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

Abstract

Type 2 diabetes mellitus (T2DM) is a chronic and progressive hyperglycemic condition. Glucagon-like peptide-1 (GLP1) is an incretin secreted from pancreatic β-cells and helps to produce insulin to balance the blood glucose level without the risk of hypoglycemia. However, the therapeutic application of GLP1 is limited by its intrinsic short half-life and rapid metabolic clearance in the body. To enhance the antidiabetic effect of GLP1, we designed a human cysteine-modified IgG1-Fc antibody-mediated oral gene delivery vehicle, which helps to produce GLP1 sustainably in the target site with the help of increased half-life of the Fc-conjugated nanocarrier, protects GLP1 from acidic and enzymatic degradation in the gastrointestinal (GI) tract, uptakes and transports the GLP1 formulation through the neonatal Fc receptor (FcRn), and helps to release the GLP1 gene in the intestine. Our formulation could reduce the blood glucose from about an average of 320 mg/dL (hyperglycemic) to 150 mg/dL (normal blood glucose concentration) in diabetic mice, which is about 50% reduction of the total blood glucose concentration. GLP1 (500 μg) complexed with the IgG1-Fc carrier was proven to be the optimal dose for a complete reduction of hyperglycemic conditions in diabetic mice. A significant amount of insulin production and the presence of GLP1 peptide were observed in the pancreatic islets of oral GLP1 formulation-treated diabetic mice in immunohistochemistry analysis compared to nontreated diabetic mice. The orally given formulation was completely nontoxic according to the histopathology analysis of mice organ tissues, and no mice death was observed. Our antibody-mediated oral gene delivery system is a promising tool for various oral therapeutic gene delivery applications to treat diseases like diabetes.

Oral Delivery of Parathyroid Hormone Using a Triple-Padlock Nanocarrier for Osteoporosis via an Enterohepatic Circulation Pathway

“…By examining numerous original research studies on ODDS, − we developed a TCA-conjugated CSA (TCSA) nanocarrier as a triple padlock system for oral delivery of recombinant human teriparatide [rhPTH (1–34)] against osteoporosis. In this research, we showed that the TCSA-triple padlock system facilitates protection of encapsulated rhPTH (1–34) from gastric or enzymatic degradation in the GIT and ASBAT- or OST α/β-mediated reabsorption of the TCSA/rhPTH nanocomplex, along with the prolonged t 1/2 , stimulates new bone formation, and reduces osteoporotic fracture by delivering the rhPTH to the type-1 PTH receptor (PTHr-1) through the intestinal portal system.…”

Carboxymethyl Cellulose, Pluronic, and Pullulan-Based Compositions Efficiently Enhance Antiadhesion and Tissue Regeneration Properties without Using Any Drug Molecules

“…Special considerations should be given to developing successful antiadhesion agents that are highly effective and safe in preventing adhesion, easy to use, and cost-effective in routine surgery . Biocompatible polymers are nontoxic , and vastly used to apply physical barriers directly to the body. ,, However, only biocompatible polymers without any other supporting material cannot be applied successfully to the patients because of the gravitational pull that flows down from the damaged tissue surface . Increasing the injected amount of antiadhesion agent does not allow the use of large amounts of antiadhesion agent because of the psychological burden and concerns of abuse caused by excessive administration in the body .…”

“…13,14 Special considerations should be given to developing successful antiadhesion agents that are highly effective and safe in preventing adhesion, easy to use, and cost-effective in routine surgery. 15 Biocompatible polymers are nontoxic 16,17 T h i s c o n t e n t i s and vastly used to apply physical barriers directly to the body. 9,18,19 However, only biocompatible polymers without any other supporting material cannot be applied successfully to the patients because of the gravitational pull that flows down from the damaged tissue surface.…”

Plasmid DNA Nanoparticles for Nonviral Oral Gene Therapy

“…However, it took approximately 14 days for the second-generation containing 500 μg of GLP1 per dose to reach the target glycemic level in the Lepr DB /Lepr DB mice after multiple administrations. 4 The number and amount of doses, poor transfection efficiencies, and slow therapeutic outcomes of previous oral dosage forms have led us to develop an optimized and effective oral dosage form targeting T2DM.…”

“…It was only effective for pre-T2DM mice model (DIO) but not for the Lepr DB /Lepr DB and Lepr OB /Lepr OB mouse models that are well-accepted diabetes animal models recapitulating human T2DM characterized by the progressive development of high blood glucose level, insulin resistance, and β cell loss. However, it took approximately 14 days for the second-generation containing 500 μg of GLP1 per dose to reach the target glycemic level in the Lepr DB /Lepr DB mice after multiple administrations . The number and amount of doses, poor transfection efficiencies, and slow therapeutic outcomes of previous oral dosage forms have led us to develop an optimized and effective oral dosage form targeting T2DM.…”