Articulo Científico Sobre Como Prevenir La Diabetes

Biomaterials


The glucose-lowering potential of exendin-4 orally delivered via a pH-sensitive nanoparticle vehicle and effects on subsequent insulin secretion in vivo

Abstract
Exendin-4 is a potent insulinotropic agent in diabetes patients; however, its therapeutic utility is limited due to the frequent injections required. In this study, an orally available exendin-4 formulation,using an enteric-coated capsule containing pH-responsive NPs, was developed. Following oral administration of 123I-labeled-exendin-4 loaded NPs in rats, the biodistribution of the administered drug was investigated using a dual isotope dynamic SPECT/CT scanner. The results showed that the radioactivity of 123I- exendin-4 propagated from the esophagus, stomach, and small intestine and then wasabsorbed into the systemic circulation; with time progressing, 123I-exendin-4 was metabolized and excreted into the urinary bladder. In the in vivo dissolution study, it was found that the enteric-coated capsule remained intact while in the stomach; the capsule was completely dissolved in the proximal segment of the smallintestine and the loaded contents were then released. Oral administration ofthe capsule containing exendin-4 loaded NPs showed a maximum plasma concentration at 5 h after treatment; the bioavail- ability, relative to its subcutaneous counterpart, was found to be 14.0 1.8%. The absorbed exendin-4 could then stimulate the insulin secretion and provide a prolonged glucose-lowering effect. The afore-mentioned results suggest that the orally available exendin-4 formulationdeveloped warrants further exploration as a potential therapy for diabetic patients.
1. Introduction
Exendin-4, a 39-amino-acid peptide, is an incretin mimetic found in the lizard saliva [1,2]. It shares several glucoregulatory activities with the mammalian incretin hormone glucagon-like peptide-1 (GLP-1) such as glucose-dependent enhancement of insulin secretion, suppression ofglucagon secretion, reduction of gastric mobility and food intake [2,3]. Exenatide, a synthetic version of exendin-4, has been approved as adjunctive therapy for patients with type 2 diabetes failing to achieve glycemic control with oral antidiabetic agents [2,4]; one potential disadvantage in itsclinical applications is the frequent subcutaneous (SC) injections required. SCinjections could cause pain, side effects and possible infections at the sites of injection which could adversely affect patient compliance [4].
The oral route is considered to be the most convenient and comfortable means of drug administration for patients [5]. However, oral administration of protein drugs is encountered with many difficulties such as their proteolytic instabilities and limitedabilities to traverse biological barriers [5]. Consequently, the development of a delivery vehicle for oral administration of protein drugs, including that of exendin-4, presents an interesting challenge. Recently, we reported a pH-sensitive nanoparticle (NP) vehicle, composed of chitosan (CS) and poly(γ-glutamic acid)(γ-PGA), as a platform technology for oral delivery ofprotein drugs[6-8]. CS, a cationic polysaccharide, has special features of adhering to the mucus layer and transiently opening the tight junctions between epithelial cells, thus increasing the permeation of protein drugs via the paracellular pathway [9, 10]. γ-PGA, an anionic peptide, is water-soluble, biodegradable, and nontoxic [6].

Table 1
Formulation, mean particle size in water andloading efficiency (LE) of exendin-4 loaded nanoparticles (NPs, n ¼ 5). N/A: data not available.
Formulation | Mean Particle Size (nm) | LE (%) |
Exendin-4 loaded NPs without metal ions | 230.9±10.9 | 24.4±0.5 |
Exendin-4 loaded NPs formed with Cu+2 | Precipitated | N/A |
Exendin-4 loaded NPs formed with Fe+2 | Precipitated | N/A |
Exendin-4 loaded NPs formed...