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

Abstract

BackgroundDiabetes 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.MethodsHuman 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.ResultsA 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.ConclusionIn 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 materialThe online version of this article (10.1186/s40824-018-0129-7) contains supplementary material, which is available to authorized users.

Therapeutic efficacy of nanoparticles and routes of administration

“…Because of very short plasma half-life (< 5 min) and rapid metabolic clearance, the anti-diabetic effect of GLP-1 could be better utilized with oral-gene delivery methods. In this context, antibody-mediated (human IgG1 (hIgG1)-Fc-Arg/pDNA complexes were prepared as an oral-gene delivery system for the prevention of type 2 diabetes mellitus (T2DM) [218].…”

Oral GLP1 Gene Delivery by an Antibody-Guided Nanomaterial to Treat Type 2 Diabetes Mellitus

“…Some previous reports also mentioned that such short treatment of GLP1 could not contribute to a significant reduction of the body weight. 2,16 However, a food uptake analysis revealed that mice treated with GLP1 started to consume less food compared to the PBS-treated mice after 1−2 doses of oral GLP1/ protamine-SMCC-Fc administration. The difference in food intake between the groups became noticeable during 32 days of study due to the effect of the delayed gastric emptying by GLP1 (Figure 5d).…”

“…Diabetes mellitus is a metabolic disorder caused by the dysfunction of the pancreas, resulting in the absence or insufficient production of insulin. − About 366 million people lived with diabetes in 2011, according to the World Health Organization (WHO). , There are two major types of diabetes, type 1 and type 2, in which 90% of the population is suffering from type 2 diabetes . In type 2 diabetes, the body does not use insulin properly, and the blood glucose level becomes high, which is called a hyperglycemic condition .…”

“…Diabetes mellitus is a metabolic disorder caused by the dysfunction of the pancreas, resulting in the absence or insufficient production of insulin. − About 366 million people lived with diabetes in 2011, according to the World Health Organization (WHO). , There are two major types of diabetes, type 1 and type 2, in which 90% of the population is suffering from type 2 diabetes . In type 2 diabetes, the body does not use insulin properly, and the blood glucose level becomes high, which is called a hyperglycemic condition . Glucagon-like peptide-1 (GLP1), an incretin that is naturally secreted from intestinal L-cells after a meal, improves both insulin sensitivity and glucose tolerance in type 2 diabetes mellitus (T2DM) patients. , GLP1 helps to maintain normal blood glucose level but restrict the glucose level from going down below the normal range.…”

“…4 In type 2 diabetes, the body does not use insulin properly, and the blood glucose level becomes high, which is called a hyperglycemic condition. 2 Glucagon-like peptide-1 (GLP1), an incretin that is naturally secreted from intestinal L-cells after a meal, improves both insulin sensitivity and glucose tolerance in type 2 diabetes mellitus (T2DM) patients. 4,5 GLP1 helps to maintain normal blood glucose level but restrict the glucose level from going down below the normal range.…”