KAIST Institute for the BioCentury, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
J Control Release. 2013 Sep 10;170(2):226-32. doi: 10.1016/j.jconrel.2013.05.031. Epub 2013 Jun 4.
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.
尽管 exendin-4 作为胰高血糖素样肽-1 (GLP-1) 类似物具有治疗 2 型糖尿病的潜力，但由于需要频繁注射，患者的依从性低，因此其应用受到限制。在这项研究中，通过将其与低分子量壳聚糖（LMWC）缀合，产生了一种可口服的 exendin-4。为了最大限度地提高活性肽的可用性，使用可裂解的连接子系统将 LMWC 与半胱氨酸化的 exendin-4 进行缀合。LMWC-exendin-4 缀合物通过带正电荷的 LMWC 主链与单个缀合分子的带负电荷的 exendin-4 之间的复合，形成了平均粒径为 101±41nm 的纳米颗粒结构。LMWC-exendin-4 缀合物在 INS-1 细胞系中的生物活性进行了评估。LMWC-exendin-4 缀合物以类似于天然 exendin-4 的方式，以剂量依赖性方式刺激胰岛素分泌。从口服给予缀合物后的药代动力学研究中，观察到 C(max)值为 344pg/mL 和 T(max)为 6h，与皮下对照物相比，生物利用度为 6.4%。此外，吸收的 exendin-4 表现出显著增强的降血糖作用。这些结果表明，LMWC-exendin-4 缀合物可用作治疗 2 型糖尿病的潜在口服抗糖尿病药物。
