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Antibody-mediated oral delivery of therapeutic DNA for type 2 diabetes mellitus

BACKGROUND: Diabetes mellitus (DM) is a chronic progressive metabolic disease that involves uncontrolled elevation of blood glucose levels. Among various therapeutic approaches, GLP-1 prevents type 2 diabetes mellitus (T2DM) patients from experiencing hyperglycemic episodes. However, the short half-...

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Autores principales: Cha, Seungbin, Lee, Sun Hwa, Kang, Sung Hun, Hasan, Mohammad Nazmul, Kim, Young Jun, Cho, Sungpil, Lee, Yong-Kyu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062860/
https://www.ncbi.nlm.nih.gov/pubmed/30065848
http://dx.doi.org/10.1186/s40824-018-0129-7
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author Cha, Seungbin
Lee, Sun Hwa
Kang, Sung Hun
Hasan, Mohammad Nazmul
Kim, Young Jun
Cho, Sungpil
Lee, Yong-Kyu
author_facet Cha, Seungbin
Lee, Sun Hwa
Kang, Sung Hun
Hasan, Mohammad Nazmul
Kim, Young Jun
Cho, Sungpil
Lee, Yong-Kyu
author_sort Cha, Seungbin
collection PubMed
description BACKGROUND: Diabetes mellitus (DM) is a chronic progressive metabolic disease that involves uncontrolled elevation of blood glucose levels. Among various therapeutic approaches, GLP-1 prevents type 2 diabetes mellitus (T2DM) patients from experiencing hyperglycemic episodes. However, the short half-life (< 5 min) and rapid clearance of GLP-1 often limits its therapeutic use. Here, we developed an oral GLP-1 gene delivery system to achieve an extended antidiabetic effect. METHODS: Human IgG1 (hIgG1)-Fc-Arg/pDNA complexes were prepared by an electrostatic complexation of the expression plasmid with various ratios of the positively modified Fc fragments of an antibody (hIgG1-Fc-Arg) having a targeting ability to FcRn receptor. The shape and size of the complexes were examined by atomic force and field emission electron microscope. The stability of the complexes was tested in simulated gastrointestinal pH and physiological serum condition. Cellular uptake, transport, and toxicity of the complexes were tested in the Caco-2 cells. Biodistribution and antidiabetic effect of the complexes were observed in either Balb/c mice or Lep(db/db) mice. RESULTS: A 50/1 ratio of the hIgG1-Fc-Arg/pDNA produced a complex structure having approximately 40 ~ 60 nm size and also demonstrated protection of pDNA in the complex from the physiological pH and serum conditions. Cellular uptake and transport of the complex were demonstrated in Caco-2 cells having FcRn receptor expression and forming the monolayer-polarized structure. The cellular toxicity of both delivery vehicle and the complex revealed their minimal toxicity comparable with nontoxicity of a commercial transfection reagent. Biodistribution of the complex showed the detectable distribution of the complex in the most parts of gastrointestinal tract due to ubiquitous expression of the FcRn receptors. An in vivo type 2 diabetes treatment study of oral administration of hIgG1-Fc-9Arg/pGLP-1 complexes showed absorption and expression in GI tract of either Balb/c mice or Lep(db/db) mice. CONCLUSION: In this study, we developed an oral GLP-1 gene delivery system on the platform of cationic hIgG1-Fc-9Arg. Prolonged t1/2, less immunoactivity, and better bioactivities of hIgG-Fc-9Arg/pGLP-1 complexes appeared to be a promising approach to achieve potent treatment of type 2 diabetes treatment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40824-018-0129-7) contains supplementary material, which is available to authorized users.
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spelling pubmed-60628602018-07-31 Antibody-mediated oral delivery of therapeutic DNA for type 2 diabetes mellitus Cha, Seungbin Lee, Sun Hwa Kang, Sung Hun Hasan, Mohammad Nazmul Kim, Young Jun Cho, Sungpil Lee, Yong-Kyu Biomater Res Research Article BACKGROUND: Diabetes mellitus (DM) is a chronic progressive metabolic disease that involves uncontrolled elevation of blood glucose levels. Among various therapeutic approaches, GLP-1 prevents type 2 diabetes mellitus (T2DM) patients from experiencing hyperglycemic episodes. However, the short half-life (< 5 min) and rapid clearance of GLP-1 often limits its therapeutic use. Here, we developed an oral GLP-1 gene delivery system to achieve an extended antidiabetic effect. METHODS: Human IgG1 (hIgG1)-Fc-Arg/pDNA complexes were prepared by an electrostatic complexation of the expression plasmid with various ratios of the positively modified Fc fragments of an antibody (hIgG1-Fc-Arg) having a targeting ability to FcRn receptor. The shape and size of the complexes were examined by atomic force and field emission electron microscope. The stability of the complexes was tested in simulated gastrointestinal pH and physiological serum condition. Cellular uptake, transport, and toxicity of the complexes were tested in the Caco-2 cells. Biodistribution and antidiabetic effect of the complexes were observed in either Balb/c mice or Lep(db/db) mice. RESULTS: A 50/1 ratio of the hIgG1-Fc-Arg/pDNA produced a complex structure having approximately 40 ~ 60 nm size and also demonstrated protection of pDNA in the complex from the physiological pH and serum conditions. Cellular uptake and transport of the complex were demonstrated in Caco-2 cells having FcRn receptor expression and forming the monolayer-polarized structure. The cellular toxicity of both delivery vehicle and the complex revealed their minimal toxicity comparable with nontoxicity of a commercial transfection reagent. Biodistribution of the complex showed the detectable distribution of the complex in the most parts of gastrointestinal tract due to ubiquitous expression of the FcRn receptors. An in vivo type 2 diabetes treatment study of oral administration of hIgG1-Fc-9Arg/pGLP-1 complexes showed absorption and expression in GI tract of either Balb/c mice or Lep(db/db) mice. CONCLUSION: In this study, we developed an oral GLP-1 gene delivery system on the platform of cationic hIgG1-Fc-9Arg. Prolonged t1/2, less immunoactivity, and better bioactivities of hIgG-Fc-9Arg/pGLP-1 complexes appeared to be a promising approach to achieve potent treatment of type 2 diabetes treatment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40824-018-0129-7) contains supplementary material, which is available to authorized users. BioMed Central 2018-07-27 /pmc/articles/PMC6062860/ /pubmed/30065848 http://dx.doi.org/10.1186/s40824-018-0129-7 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Cha, Seungbin
Lee, Sun Hwa
Kang, Sung Hun
Hasan, Mohammad Nazmul
Kim, Young Jun
Cho, Sungpil
Lee, Yong-Kyu
Antibody-mediated oral delivery of therapeutic DNA for type 2 diabetes mellitus
title Antibody-mediated oral delivery of therapeutic DNA for type 2 diabetes mellitus
title_full Antibody-mediated oral delivery of therapeutic DNA for type 2 diabetes mellitus
title_fullStr Antibody-mediated oral delivery of therapeutic DNA for type 2 diabetes mellitus
title_full_unstemmed Antibody-mediated oral delivery of therapeutic DNA for type 2 diabetes mellitus
title_short Antibody-mediated oral delivery of therapeutic DNA for type 2 diabetes mellitus
title_sort antibody-mediated oral delivery of therapeutic dna for type 2 diabetes mellitus
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062860/
https://www.ncbi.nlm.nih.gov/pubmed/30065848
http://dx.doi.org/10.1186/s40824-018-0129-7
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