title: Oral delivery of an anti-diabetic peptide drug via conjugation and complexation with low molecular weight chitosan.
abstract: Despite the therapeutic potential of exendin-4 as a glucagon-like peptide-1 (GLP-1) mimetic for the treatment of type 2 diabetes, its utility has so far been limited because of the low level of patient compliance due to the requirement for frequent injections. In this study, an orally available exendin-4 was produced by conjugating it to low molecular weight chitosan (LMWC). Conjugation between the LMWC and cysteinylated exendin-4 was carried out using a cleavable linker system in order to maximize the availability of the active peptide. The LMWC-exendin-4 conjugate formed a nanoparticle structure with a mean particle size of 101 ± 41 nm through complexation between the positively charged LMWC backbone and the negatively charged exendin-4 of individual conjugate molecules. The biological activity of the LMWC-exendin-4 conjugate was evaluated in an INS-1 cell line. The LMWC-exendin-4 conjugate stimulated insulin secretion in a dose dependent manner as similar as that of native exendin-4. From the pharmacokinetic study after oral administration of the conjugate, a C(max) value of 344 pg/mL and a T(max) of 6 h were observed, and the bioavailability, relative to the subcutaneous counterpart, was found to be 6.4%. Furthermore, the absorbed exendin-4 demonstrated a significantly enhanced hypoglycemic effect. These results suggest that the LMWC-exendin-4 conjugate could be used as a potential oral anti-diabetic agent for the treatment of type 2 diabetes.
authors.affiliation: KAIST Institute for the BioCentury, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors.forename: Sukyung
authors.initials: S
authors.lastname: Ahn
authors.forename: In-Hyun
authors.initials: IH
authors.lastname: Lee
authors.forename: Eunhye
authors.initials: E
authors.lastname: Lee
authors.forename: Hyungjun
authors.initials: H
authors.lastname: Kim
authors.forename: Yong-Chul
authors.initials: YC
authors.lastname: Kim
authors.forename: Sangyong
authors.initials: S
authors.lastname: Jon
mesh_terms: D000284:Administration, Oral; D000818:Animals; D045744:Cell Line, Tumor; D048271:Chitosan / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000378:metabolism; D000077270:Exenatide; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D014688:Venoms / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D014688:Venoms; D048271:Chitosan; D000077270:Exenatide
keywords: Chitosan; Conjugates; Exendin-4; Oral delivery; Peptides; Type 2 diabetes