Low molecular weight (1 kDa) polyethylene glycol conjugation markedly enhances the hypoglycemic effects of intranasally administered exendin-4 in type 2 diabetic db/db mice.
An intranasally active glucagon-like peptide-1 (GLP-1) formulation would have great advantages over conventional injectable therapies for the treatment of diabetic patients. The purpose of this study was to investigate the biological potentials of PEGylated exendin-4 (PEG-Ex4) analogs administered intranasally and the effects of polyethylene glycol (PEG) molecular weight (1, 2, 5 kDa) on nasal absorption. Initially, PEGEx4 analogs were site-specifically PEGylated to Lys²⁷-amine, and their bioactivities and stabilities were studied in vitro. The hypoglycemic effects and pharmacokinetics of these analogs after nasal administration were evaluated in type 2 diabetic animal models. PEG-Ex4 analogs had 3.1-, 3.8-, and 5.9-fold increased stabilities in rat nasal homogenates than Ex4. However, Lys²⁷-PEG(1k)-Ex4 was found to have well-preserved bioactivities (83.3% potency vs. Ex4), and other analogs were found to have much lower bioactivities than Lys²⁷-PEG(1k)-Ex4. In particular, the in vivo pharmacokinetic parameters of Lys²⁷-PEG(1k)-Ex4 in intranasally administered rats were significantly improved by PEGylation. Area under the curve (AUC) values of Lys²⁷-PEG(1k)-Ex4 were 33.6-fold higher and circulating t(1/2) values was 27.1-fold higher than Ex4. But, other analogs were not effectively absorbed via the intranasal route, because the higher molecular weight PEG (over 2 kDa) limited intranasal absorption. Finally, in vivo hypoglycemic experiment showed that Lys²⁷-PEG(2k)-, Lys²⁷-PEG(5k)-Ex4 had significantly lower hypoglycemic efficacies than Lys²⁷-PEG(1k)-Ex4, probably because of their lower intrinsic bioactivities and intranasal absorptions. Taken together, our findings suggest that the site-specific conjugation of appropriately sized PEG (1 kDa) substitution onto peptides like Ex4 offers two advantages for deliveryvia the intranasal route, namely, increased stability and extended circulating half-life.
College of Pharmacy, SungKyunKwan University, 300 Chonchon-dong, Jangan-ku, Suwon 440-746, Korea.
Tae Hyung
TH
Kim
Chan Woong
CW
Park
Hoi Yun
HY
Kim
Moon Hyuk
MH
Chi
Sung Kyung
SK
Lee
Young Me
YM
Song
Hai Hua
HH
Jiang
Sung Mook
SM
Lim
Yu Seok
YS
Youn
Kang Choon
KC
Lee
D000281:Administration, Intranasal; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D000077270:Exenatide; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D014688:Venoms / Q000008:administration & dosage* / Q000737:chemistry
D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D011092:Polyethylene Glycols; D000077270:Exenatide