JOURNAL OF NANOBIOTECHNOLOGY
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2021
·Vol. 19
·期 1
·1-16
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IF 10.435
Xu Jiangkang,Yang Xiaoye,Ji Jianbo,Gao Yuan,Qiu Na,Xi Yanwei,Liu Anchang,Zhai Guangxi
Background Glioblastoma is a lethal neoplasm with few effective therapy options. As a mainstay in the current treatment of glioma at present, chemotherapeutic agents usually show inadequate therapeutic efficiency due to their low blood brain barrier traversal and brain targeting, together with tumor multidrug resistance. Novel treatment strategies are thus urgently needed to improve chemotherapy outcomes. Results Here, we report that nanomedicines developed by functionalizing the neurotropic rabies virus-derived polypeptide, RVG, and loading reduction-sensitive nanomicelles (polymer and doxorubicin) enable a highly specific and efficacious drug accumulation in the brain. Interestingly, curcumin serves as the hydrophobic core of the polymer, while suppressing the major efflux proteins in doxorubicin-resistant glioma cells. Studies on doxorubicin-resistant rat glioma cells demonstrate that the RVG-modified micelles exhibit superior cell entry and antitumor activity. In vivo research further showed that RVG modified nanomicelles significantly enhanced brain accumulation and tumor inhibition rate in mice, leading to a higher survival rate with negligible systemic toxicity. Moreover, effective suppression of recurrence and pulmonary metastatic nodules were also determined after the RVG-modified nanomicelles treatment. Conclusions The potential of RVG-modified nanomicelles for glioma was demonstrated. Brain accumulation was markedly enhanced after intravenous administration. This unique drug delivery nanoplatform to the brain provides a novel and powerful therapeutic strategy for the treatment of central nervous system disorders including glioma. Graphic abstract
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Nature Communications
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2021
·Vol. 12
·期 1
·1-17
·
IF 14.919
Qi Jing,Jin Feiyang,You Yuchan,Du Yan,Liu Di,Xu Xiaoling,Wang Jun,Zhu Luwen,Chen Minjiang,Shu Gaofeng,Wu Liming,Ji Jiansong,Du Yongzhong
Some specific chemotherapeutic drugs are able to enhance tumor immunogenicity and facilitate antitumor immunity by inducing immunogenic cell death (ICD). However, tumor immunosuppression induced by the adenosine pathway hampers this effect. In this study, E-selectin-modified thermal-sensitive micelles are designed to co-deliver a chemotherapeutic drug (doxorubicin, DOX) and an A2A adenosine receptor antagonist (SCH 58261), which simultaneously exhibit chemo-immunotherapeutic effects when applied with microwave irradiation. After intravenous injection, the fabricated micelles effectively adhere to the surface of leukocytes in peripheral blood mediated by E-selectin, and thereby hitchhiking with leukocytes to achieve a higher accumulation at the tumor site. Further, local microwave irradiation is applied to induce hyperthermia and accelerates the release rate of drugs from micelles. Rapidly released DOX induces tumor ICD and elicits tumor-specific immunity, while SCH 58261 alleviates immunosuppression caused by the adenosine pathway, further enhancing DOX-induced antitumor immunity. In conclusion, this study presents a strategy to increase the tumor accumulation of drugs by hitchhiking with leukocytes, and the synergistic strategy of chemo-immunotherapy not only effectively arrested primary tumor growth, but also exhibited superior effects in terms of antimetastasis, antirecurrence and antirechallenge.
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Nanoscale Research Letters
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2021
·Vol. 16
·期 1
·1-12
·
IF 4.703
Huang Xin,Chen Qian,Li Xin,Lin Chenyu,Wang Kun,Luo Cici,Le Wenjun,Pi Xiaodong,Liu Zhongmin,Chen Bingdi
At present, various fluorescent nanomaterials have been designed and synthesized as optical contrast agents for surgical navigation. However, there have been no reports on the preparation of fluorescent contrast agents for lung cancer surgery navigation using silicon quantum dots (Si QDs). This study improved and modified the water-dispersible Si QD micelles reported by Pi et al. to prepare Si QD micelles-CKAP4. The data showed that the Si QD micelles-CKAP4 were spherical particles with a mean hydrodiameter of approximately 78.8 nm. UV–visible absorption of the Si QD micelles-CKAP4 ranged from 200 to 500 nm. With an excitation wavelength of 330 nm, strong fluorescence at 640 nm was observed in the fluorescence emission spectra. Laser confocal microscopy and fluorescence microscopy assay showed that the Si QD micelles-CKAP4 exhibited good targeting ability to lung cancer cells and lung cancer tissues in vitro. The in vivo fluorescence-imaging assay showed that the Si QD micelles-CKAP4 was metabolized by the liver and excreted by the kidney. In addition, Si QD micelles-CKAP4 specifically targeted lung cancer tissue in vivo compared with healthy lung tissue. Cytotoxicity and hematoxylin and eosin staining assays showed that the Si QD micelles-CKAP4 exhibited high biosafety in vitro and in vivo. Si QD micelles-CKAP4 is a specifically targeted imaging agent for lung cancer and is expected to be a fluorescent contrast agent for lung cancer surgical navigation in the future.
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Colloid and Interface Science Communications
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2021
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IF 4.914
Shuting Wang,Yu Fang,Zequn Zhang,Qiao Jin,Jian Ji
Because of the severe antibiotic resistance , photodynamic therapy is considered as a potent method for the treatment of bacterial infection with bare drug resistance. However, its therapeutic efficacy is not always satisfactory in practical treatment. In this study, pH-responsive prodrug micelles were prepared by conjugation of chlorin e6 to polyethylene glycol- b -poly(2-(hexamethyleneimino) ethyl methacrylate- co -aminoethyl methacrylate) for improving the antimicrobial activity of photodynamic therapy. The micelles were negatively charged in normal physiological environment, which was very important for long blood circulation. However, the micelles could turn to be positively charged in bacterial infection microenvironment and then adhere to negatively charged bacterial membranes, which could significantly improve their antibacterial activity against both methicillin-resistant Staphylococcus aureus and Escherichia coli after laser irradiation. The in vivo experiment showed excellent antibacterial effect of pH-sensitive micelles in a subcutaneous infection model. The micelles showed great potential in the photodynamic therapy of stubborn bacterial infections.
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International Journal of Nanomedicine
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2020
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IF 5.115
Yun-Chun Zhao,Hai-Li Zheng,Xiao-Rong Wang,Xiao-Ling Zheng,Yue Chen,Wei-Dong Fei,Yong-Quan Zheng,Wen-Xi Wang,Cai-Hong Zheng
Background Methotrexate (MTX) is an antiproliferative drug widely used to treat inflammatory diseases and autoimmune diseases. The application of percutaneous administration is hindered due to its poor transdermal penetration. To reduce side effects and enhanced percutaneous delivery of MTX, novel methotrexate (MTX)-loaded micelles prepared with a amphiphilic cationic material, N,N-dimethyl-(N′,N′-di-stearoyl-1-ethyl)1,3-diaminopropane (DMSAP), was designed.Materials and Methods DMSAP was synthesized via three steps using simple chemical agents. H nuclear magnetic resonance and mass spectroscopy were used to confirm the successful synthesis of DMSAP. A safe and non-toxic phosphatidylcholine, soybean phosphatidylcholine (SPC), was added to DMSAP at different ratios to form P/D-micelles. Then, MTX-entrapped micelles (M/P/D-micelles) were prepared by electrostatic adsorption. The physicochemical properties and blood stability of micelles were examined thoroughly. In addition, the transdermal potential of the micelles was evaluated by permeation experiments.Results In aqueous environments, DMSAP conjugates could self-assemble spontaneously into micelles with a low critical micelle concentration (CMC) of 0.056 mg/mL. Stable, spherical MTX-entrapped micelles (M/P/D-micelles) with a size of 100–120 nm and high zeta potential of +36.26 mV were prepared. In vitro permeation studies showed that M/P/D-micelles exhibited superior skin permeability and deposition of MTX in the epidermis and dermis compared with that of free MTX.Conclusion These special novel cationic M/P/D-micelles can enhance the permeability of MTX and are expected to be a promising percutaneous delivery system for therapy skin diseases.
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ACS Omega
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2019
·
IF 2.584
Danxuan Fang,Menghan Pi,Zhicheng Pan,Nijia Song,Xueling He,Jiehua Li,Feng Luo,Hong Tan,Zhen Li
Polymeric nanocarriers have been extensively used in medicinal applications for drug delivery. However, intravenous nanocarriers circulating in the blood will be rapidly cleared from the mononuclear macrophage system. The surface physicochemical characterizations of nanocarriers are the primary factors to determine their fate in vivo, such as evading the reticuloendothelial system, exhibiting long blood circulation times, and accumulating in the targeted site. In this work, we develop a series of polyurethane micelles containing segments of an anionic tripeptide, hydrophilic mPEG, and disulfide bonds. It is found that the long hydrophilic mPEG can shield the micellar surface and have a synergistic effect with the negatively charged tripeptide to minimize macrophage phagocytosis. Meanwhile, the disulfide bond can rapidly respond to the intracellular reduction environment, leading to the acceleration of drug release and improvement of the therapeutic effect. Our results verify that these anionic polyurethane micelles hold great potential in the development of the stealth immune system and controllable intracellular drug transporters.
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AAPS PHARMSCITECH
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2022
·Vol. 23
·期 7
·1-13
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IF 4.026
Cao Xia,He Qing,Adu-Frimpong Michael,Shen Xinyi,Rong Wanjing,Li Xiaoxiao,Zhang Jian,Xia Xiaoli,Shi Feng,Ji Hao,Toreniyazov Elmurat,Wang Qilong,Yu Jiangnan,Xu Ximing
Pinocembrin (PCB) is 5,7-dihydroxyl flavanone and has multiple pharmacological activities, namely, anti-inflammation, anti-osteoporotic, and so on. However, low water solubility and bioavailability have hindered its application. Herein, we aimed to increase its bioavailability through preparation of F127/MPEG-PDLLA polymer micelles (PCB-M). We characterized the micelles through appropriate attributes such as analysis of particle size (PS), polydispersity (PDI), transmission electron microscopic (TEM) image, stability test, and evaluation of in vitro release of drug. After physical characterization, the respective PS, PDI, and entrapment efficiency (EE) of PCB-M were estimated to be 27.63 ± 0.17 nm, 0.055 ± 0.02, and 90.53 ± 0.01%. Fluorescence probe method was employed to measure critical micelle concentration (CMC) of PCB-M, we observed CMC was low, thereby suggesting that PCB-M had good stability. In vitro release analysis indicated that the rate of cumulative PCB release from PCB-M was greater than 90% in each medium compared with free PCB, which was less than 40%, thus pointing to a significantly improved solubility of PCB. In vivo pharmacokinetic results showed that oral biological availability of PCB-M increased 5.3 folds comparable to free PCB. The effects of PCB on osteoblasts and ALP activities were investigated; subsequently, zebrafish osteoporotic model was established with prednisolone to study the anti-osteoporotic effects of PCB and PCB-M. The results showed that PCB improved osteoporosis with PCB-M being more effective than free PCB. Finally, PCB-M can be used as a promising method to improve the solubility of PCB, while the bioavailability and anti-osteoporotic effect of PCB could be improved, thus laying a foundation for clinical use in the future. Graphical Abstract
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BIOMACROMOLECULES
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2015
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IF 5.75
Haisheng Wang,Wenbo Zhang,Changyou Gao
The amphiphilic pyrene-containing random copolymers with light-responsive pyrene ester bonds were synthesized by copolymerizing 1-pyrenemethyl acrylate (PA) and N,N-dimethylacrylamide (DMA). The P(DMA-co-PA) copolymers formed spherical micelles in water, which were transformed into nanorods as a result of cleavage of the pyrene ester bonds under UV irradiation. In vitro culture with A549 cells and Raw cells showed that compared to the nonphotodegradable ones, the photodegradable P(DMA-co-PA) micelles caused significantly higher cytotoxicity under the same UV irradiation. The intracellular reactive oxygen species (ROS) level had a positive correlation with the cytotoxicity regardless of the cell types. The nonphotodegradable pyrene-containing micelles produced a lower level of ROS under UV irradiation. However, the photodecomposable P(DMA-co-PA) micelles produced a significant higher level of ROS under the same trigger of UV irradiation, which caused the shape transformation of micelles to nanorods and higher cytotoxicity simultaneously.
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RSC Advances
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2016
·Vol. 6
·期 46
·39896-39902
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IF 3.289
Lipeng Qiu,Mengqin Zhu,Yan Huang,Kai Gong,Jinghua Chen
Plenty of hyaluronic acid (HA) drug delivery systems have been developed to target cancer cells. Carboxyl of HA is the active group for targeting CD44 receptor, which is overexpressed in several different types of cancer cells. To verify whether the number of carboxyl is the main factor in cellular uptake, hyaluronic acid–octadecylamine (HM) conjugates with 12–51% degrees of substitution (DS) were synthesized. Moreover, a series of doxorubicin (DOX)-loaded HM micelles (DOX/HM) were prepared and characterized. With the increase of DS, the sizes of DOX/HM decreased obviously. The micelles had good fetal bovine serum stability and presented a controlled-release manner. In vitro cytotoxicity tests showed that all the blank micelles were nontoxic against Michigan Cancer Foundation-7 (MCF-7) cells (overexpressed CD44 receptors), whereas DOX/HM micelles with DS of 23% (DOX/HM23) exhibited optimal enhanced anticancer activity. Cellular uptake experiments showed that compared with the other micelles, DOX/HM23 had the appropriate DS and particle size, which led to remarkably efficient internalization to achieve the highest intracellular drug concentration. These results indicate that both the carboxyl groups and particle size play important roles in the cellular uptake of HA-based micelles.
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JOURNAL OF POLYMER SCIENCE PART A-POLYMER CHEMISTRY
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2017
·Vol. 55
·期 9
·1536-1546
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IF 2.952
Shudong Lin,Shiting Feng,Yangmiao Mo,Yuanyuan Tu,Yu Guo,Jiwen Hu,Guojun Liu,Zhiwei Zhong,Lei Miao,Hailiang Zou,Feng Liu
A novel multifunctional amphiphilic graft copolymer has been synthesized consisting of a biodegradable poly( l -aspartic acid) backbone that was decorated by water-soluble poly(ethylene glycol) (PEG) and pH-responsive poly( N , N -diethylaminoethyl methacrylate) (PDEAEMA) side-chains as well as thiol pendant groups. This graft copolymer together with doxorubicin (DOX) formed micelles in water at pH = 10.0 with PDEAEMA and DOX acting as the core and PEG serving as the micellar corona. Upon oxidation, the thiol groups dimerized to form disulfide bonds, thus “locking in” the micellar structure. These crosslinked micelles expanded as the pH was decreased from 7.4 to 5.0 or upon the addition, at pH = 7.4, of glutathione (GSH), a thiol-containing oligopeptide that is present in cancerous cells and cleaves disulfide bonds. At pH = 5.0, GSH addition triggered the disassembly of the micelles. The expansion and disassembly of the micelles have been determined via in vitro experiments to evaluate their DOX release behavior. More importantly, the graft copolymer micelles could enter cells by means of endocytosis and deliver DOX to the nuclei of ovarian cancer BEL-7402 cells. Thus, this polymer and its micelles are promising candidates for drug delivery applications. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55 , 1536–1546
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BIOMACROMOLECULES
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2016
·
IF 5.583
Yuejing Xi,Tao Song,Songyao Tang,Nuosha Wang,Jianzhong Du
Traditional antibiotics usually sterilize in chemical ways, which may lead to serious drug resistance. By contrast, peptide-based antibacterial materials are less susceptible to drug resistance. Herein we report the preparation of an antibacterial peptide-based copolymer micelle and the investigation of its membrane-penetration antibacterial mechanism by transmission electron microscopy (TEM). The copolymer is poly(l-lactide)-block-poly(phenylalanine-stat-lysine) [PLLA31-b-poly(Phe24-stat-Lys36)], which is synthesized by ring-opening polymerization. The PLLA chains form the core, whereas the polypeptide chains form the coronas of the micelle in aqueous solution. This micelle boasts excellent antibacterial efficacy against both Gram-positive and Gram-negative bacteria. Furthermore, TEM studies clearly reveal that the micelles pierce and then destroy the cell membrane of the bacteria. We also compared the advantages and disadvantages of two general methods for measuring the Minimal Inhibitory Concentration (MIC) values of antibacterial micelles. Overall, this study provides us with direct evidence for the antibacterial mechanism of polypeptide-based micelles and a strategy for synthesizing biodegradable antibacterial nanomaterials without antibiotic resistance.
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ACS Applied Materials & Interfaces
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2016
·
IF 7.145
Haitao Zhang,Xiuqi Kong,Yonghe Tang,Weiying Lin
Currently, the development of polymeric micelles combining diagnosis and targeted therapy is theoretically and practically significant in cancer treatment. In addition, it has been reported that cancer cells can produce large amounts of hydrogen sulfide (H2S) and their survival depends on the content of H2S. In this study, a series of N-(2-hydroxyethyl)-4-azide-1,8-naphthalimide ended amphiphilic diblock copolymer poly(2-hydroxyethyl methacrylate)-block-poly(methyl methacrylate) (N3-Nap-PHEMA-b-PMMA-N3) micelles were prepared. Around cancer tissues, the N3-Nap-PHEMA45-b-PMMA42-N3 micelles exhibited dual characteristics of monitoring H2S and H2S triggered charge reversal with the reduction of the azido group. The surface charge of N3-Nap-PHEMA45-b-PMMA42-N3 micelles reversed from negative to positive after monitoring H2S. With H2S triggered charge reversal, the cellular uptake of DOX-loaded N3-Nap-PHEMA45-b-PMMA42-N3 micelles was effectively enhanced through electrostatic attraction mediated targeting, and a fast doxorubicin (DOX) release rate was observed. The MTT assay demonstrated that N3-Nap-PHEMA45-b-PMMA42-N3 micelles were biocompatible to HeLa cells, and DOX-loaded N3-Nap-PHEMA45-b-PMMA42-N3 micelles showed enhanced cytotoxicity in HeLa cells in the presence of H2S. Furthermore, in vivo fluorescence imaging and biodistribution experiments revealed that DOX-loaded N3-Nap-PHEMA45-b-PMMA42-N3 micelles could provide good tumor imaging and accumulate in tumor tissue. Therefore, N3-Nap-PHEMA45-b-PMMA42-N3 micelles can be used as a promising platform for tumor diagnosis and therapy.
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