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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.

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Low Molecular Weight (1 kDa) Polyethylene Glycol Conjugation Markedly Enhances the Hypoglycemic Effects of Intranasally Administered Exendin-4 in Type 2 Diabetic &lt;i&gt;db&lt;/i&gt;/&lt;i&gt;db&lt;/i&gt; Mice