JOURNAL OF MOLECULAR LIQUIDS
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2020
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IF 5.065
Han Jia,Wenjian Huang,Yugui Han,Qiuxia Wang,Juan He,Jinyong Song,Jiajun Dai,Hui Yan,Dexin Liu
The effects of both hydrophilic and hydrophobic SiO 2 nanoparticles (NPs) on the viscoelasticity of stearyltrimethylammonium bromide/sodium salicylate wormlike micelles (WLMs) solutions were investigated. The micelle-nanoparticle junctions obviously increased the contour length L c of the WLMs to facilitate the viscoelasticity of WLMs solution, which could be reflected by cryo-TEM images and Maxwell model. The effects of SiO 2 NPs on the zero-shear viscosity and the flow activation energies of WLMs with different surfactant alkyl chain lengths were explored in the controlled experiments. It was found that the viscoelasticity of WLMs/NPs mixture was associated with the strength of the hydrophobic effect between the SiO 2 NPs and surfactant molecules in the micelle-nanoparticle junction. The number densities of micelle-nanoparticle junction in hydrophilic and hydrophobic SiO 2 NPs systems were calculated by the mathematical model to confirm our proposed hypothesis.
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ACS Biomaterials Science & Engineering
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2020
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IF 4.152
Chuyu He,Yao Jin,Yunqiang Deng,Yang Zou,Shidi Han,Chuhang Zhou,Yuanhang Zhou,Yan Liu
The intestine epithelium is considered to be the most critical obstacle for nanoparticles for oral delivery of water-insoluble and poorly absorbed drugs. Based on the specific transporters located on the apical membrane of the intestinal epithelium, the carnitine-conjugated polymeric micelles targeting to the carnitine/organic cation transporter 2 (OCTN2) were developed by combining carnitine-conjugated poly(2-ethyl-2-oxazoline)-poly(d,l-lactide) with monomethoxy poly(ethylene-glycol)-poly(d,l-lactide). The carnitine-conjugated micelles with favorable stability in gastrointestinal fluid were validated to remarkably increase the cellular internalization and transcellular transport, while these were not the cases in the presence of free carnitine. These were further confirmed by more distribution of the micelles within epithelial cells, on the apical and basolateral side of the epithelium in mice. Additionally, identification of the carnitine-conjugated micelles by OCTN2 was detected to facilitate cellular uptake of the micelles via fluorescence immunoassay. Both clathrin and caveolae/lipid rafts pathways mediated endocytosis and transcellular transport of the carnitine-conjugated micelles, implying the enrichment of endocytic and transcellular transport pathway compared with that of carnitine-unconjugated micelles. Further, the intracellular trafficking process of the carnitine-conjugated micelles was tracked under confocal laser scanning microscopy, which involved in intracellular compartments such as late endosomes, lysosomes, endoplasmic reticulum, and Golgi apparatus as well. In conclusion, the current study provided an efficient strategy to facilitate the oral absorption of water-insoluble and poorly absorbed agents using intestinal transporter-mediated polymeric micelles.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2020
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IF 4.845
Tian'e Chen,Liangxing Tu,Ge Wang,Na Qi,Wei Wu,Wei Zhang,Jianfang Feng
Chitosan is widely used as a permeation enhancer for oral drug delivery, although its drawbacks include a limited enhancement of drug bioavailability and an inability to form micelles. In this study, we designed a novel chitosan derivative (GA-CS-TPGS copolymer) and constructed paclitaxel micelles (PTX-Micelles) designed to have multiple functions associated with the GA-CS-TPGS copolymer (enhanced bioadhesion, inhibited P-gp efflux and drug metabolism in liver) and the micelles (enhanced solubility and permeability) to enhance the bioavailability and anti-tumor efficacy of PTX. The results showed that the PTX-Micelles system could alter the in vivo pharmacokinetic performance and therapeutic effect of PTX via its predesigned functions. The bioavailability of PTX was enhanced approximately 3.80-fold by the PTX-Micelles, and an enhanced anti-lung tumor efficacy of PTX-Micelles was observed when compared to Taxol®. The results of this study indicate that constructing micelles with a multifunctional chitosan derivative may be a promising approach to enhance the oral bioavailability and anti-tumor efficacy of poorly soluble drugs.
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POLYMER
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2020
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IF 4.231
Liangjie Shi,Yong Jin,Weining Du,Shuangquan Lai,Yichao Shen,Rong Zhou
Redox-responsive polymeric micelles carriers have been developing rapidly in recent years. Despite great achievements having been made, the acute defects of low drug loading content and drug loading efficiency, weak sensitivity to redox environment of tumor tissue, limited stability in the circulation fluids and less programmable release hinder their further applications. In this work, a sort of diselenide-containing nonionic gemini polymeric micelles carriers (PEG-Gn, n = 8, 12, 16) was synthesized. The resultant micelles of PEG-G12 have a small average size (less than 100 nm), high drug loading efficiency (77%) and acceptable drug loading content (7.1%), which may be attributed to their gemini structure with a lower critical micelle concentration and a larger average minimum area per polymer molecules of micelles. In addition, PEG-G12 can smartly judge the redox environment to release the loaded drugs. In vitro release experiments showed that the indometacin-loaded polymeric micelles could hold the drugs in the circulation fluids in 0.02 mM 1,4-dithiothreitol (only 27% release in 24 h) and release the drugs rapidly and sufficiently in 10 mM 1,4-dithiothreitol (82% in 24 h). More interestingly, these indometacin-loaded micelles could first respond to the reactive oxygen species and then to the 1,4-dithiothreithol, achieving a programmable release of indometacin. We expect that this work could provide a versatile platform for the next generation of redox-responsive polymeric micelles carriers with better comprehensive performances.
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LANGMUIR
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2020
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IF 3.557
Wenwen Liu,Junjie Li,Zhihui Qin,Mengmeng Yao,Xinlu Tian,Zhiming Zhang,Li Zhang,Qin Guo,Linhua Zhang,Dunwan Zhu,Fanglian Yao
Circulation stability in vivo and stimuli-responsiveness under a tumor microenvironment of the polymeric prodrug micellar drug delivery systems are very critical to improve the tumor therapeutic efficiency. In this study, a series of polyamidoamine (PAMAM)-graft-poly(2-(diethylamino) ethyl methacrylate) (PDEAEMA)-block-poly(betaine sulfonate) (PSBMA) (PDS) unimolecular micelles were prepared via atom transfer radical polymerization. PAMAM served as a hydrophobic core to load the drug, the PDMAEMA segment was a middle layer to provide both thermo- and pH-sensitivity, whereas the PSMBA shell layer was used to improve the stability of the unimolecular micelles. The PDS exhibited a spherical structure with the size of 10–20 nm at pH 7.4. PDS micelles had excellent stability to resist the large volume liquid dilution. Moreover, it exhibited excellent stability in a complex biological microenvironment because of a superhigh antiprotein adhesion capacity of the PSBMA shell layer compared with PAMAM micelles. Drug release studies confirmed that the DOX can remain in the PDS micelles at pH 7.4 and 37 °C, whereas it can rapidly be released when the pH decreases to 5.0 and/or the temperature increases to 40 °C. In vitro studies suggested that the PDS drug delivery system can effectivity induce apoptosis and inhibit the proliferation of cancer cells. In vivo studies suggested that the PDS micelles prolonged the circulation time, decreased the side effects, and increased the antitumor efficacy. Therefore, the prepared PDS micelles are a potential anticancer drug delivery carrier for cancer therapy.
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EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
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2020
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IF 3.616
Jiahui Sun,Jing Li,Qi Liu,Min Jiang,Mengjia Yang,Siwen Zhan,Tong Qiu,Kaiyong He,Xueqiong Zhang
This study aimed to develop, evaluate, and optimize the mPEG-PLA/vitamin E-TPGS mixed micelle drug delivery system to encapsulate celecoxib (CXB) and honokiol (HNK) for intravenous treatment of breast cancer. To this end, we formulated CXB-loaded mPEG-PLA/vitamin E-TPGS (PV-CXB) and HNK-loaded mPEG-PLA/vitamin E-TPGS (PV-HNK) mixed micelles and analyzed their characteristics. The 4T1 cell line was used for cytotoxicity determination and cellular uptake experiments, and for establishing a 4T1-bearing mouse model for histopathology, immunofluorescence, terminal deoxynucleotidyl transferase-mediated nick end labeling, and Western blot analysis . The synergistic effects of PV-CXB and PV-HNK combination therapy were investigated in vitro and in vivo using the coefficient of drug interaction values. The mean size of PV-CXB and PV-HNK prepared with optimal formulation was approximately 50 nm , with a spherical shape. PV-CXB and PV-HNK combination therapy exhibited cytotoxicity in 4T1 cells in vitro. However, the toxicity of PV-CXB and PV-HNK combination therapy was not apparent in normal tissues (heart, liver, spleen, lung, and kidney) in vivo and reduced the expression of collagen fibers in tumor tissues. Moreover, the combination therapy reduced the expression of tumor growth biomarkers (Foxp3, CD4, Gr-1, CD11b, CD31, Ki67, FoxM1, and VEGF). In addition, the tumor cell apoptosis rate reached 45.71 ± 0.62%. The combined treatment with PV-CXB and PV-HNK showed synergistic effect both in vitro and in vivo. Thus, the PV-CXB and PV-HNK drug delivery system could be used as a potential combination therapy for breast cancer .
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Polymer Chemistry
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2020
·Vol. 11
·期 12
·2252-2261
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IF 5.342
Li Zhang,Dongjian Shi,Yunyun Gao,Tianyang Zhou,Mingqing Chen
To overcome the thermodynamic instability of polymeric micelles in an extremely high dilution bio-environment, unimolecular micelles with covalently-bound molecular architectures have been widely studied for drug delivery. In this work, an amphiphilic multi-arm star random copolymer, polyamidoamine-poly(butenyl phospholane-co-methoxy phospholane) with phenylboronic acid end groups (abbreviated as PAMAM-P(BEP-co-MP)-PBA), was synthesized by a simple one-pot ring-opening polymerization with the fourth-generation PAMAM dendrimer as a macro-initiator. Then, unimolecular micelles (UMs) were formed by the obtained copolymers in a dilute aqueous solution. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) results showed that the UMs possess uniform spherical structures and stable hydrodynamic sizes (ca. 20 nm). Besides, further information on polymer repeat unit numbers could be theoretically calculated by comparison of hydrodynamic sizes and contour lengths. Doxorubicin (DOX) could be encapsulated into the inner hydrophobic regions of the UMs. The obtained DOX-loaded UMs exhibited a slow and sustainable release behavior in an intracellular simulated environment. Furthermore, in vitro cytotoxicity and cellular uptake studies demonstrated that the DOX-loaded UMs could specifically recognize and accumulate in HepG2 cells, and then inhibit tumor cell growth effectively. Therefore, this PBA-functionalized unimolecular micelle could be a promising candidate for targeted drug delivery.
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RSC Advances
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2019
·Vol. 9
·期 5
·2371-2378
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IF 3.049
Nan Wang,Xiao-Chuan Chen,Ruo-Lin Ding,Xian-Ling Yang,Jun Li,Xiao-Qi Yu,Kun Li,Xi Wei
Stimulus-responsive, controlled-release systems are of great importance in medical science and have drawn significant research attention, leading to the development of many stimulus-responsive materials over the past few decades. However, these materials are mainly designed to respond to external stimuli and ignore the key problem of the amount of drug loading. In this study, exploiting the synergistic effect of boronic esters and N-isopropylacrylamide (NIPAM) pendant, we present a copolymer as an ROS and esterase dual-stimulus responsive drug delivery system that has a drug loading of up to 6.99 wt% and an entrapment efficiency of 76.9%. This copolymer can successfully self-assemble into polymer micelles in water with a narrow distribution. Additionally, the measured CMC hinted at the good stability of the polymeric micelles in water solution, ensuing long circulation time in the body. This strategy for increasing the drug loading on the basis of stimulus response opens up a new avenue for the development of drug delivery systems.
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ACS Applied Materials & Interfaces
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2019
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IF 8.456
Yuxin Xing,Tao Ding,Zhenqiang Wang,Liucan Wang,Haidi Guan,Jia Tang,Dong Mo,Jixi Zhang
Currently, the simple integration of multiple therapeutic agents within a single nanostructure for combating multidrug resistance (MDR) tumors yet remains a challenge. Herein, we report a photoresponsive nanocluster (NC) system prepared by installing polydopamine (PDA) nanoparticle clusters on the surface of d-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS) (a drug efflux inhibitor) micelles solubilized with IR780 (a photosensitizer) to achieve a combined chemotherapy (CT)/photothermal therapy (PTT)/photodynamic therapy (PDT) for drug-resistant breast cancer. Mediated by the fluorescence resonance energy transfer and radical scavenging properties of PDA, NC shows prominently quenched fluorescence emission (∼78%) and inhibited singlet oxygen generation (∼67%) upon exposure to near-infrared (NIR) light (808 nm, 0.5 W cm–2), favoring a highly efficient PTT module. Meanwhile, the photothermal heat can also boost the release of doxorubicin hydrochloride whose intracellular accumulation can be greatly enhanced by TPGS. Interestingly, the first NIR irradiation and subsequent incubation (∼24 h) can induce the gradual relocation and disintegration of PDA nanoparticles, thereby leading to activated PDT therapy under the second irradiation. Upon the temporally controlled sequential application of PTT/PDT, the developed NC exhibited a great potential to treat MDR cancer both in vitro and in vivo. These findings suggest that complementary interactions among PTT/PDT/CT modalities can enhance the efficiency of the combined therapy for MDR tumor.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2019
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IF 4.784
Mei Zhang,Sajid Asghar,Xin Jin,Ziyi Hu,Qineng Ping,Zhipeng Chen,Feng Shao,Yanyu Xiao
A micelle system based on hyaluronic acid (HA)-octadecylamine (OA) conjugate (HOA) functionalized with N -acetylcysteine (NAC) was constructed to yield NAC modified HOA conjugate (NHOA) for improving oral paclitaxel (PTX) delivery (PTX-NHOA). The average size of spherical PTX-NHOA micelles was 162.7 nm with a zeta potential of −27.6 mv. The encapsulation efficiency (EE) and drug loading (DL) of PTX-NHOA micelles were 92.64% and 6.96%, respectively. Additionally, NHOA micelles exihibited significantly higher cellular uptake in comparison with HOA micelles by caveolin-mediated and clathrin-mediated endocytosis. Higher permeation ability of NHOA micelles (2.75-fold and 1.32-fold, respectively) through cell monolayers of Caco-2/HT29 cells than that of Taxol and HOA micelles were also observed. The intestinal biodistribution result showed that NAC-modified micelles could enhance its adhesion to the intestinal surface and permeate deeply within the intestinal villi. The NHOA micelles were better absorbed in the duodenum, followed by the jejunum and the ileum. In vivo pharmacokinetic studies showed that AUC 0-t value of PTX-NHOA micelles was about 5.92-fold and 2.47-fold higher compared to that of Taxol and PTX-HOA micelles, respectively. In a word, NHOA micelles is a promising drug delivery system in improving the oral absorption of insoluble drugs.
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RSC Advances
·
2019
·Vol. 9
·期 27
·15196-15204
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IF 3.049
Yun Hong,Dongsen Mao,Rui Wu,Zhe Gao,Tingting Meng,Rongrong Wang,Lin Liu,Jing Miao
DNAzymes have the potential to suppress gene expression through sequence-specific mRNA cleavage and can therefore play an important role in various gene therapies. Hepatitis B virus (HBV) is still one of the most serious liver infections in people around the world and is difficult to treat. We previously designed a 10-23 DNAzyme called DrzBS, which targets HBV S gene expression, but this enzyme depends on exogenous delivery, and so its application has been limited. To overcome this limitation, we have now developed a chitosan-based nanocarrier (chitosan-g-stearic acid, CSO–SA) for intracellular delivery of DrzBS, then compared the inhibition effect of our CSO–SA/DrzBS complex to a common transfection reagent, Lipofectamine™ 2000/DrzBS, on hepatitis B surface antigen expression. The synthesized CSO–SA assembles into micelles in an aqueous solution and exhibits excellent cytoplasmic targeting, and could protect DrzBS from degradation by ribonuclease. CSO–SA/DrzBS showed a higher inhibition rate (IR) than Lipofectamine™ 2000/DrzBS. Moreover, at the same DrzBS concentration (1.2 μmol L−1), the maximum IR of CSO–SA/DrzBS micelles was 2.4-fold that of the Lipofectamine™ 2000/DrzBS complex, and held on for 96 hours. Compared with Lipofectamine™ 2000/DrzBS, CSO–SA/DrzBS achieved a higher HBV inhibition effect. This study demonstrates that CSO–SA micelles can serve as a potential vector for DrzBS and that CSO–SA/DrzBS micelles are a promising application for anti-HBV gene therapy.
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COLLOID AND POLYMER SCIENCE
·
2019
·Vol. 297
·期 10
·1321-1330
·
IF 1.906
Chen Jun,Ding Amin,Zhou Yifeng,Chen Pengpeng,Xu Ying,Nie Wangyan
Star-shaped copolymers based on star-shaped poly (L-lactide) (s-PLLA) and tocopheryl polyethylene glycol 1000 succinate (TPGS) (s-PLLA-TPGS) were synthesized with structural variation on arm numbers in order to investigate the relationship between the arm numbers of s-PLLA-TPGS copolymers and their micelle properties. The structure and M w of s-PLLA-TPGS were characterized with 1 H NMR, GPC, DSC, and XRD. The indometacin(IMC)-loaded s-PLLA-TPGS micelles were obtained by dialysis method. The effects of arm numbers of s-PLLA-TPGS copolymers on surface morphology, particle size, zeta potential, drug loading content (LC), drug encapsulation efficiency (EE), and in vitro drug release behavior of prepared micelles were studied. The results indicated that the average diameters, LC, and EE of IMC-loaded s-PLLA-TPGS micelles gradually increased in the order of 4-arm, 5-arm, and 6-arm s-PLLA-TPGS copolymers. The in vitro release studies showed that the IMC accumulative release can be decreased by increasing the arm numbers of the s-PLLA-TPGS copolymers, and the release profiles of IMC from the s-PLLA-TPGS copolymers followed the Baker-Lonsdale model equation. The results suggest that the arm number regulation of s-PLLA-TPGS copolymers can provide a new strategy for designing drug carriers of high efficiency.
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危险品化学品经营许可证（带存储）