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Antibody-mediated oral GLP-1 gene delivery to treat type 2 diabetes
( Mohammad Nazmul Hasan ),김다혜,이지훈,황주나,조성필,이용규 한국공업화학회 2019 한국공업화학회 연구논문 초록집 Vol.2019 No.1
Diabetes mellitus is a global epidemic associated with uncontrolled elevation of blood glucose levels. GLP-1 prevents type 2 diabetic patients from experiencing hyperglycemic episodes without concern of unexpected hypoglycemic situation from conventional insulin treatment. However, the short half-life and rapid clearance of GLP-1 often limit its therapeutic use. Here we developed an oral GLP-1 gene delivery system to extend the antidiabetic effect of GLP-1. A nanocomplex for oral GLP-1 gene delivery has consisted of GLP-1 gene and vehicle with protamine and hIgG-Fc, an Fc segment from an FcRn receptor-specific antibody. The nanocomplex showed superior stability against pH fluctuation and enzymatic digestion in the gastrointestinal tract, and high cellular uptake to the intestinal cells. The functional expression of GLP-1 also led to the extended antidiabetic effect of GLP-1 in type 2 diabetic mice, suggesting a promise for the treatment of type 2 diabetes mellitus.
Oral siRNA delivery using dual transporting systems to efficiently treat colorectal liver metastasis
Hyun, Eun-Ju,Hasan, Mohammad Nazmul,Kang, Sung Hun,Cho, Sungpil,Lee, Yong-Kyu Elsevier 2019 International journal of pharmaceutics Vol.555 No.-
<P><B>Abstract</B></P> <P>Oral siRNA delivery is an ideal way to translate siRNA therapeutic effects in the clinic due to its ability to be administered in convenient and multiple dosages. However, an effective oral delivery system requires overcoming both a hostile gastrointestinal (GI) environment and non-specific targeting. Here, an HTsRP-NC system is a new oral siRNA delivery system consisting of a siRNA/protamine (sRP) nano-complex protected by a multi-functional hyaluronic acid-taurocholic acid (HA-TCA) conjugate. The HTsRP-NC promotes cell penetration and enhances endosomal escape in cancer cells. Moreover, protection of the sRP by HA-TCA from the hostile GI environment helps the AKT siRNA complex to reach the liver through the utilization of a TCA-mediated enterohepatic bile acid recycling system. AKT siRNA was released by 90% in presence of hyaluronidase in the tumor cells which indicate the potential use of HTsRP-NCs for siRNA delivery to treat tumor. After HA receptor (CD44)-mediated cellular uptake of the HTsRP-NC by the liver cancer cells, functional expression of AKT siRNA leads to the suppression of metastatic liver cancer growth in a colorectal liver metastasis (CLM) murine model. Tumor nodules were reduced by more than 1 mm size compared to control group and tumor cells were suppressed by 50% after HTsRP-NCs treatment with AKT siRNA. Overall, oral administration of the HTsRP-NC supports its potential in therapeutic applications for the effective treatment of CLM.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Antibody-mediated oral delivery of therapeutic DNA for type 2 diabetes mellitus
Seungbin Cha,Sun Hwa Lee,Sung Hun Kang,Mohammad Nazmul Hasan,김영준,조성필,Yong-kyu Lee 한국생체재료학회 2018 생체재료학회지 Vol.22 No.3
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 Lepdb/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 Lepdb/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.