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      Cationic/Anionic Polyelectrolyte (PLL/PGA) Coated Vesicular Phospholipid Gels (VPGs) Loaded with Cytarabine for Sustained Release and Anti-glioma Effects

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          Abstract

          Background

          Cationic and anionic polymer-modified nanoparticles offer promising properties for the drug and gene delivery. Our study uses cationic/anionic polyelectrolyte coated vesicular phospholipid gels (VPGs) loaded with cytarabine (Ara-C) that enhance in vitro and in vivo anti-glioma effects.

          Methods

          Sodium cholesteryl sulfate (SCS) or octadecylamine (ODA) incorporated in a phospholipids phase were used to prepare charged VPGs, and cationic ε-polylysine (PLL) coated VPGs (PLL-SCS VPGs) and anionic γ-polyglutamic acid (PGA) coated VPGs (PGA-ODA VPGs) were prepared via electrostatic interactions, respectively. The morphology, particle size, zeta potential, rheology properties, and in vitro release were then characterized. The in vitro cytotoxicity and cellular uptake were evaluated on U87-MG glioma cells. The in vivo antitumor effects were studied on BALB/c nude mice bearing a right flank U87-MG glioma model.

          Results

          The TEM images and physicochemical properties of cationic/anionic polyelectrolyte coated VPGs exhibited that polymers covered on the vesicular surface. The results of rheologic property analysis showed that cationic/anionic polyelectrolyte coated VPGs enhanced the viscosity of uncoated VPGs. The in vitro release experiments revealed that cationic/anionic polyelectrolyte coated VPGs kept Ara-C sustained release up to 18 days. Specially, compared with PLL-SCS VPGs, PGA-ODA VPGs demonstrated higher in vitro cytotoxicity and cellular uptake efficiency in U87-MG glioma cells, and enhanced in vivo antitumor effects when subcutaneously injected around the tumor. No severe toxicity appeared in the right flank U87-MG glioma model of BALB/c nude mice.

          Conclusion

          Anionic γ-PGA coated VPGs were superior to cationic PLL coated VPGs in terms of improving the anti-glioma effect for local delivery.

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          Most cited references 32

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          Potentiation of pH-sensitive polymer-modified liposomes with cationic lipid inclusion as antigen delivery carriers for cancer immunotherapy.

          Cationic lipid-incorporated liposomes modified with pH-sensitive polymers were prepared by introducing 3, 5-didodecyloxybenzamidine as a cationic lipid to egg yolk phosphatidylcholine liposomes modified with 3-methylglutarylated hyperbranched poly(glycidol) (MGlu-HPG) as a pH-sensitive polymer. These liposomes were stable at neutral pH, but were destabilized below pH 6.0 because MGlu-HPG changed its characteristics from hydrophilic to hydrophobic in response to the pH decrease. Cationic lipid inclusion improved their pH sensitivity at weakly acidic pH and association of liposomes with murine dendritic cell (DC) lines. Cationic lipid-incorporated liposomes delivered entrapped ovalbumin (OVA) molecules not only to cytosol but also to endosome/lysosome. Treatment with cationic lipid-incorporated liposomes induced up-regulation of antigen presentation-involved molecules on DCs, the promotion of cytokine production, and antigen presentation via both major histocompatibility complex (MHC) class I and II molecules. Especially, antigen presentation via MHC class II was promoted by cationic lipid inclusion, which might correspond to efficient endosome/lysosome delivery of OVA. Subcutaneous administration of OVA-loaded cationic lipid-incorporated liposomes induced antigen-specific antibody production in serum and Th1-dominant immune responses in the spleen. Furthermore, administration of the cationic lipid-incorporated liposomes to mice bearing E.G7-OVA tumor more significantly reduced the tumor volume than liposomes without cationic lipids. Therefore, cationic lipid inclusion into pH-sensitive polymer-modified liposomes, which can achieve both efficient antigen intracellular delivery and activation of antigen presenting cell, is an effective approach to develop antigen carriers for efficient cancer immunotherapy. Copyright © 2014 Elsevier Ltd. All rights reserved.
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            Enhanced electrostatic interaction between chitosan-modified PLGA nanoparticle and tumor.

            In our previous study, lung tumor-specific targeting of paclitaxel was achieved in mice by intravenous administration of chitosan-modified paclitaxel-loaded PLGA nanoparticles (C-NPs-paclitaxel). Transient formation of aggregates in the blood stream followed by enhanced trapping in the capillaries was proposed as a mechanism of the lung-specific accumulation of paclitaxel. In the present study, the mechanism of tumor lung preferential accumulation of paclitaxel from C-NPs-paclitaxel was investigated. Zeta potential and in vitro cellular cytotoxicity (A549 cells and CT-26 cells) of C-NPs-paclitaxel, and in vitro uptake of coumarin 6 to these cells from chitosan-modified coumarin 6 containing PLGA nanoparticles (C-NPs-coumarin 6) were examined as a function of pH (6.8, 7.4 and 8.0). The zeta potential of C-NPs-paclitaxel increased as the medium pH became more acidic. In vitro uptake of coumarin 6 by A549 cells and CT-26 cells was enhanced at lower pH for C-NPs-coumarin 6. In vitro cytotoxicity experiment with C-NPs-paclitaxel demonstrated enhanced cytotoxicity as the pH became more acidic. Therefore, enhanced electrostatic interaction between chitosan-modified PLGA nanoparticles and acidic microenvironment of tumor cells appears to be an underlying mechanism of lung tumor-specific accumulation of paclitaxel from C-NPs-paclitaxel.
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              Ternary complexes of pDNA, polyethylenimine, and gamma-polyglutamic acid for gene delivery systems.

              We discovered a vector coated by gamma-polyglutamic acid (gamma-PGA) for effective and safe gene delivery. In order to develop a useful non-viral vector, we prepared several ternary complexes constructed with pDNA, polyethylenimine (PEI), and various polyanions, such as polyadenylic acid, polyinosinic-polycytidylic acid, alpha-polyaspartic acid, alpha-polyglutamic acid, and gamma-PGA. The pDNA/PEI complex had a strong cationic surface charge and showed extremely high transgene efficiency although it agglutinated with erythrocytes and had extremely high cytotoxicity. Those polyanions changed the positive zeta-potential of pDNA/PEI complex to negative although they did not affect the size. They had no agglutination activities and lower cytotoxicities but most of the ternary complexes did not show any uptake and gene expression; however, the pDNA/PEI/gamma-PGA complex showed high uptake and gene expression. Most of the pDNA/PEI/gamma-PGA complexes were located in the cytoplasm without dissociation and a few complexes were observed in the nuclei. Hypothermia and the addition of gamma-PGA significantly inhibited the uptake of pDNA/PEI/gamma-PGA by the cells, although l-glutamic acid had no effect. These results strongly indicate that the pDNA/PEI/gamma-PGA complex was taken up by gamma-PGA-specific receptor-mediated energy-dependent process. Thus, the pDNA/PEI/gamma-PGA complex is useful as a gene delivery system with high transfection efficiency and low toxicity.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                12 May 2020
                2020
                : 14
                : 1825-1836
                Affiliations
                [1 ]Integrated Hospital of Traditional Chinese Medicine, Southern Medical University , Guangzhou 510315, People’s Republic of China
                [2 ]Department of Pharmacy, Guilin Medical University , Guilin 541004, People’s Republic of China
                [3 ]Department of Pharmaceutics, Shenyang Pharmaceutical University , Shenyang 110016, People’s Republic of China
                Author notes
                Correspondence: Aimin Li; Xing Tang Email liaimin2005@163.com; tanglab@126.com
                Article
                248362
                10.2147/DDDT.S248362
                7229786
                © 2020 Qi et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 7, Tables: 1, References: 36, Pages: 12
                Categories
                Original Research

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