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Journal of pharmaceutical investigation v.40 no.3, 2010년, pp.175 - 180  
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Preparation and Evaluation of a 4-Branched Polyethylene Glycol Derivative Modified with Exendin-4 and Stearylamine for Extended Hypoglycemic Action

Kim, In-Soo    (College of Pharmacy, Pusan National University   ); Ma, Kyung-Wan    (College of Pharmacy, Pusan National University   ); Bae, Sung-Ho    (College of Pharmacy, Pusan National University   ); Yoon, Jeong-Hyun    (College of Pharmacy, Pusan National University   ); Oh, Kyung-Taek    (College of Pharmacy, Chung-Ang University   ); Lee, Eun-Seong    (Division of Biotechnology, The Catholic University of Korea   ); Lee, Don-Haeng    (Department of Internal Medicine, Inha University   ); Lee, Kang-Choon    (College of Pharmacy, Sungkyunkwan University   ); Youn, Yu-Seok    (College of Pharmacy, Pusan National University  );
  • 초록

    Albumin-modification has been viewed as one of the most effective ways of extending the short in vivo lifetimes of peptide drugs by delaying glomerular filtration. In this study, we describe a new type 2 anti-diabetic exendin-4 (Ex4) peptide derivative with significant binding ability to human serum albumin (HSA). This exendin-4 derivative consists of a 4-branched polyethylene glycol $(PEG)_{5k}$ (Mw: 20 kDa) modified with three stearylamines ( $C_{18}-NH_2$ ) and one exendin-4 on its branches. PEG and stearylamine were selected to provide functionality to increase molecular size and bind to albumin, respectively. This derivative ( $3C_{18}-4PEG_{5k}$ -Ex4) was shown to have larger molecular size (Ca. 152 kDa) than actual (25.0 kDa) when subjected to size-exclusion chromatography, and the fluorescein-tagged $3C_{18}-4PEG_{5k}$ -Ex4 displayed significant binding to the HSA-immobilized Sepharose CL-4B resin using confocal laser scanning microscopy. Furthermore, $3C_{18}-4PEG_{5k}$ -Ex4 was found to have acceptable anti-hyperglycemic efficacy via three consecutive oral glucose tolerance testings (OGTT) in fasted type 2 diabetic db/db mice. The $HD_{total}$ value ( $57.6{\pm}12.3%$ ) of $3C_{18}-4PEG_{5k}$ -Ex4 at a 50 nmol/kg dose was 2-fold greater than that ( $31.0{\pm}8.7%$ ) of native exendin-4 in non-fasted db/db mice. Especially, the blood glucose levels in the mice group treated with $3C_{18}-4PEG_{5k}$ -Ex4 did not rebound to ~150 mg/dL until 24 h after the injection, which obviously shows the extended hypoglycemia. We believe that this derivative has great pharmaceutical potential as a novel long-acting type 2 anti-diabetic injection treatment.


  • 주제어

    Exendin-4 .   4-arm PEG .   albumin-binding .   PEG .   type 2 diabetes.  

  • 참고문헌 (17)

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