of the transcranial drug delivery and therapeutic effect of the tumour on rats bearing in situ glioma.
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DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY
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2019
·
IF 2.367
Xin-Cheng Zhong,Wen-Hong Xu,Zi-Ting Wang,Wang-Wei Guo,Jie-Jian Chen,Ning-Ning Guo,Tian-Tian Wang,Meng-Ting Lin,Zhen-Tao Zhang,Yi-Ying Lu,Qi-Yao Yang,Min Han,Dong-Hang Xu,Jian-Qing Gao
Objective: This study was aimed to develop DOX-TPP loaded acetal-PEG-PCCL micelles to improve the clinical efficacy of drug resistance tumor.Significance: Chemotherapy is one of the main treatments for breast cancer but is plagued by multidrug resistance (MDR). DOX-TPP-loaded micelles can enhance the specific concentration of drugs in the tumor and improve the efficacy and overcome MDR.Methods: In this study, DOX-TPP-loaded micelles based on acetal-PEG-PCCL were prepared and their physicochemical properties were characterized. The cellular uptake and ability to induce apoptosis of the micelles was confirmed by flow cytometry in MCF-7/ADR cells. In addition, cytotoxicity of the micelles was studied in MCF-7 cells and MCF-7/ADR cells. Confocal is used to study the subcellular distribution of DOX. Free DOX-TPP or DOX-TPP-loaded acetal-PEG-PCCL micelles were administered via intravenous injection in the tail vain for the biodistribution study in vivo.Results: The diameter of micelles was about 102.4 nm and their drug-loading efficiency is 61.8%. The structural characterization was confirmed by 1H NMR. The micelles exhibited better antitumor efficacy compared to free doxorubicin in MCF-7/ADR cells by MTT assay. The apoptotic rate and the cellular uptake of micelles were significantly higher than free DOX and DOX-TPP. Micelles can efficiently deliver mitochondria-targeting DOX-TPP to tumor cells. The result of bio-distribution showed that the micelles had stronger tumor infiltration ability than free drugs.Conclusions: In this study, mitochondriotropic DOX-TPP was conjugated to the nanocarrier acetal-PEG-PCCL via ionic interaction to form a polymer, which spontaneously formed spherical micelles. The cytotoxicity and cellular uptake of the micelles are superior to free DOX and exhibit mitochondrial targeting and passive tumor targeting, indicating that they have potential prospects.
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MOLECULAR PHARMACEUTICS
·
2017
·
IF 4.44
Yujie Zhang,Yifei Lu,Yu Zhang,Xi He,Qinjun Chen,Lisha Liu,Xinli Chen,Chunhui Ruan,Tao Sun,Chen Jiang
Most small molecular chemotherapeutics have poor water solubility and unexpected pharmacokinetics and toxicity to normal tissues. A series of nano drug delivery systems have been developed to solve the problems, among which a micelle based on linear–dendritic polymer–drug conjugates (LDPDCs) is a promising strategy to deliver hydrophobic chemotherapeutics due to its small size, fine stability in blood circulation, and high drug loading capacity. In this work we synthesized a novel amphiphilic linear–dendritic PEG–PTX8 conjugate which can also encapsulate extra free PTX and self-assemble into uniform ultrasmall micelles with a hydrated diameter of 25.50 ± 0.27 nm. To realize efficient drug delivery to tumor sites, a cyclic tumor homing and penetrating peptide iNGR was linked to the PEG–PTX8 conjugate. The biological evaluation was performed on a human triple negative breast cancer model. PTX accumulation in tumor at 24 h of the TNBC-bearing mice treated with iNGR–PEG–PTX8/PTX micelles was significantly enhanced (P < 0.001, two-way ANOVA) compared to that of Taxol and untargeted MeO–PEG–PTX8/PTX micelles. Furthermore, iNGR–PEG–PTX8/PTX micelles showed an obvious strong antitumor effect, and the median survival time of TNBC bearing mice treated with iNGR-modified micelles was significantly extended compared to Taxol. Therefore, this smart micelle system may be a favorable platform for effective TNBC therapy.
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Polymer Chemistry
·
2012
·Vol. 3
·期 9
·2403-2412
·
IF 5.321
Lesan Yan,Wenbin Wu,Wei Zhao,Ruogu Qi,Dongmei Cui,Zhigang Xie,Yubin Huang,Ti Tong,Xiabin Jing
A functionalized six-membered cyclic carbonate monomer containing a protected thiol group, 2-(2,4-dinitrophenylthio)ethyl-5-methyl-2-oxo-1,3-dioxane-5-carboxylate (MTC), was prepared. Ring-opening polymerization (ROP) of MTC and L-lactide (LA) initiated by monohydroxyl poly(ethylene glycol) (mPEG) was successfully performed with controlled polymer molecular weight and molecular weight distribution. The structures of the obtained monomer and copolymers were confirmed by NMR and FTIR. After deprotection under mild conditions, the amphiphilic block copolymer was self-assembled into micelles in aqueous solution. By oxidation of the free thiol groups in the PMTC segments, the micelles with the cross-linked core were formed, and the enhanced stability against disruptive conditions was demonstrated by dynamic light scattering (DLS) measurement in the presence of DMF. Doxorubicin (DOX) was loaded into the micelles as a model drug. The in vitro DOX release behaviors indicated that cross-linking of the micelle cores resulted in a slow drug release and this process was greatly accelerated by adding glutathione (GSH) solution with comparable concentrations to intracellular levels in tumor cells. The cross-linked micelles were demonstrated to be efficiently internalized into the cells. Faster intracellular DOX release was observed by confocal laser scanning microscopy (CLSM) in the GSH pretreated MCF-7 cells than in the unpretreated MCF-7 cells. In vitro MTT assay revealed that the cross-linked micelles were biocompatible with L929 cells and MCF-7 cells. As expected, DOX-loaded cross-linked micelles showed higher cellular proliferation inhibition towards glutathione pretreated MCF-7 cells than that towards the unpretreated ones at various GSH concentrations. These results indicated that the bioreducible core-cross-linked micelles can be used as drug carriers for intelligent drug delivery.
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International Journal of Nanomedicine
·
2015
·
IF 4.383
Liang Qiu,Chun-Yan Hong,Cai-Yuan Pan
Redox-and pH-sensitive branched star polymers (BSPs), BP(DMAEMA-co-MAEBA-co-DTDMA)(PMAIGP)ns, have been successively prepared by two steps of reversible addition–fragmentation chain transfer (RAFT) polymerization. The first step is RAFT polymerization of 2-(N,N-dimethylaminoethyl)methacrylate (DMAEMA) and p-(methacryloxyethoxy) benzaldehyde (MAEBA) in the presence of divinyl monomer, 2,2′-dithiodiethoxyl dimethacrylate (DTDMA). The resultant branched polymers were used as a macro-RAFT agent in the subsequent RAFT polymerization. After hydrolysis of the BSPs to form BP(DMAEMA-co-MAEBA-co-DTDMA)(PMAGP)ns (BSP-H), the anticancer drug doxorubicin (DOX) was covalently linked to branched polymer chains by reaction of primary amine of DOX and aldehyde groups in the polymer chains. Their compositions, structures, molecular weights, and molecular weight distributions were respectively characterized by nuclear magnetic resonance spectra and gel permeation chromatography measurements. The DOX-loaded micelles were fabricated by self-assembly of DOX-containing BSPs in water, which were characterized by transmission electron microscopy and dynamic light scattering. Aromatic imine linkage is stable in neutral water, but is acid-labile; controlled release of DOX from the BSP-H-DOX micelles was realized at pH values of 5 and 6, and at higher acidic solution, fast release of DOX was observed. In vitro cytotoxicity experiment results revealed low cytotoxicity of the BSPs and release of DOX from micelles in HepG2 and HeLa cells. Confocal laser fluorescence microscopy observations showed that DOX-loaded micelles have specific interaction with HepG2 cells. Thus, this type of BSP micelle is an efficient drug delivery system.
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PLoS One
·
2017
·Vol. 12
·期 7
·e0180037
·
IF 2.806
Weiping Ji,Bo Wang,Qiuping Fan,Chao Xu,Youwu He,Youfen Chen
Multidrug resistance (MDR) against chemotherapeutic agents has become the major obstacle to successful cancer therapy and multidrug resistance-associated proteins (MRPs) mediated drug efflux is the key factor for MDR. Indomethacin (IND), one of the non-steroidal anti-inflammatory agents, has been demonstrated to increase cytotoxic effects of anti-tumor agents as MRP substrates. In this study, dextran- g -indomethacin (DEX-IND) polymeric micelles were designed to delivery paclitaxel (PTX) for the treatment of MDR tumors. The DEX-IND polymer could effectively encapsulate PTX with high loading content and DEX-IND/PTX micelles present a small size distribution. Compared with free PTX, the release of PTX from DEX-IND/PTX micelles could be prolonged to 48 h. Cellular uptake test showed that the internalization of DEX-IND/PTX micelles by drug-sensitive MCF-7/ADR cells was significantly higher than free PTX benefiting from the inhibitory effect of IND on MRPs. In vitro cytotoxicity test further demonstrated that DEX-IND/PTX micelles could enhance the cytotoxicity of PTX against MCF-7/ADR tumor cells. In vivo pharmacokinetic results showed that DEX-IND/PTX micelles had longer systemic circulation time and slower plasma elimination rate in comparison to PTX. The anti-tumor efficacy test showed that DEX-IND/PTX micelles exhibited greater tumor growth-inhibition effects on MDR tumor-bearing mice, with good correlation between in vitro and in vivo. Overall, the cumulative evidence indicates that DEX-IND/PTX micelles hold significant promise for the treatment of MDR tumors.
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ACTA PHARMACOLOGICA SINICA
·
2017
·Vol. 38
·期 12
·1655-1662
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IF 3.223
Dong Xin-yue,Lang Tian-qun,Yin Qi,Zhang Peng-cheng,Li Ya-ping
Breast cancer is the most vicious killer for women, and tumor metastasis is one of the leading causes of breast cancer therapy failure. In this study, a new pH-sensitive polymer (polyethylene glycol-block-poly[(1,4-butanediol)-diacrylate-β-N,N-diisopropylethylenediamine], BDP) was synthesized. Based on BDP, docetaxel/silibinin co-delivery micelles (DSMs) was constructed. DSM had a well-defined spherical shape under the transmission electron microscope with average hydrodynamic diameter of 85.3±0.4 nm, and were stable in the bloodstream but could dissociate to release the chemotherapeutic agents in the low pH environment of the endo/lysosomes in the tumor cells. Compared with free drugs, DSM displayed greatly enhanced cellular uptake, higher cytotoxicity and a stronger anti-metastasis effect against mouse breast cancer cell line 4T1. In 4T1 tumor-bearing mice treated with DSM (twice a week for 3 weeks), the inhibition rate on tumor growth and metastasis reached 71.9% and 80.1%, respectively. These results reveal that DSM might be a promising drug delivery system for metastatic breast cancer therapy.
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高影响因子
JOURNAL OF MOLECULAR LIQUIDS
·
2016
·
IF 2.74
Wei Lin,Zhengming Yang,Juan Wang,Ting Chen,Xingwang Shi
The pH-induced rheological property of octadecy trimethyl ammonium bromide with anthranilic acid was investigated. The viscoelasticity property and structural transformation of molecular self-assembly were comprehensively discussed by means of rheological measurements, dynamic light scattering and cryogenic-transmission electron microscopy. On the basis of surface tension results, the change of viscoelasticity was explained by calculating the packing parameter of P . UV–vis results confirmed that the pH-dependent interaction between the aromatic ring of anthranilic acid and the head group result in the transition between WLMs and spherical micelles, thus altering the viscoelasticity of WLMs.
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JOURNAL OF CONTROLLED RELEASE
·
2016
·
IF 7.441
Qin Wang,Jiayu Jiang,Wenfei Chen,Hao Jiang,Zhirong Zhang,Xun Sun
Glucocorticoid (GC) is the cornerstone therapy of rheumatoid arthritis , but high doses are associated with serious adverse effects. In an effort to improve the efficacy of low-dose GC therapy, we developed a micelle system for targeted delivery to inflamed joints and validated the approach in a rat model of arthritis. Micelles loaded with dexamethasone (Dex) self-assembled from the amphipathic poly (ethylene glycol)-block–poly (εcaprolactone) (PCL–PEG) polymer via film dispersion, and they were injected intravenously at a dose of only 0.8 mg/kg into rats with adjuvant-induced arthritis. The micelles persisted for a relatively long time in the circulation, and they accumulated preferentially in inflamed joints. Micelle-delivered Dex potently reduced joint swelling, bone erosion, and inflammatory cytokine expression in both joint tissue and serum. PCL–PEG micelles caused only moderate adverse effects on body weight, lymphocyte count and blood glucose concentration, and they weakly activated the host complement system. These results suggest that encapsulating Dex in PCL–PEG micelles may allow for safe and effective low-dose GC therapy targeting inflammatory disorders.
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Journal of Biomedical Nanotechnology
·
2017
·Vol. 13
·期 4
·393-408
·
IF 4.521
Tan LiWei,Ma BuYun,QianZhao .,LanZhang .,Chen LiJuan,Peng JinRong,Qian ZhiYong
In this work, docetaxel (DTX) was encapsulated in monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (mPEG-PCL) micelles and monomethoxy poly(ethylene glycol)-poly(D, L-lactic acid) (mPEG-PLA) micelles, respectively. For the further application, the acute/genetic toxicity
evaluation and pharmacokinetic/pharmacodynamic study of the two kinds of micellar nanomedicines were performed. In the study of anticancer activity in vitro and in vivo, DTX micelles showed better tumorgrowth inhibition than free DTX. The pharmacokinetic and tissue distribution
studies showed that the DTX incorporated in micelles (especially in DTX-mPEG-PCL) retained significantly higher concentration in plasma and tumor tissue compared with free DTX. The acute toxicity and genotoxicity studies indicated that DTX micelles were safer than the docetaxel injection in
cancer therapy and DTX-mPEG-PCL had less damage to DNA than DTX-mPEG-PLA. So the micelles had a pronounced effect on reducing acute toxicity and genotoxicity of docetaxel. In conclusion, DTX micelles were efficient and safe on breast carcinoma chemotherapy.
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RSC Advances
·
2017
·Vol. 7
·期 34
·21328-21335
·
IF 3.108
Rujiang Ma,Chuan Zhang,Yong Liu,Chang Li,Yanling Xu,Baoxin Li,Yunliang Zhang,Yingli An,Linqi Shi
Amphiphilic block copolymer micelles in aqueous solution have been used extensively in delivery of hydrophobic drugs with the hydrophobic core serving as the reservoir. However, encapsulation of hydrophilic drugs by polymeric micelles with hydrophobic core is relatively difficult because of the poor interaction between them. Herein, we report a novel kind of pH/GSH dual-responsive complex micelles with a hydrophilic drug loaded, via direct subcomponent self-assembly of block copolymer poly(ethyleneglycol)-block-poly(L-lysine) (PEG-b-PLys), 2-formylbenzeneboronic acid (2-FPBA) and hydrophilic 1,2-diol-containing drugs (e.g. capecitabine (CAPE)) under physiological pH 7.4 based on the synergistic formation of an iminoboronate structure. The PEG-b-PLys/2-FPBA micelles without CAPE are well-characterized in terms of micellization mechanism, size, morphology, pH- and GSH-responsiveness. Encapsulation of CAPE by forming PEG-b-PLys/2-FPBA/CAPE complex micelles via synergistic formation of the iminoboronate structure is discussed and pH- and GSH-responsive drug-release studies are carried out. The complex micelles are stable under physiological neutral conditions but could be destroyed in response to the stimuli of physiological acidic condition (pH 5.0) and/or glutathione (GSH) at pH 7.4. pH- and GSH-responsive drug-releases are successfully achieved. The drug-loaded complex micelles could be endocytosed by HepG2 cells and efficiently deliver hydrophilic drugs into them. This type of complex micelles could be used as a promising platform for the delivery of hydrophilic 1,2-diol-containing drugs.
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