Journal
JOURNAL OF CONTROLLED RELEASE
Volume 170, Issue 2, Pages 226-232Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2013.05.031
Keywords
Oral delivery; Peptides; Chitosan; Exendin-4; Conjugates; Type 2 diabetes
Funding
- Converging Research Center Program through the National Research Foundation of Korea (NRF)
- Ministry of Education, Science, and Technology [2012K001408]
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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 conjugatewas 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 antidiabetic agent for the treatment of type 2 diabetes. (C) 2013 Elsevier B. V. All rights reserved.
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