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

Seungbin Cha; Sun Hwa Lee; Sung Hun Kang; Mohammad Nazmul Hasan; Young Jun Kim; Sungpil Cho; Yong-Kyu Lee

doi:10.1186/s40824-018-0129-7

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

Biomater Res. 2018 Jul 27:22:19. doi: 10.1186/s40824-018-0129-7. eCollection 2018.

Authors

Seungbin Cha¹, Sun Hwa Lee², Sung Hun Kang², Mohammad Nazmul Hasan³, Young Jun Kim¹, Sungpil Cho⁴, Yong-Kyu Lee^{2

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Affiliations

¹ 1Department of Biomedical Chemistry, Konkuk University, Chungju, 27478 Republic of Korea.
² KB-Biomed, Chungju, 27469 Republic of Korea.
³ 3Department of Chemical and Biological Engineering, Korea National University of Transportation, Chungju, 27469 Republic of Korea.
⁴ 44D Biomaterials Center, Korea National University of Transportation, Jeungpyeong, 27909 Republic of Korea.

Abstract

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.

Keywords: FcRn; GLP-1; Oral gene delivery; Type 2 diabetes.