Acquisition of absorption-enhancing abilities of cationic oligopeptides with short chain arginine residues through conjugation to hyaluronic acid

[Display omitted] Cell-penetrating peptides such as oligoarginines are one of promising tools that improve mucosal absorption of poorly membrane-permeable biologics. We have already demonstrated that conjugation of L-octaarginine to hyaluronic acid via a tetraglycine spacer resulted in a 3-fold enha...

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Bibliographic Details
Published in:	International journal of pharmaceutics Vol. 616; p. 121519
Main Authors:	Tomono, Takumi, Yagi, Haruya, Kanemoto, Saki, Ukawa, Masami, Miyata, Kohei, Shigeno, Koichi, Sakuma, Shinji
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 25-03-2022
Subjects:	Absorption enhancer Animals Arginine - chemistry Cell-Penetrating Peptides - chemistry Cell-Penetrating Peptides - metabolism Exenatide Hyaluronic acid Hyaluronic Acid - chemistry Mice Oligoarginine Oligoarginine-linked hyaluronic acid Oligopeptides - chemistry Protein drugs Short chain arginine residue Short chain arginine residue Absorption enhancer Oligoarginine Oligoarginine-linked hyaluronic acid Hyaluronic acid Protein drugs
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Summary:	[Display omitted] Cell-penetrating peptides such as oligoarginines are one of promising tools that improve mucosal absorption of poorly membrane-permeable biologics. We have already demonstrated that conjugation of L-octaarginine to hyaluronic acid via a tetraglycine spacer resulted in a 3-fold enhancement of nasal absorption of somatropin (Mw: ca. 22.1 kDa) in mice when compared with the unmodified peptide. Here, we evaluated absorption-enhancing abilities and safety profiles of oligopeptides with short chain arginine residues conjugated to hyaluronic acid. Somatropin absorption was hardly ever enhanced by diglycine-L-tetraarginine. The peptide acquired the absorption-enhancing ability through the conjugation; however, it disappeared when arginine residues were halved. In vivo data were consistent to in vitro cellular uptake of somatropin. When somatropin was substituted with exendin-4 (Mw: ca. 4.2 kDa), cellular uptake was significantly enhanced by diglycine-L-diarginine conjugated to hyaluronic acid under comparison with the unmodified peptide. The conjugate also exhibited the enhancement ability in mice, as observed for hyaluronic acid derivatives with four and more arginine residues. Another cell studies revealed that oligoarginine-linked hyaluronic acid tended to be less toxic as arginine residues were reduced. Results indicated that diglycine-L-tetraarginine-linked hyaluronic acid was the most suitable candidate as an absorption enhancer whose Mw-independent enhancement ability and safety were well-balanced.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0378-5173 1873-3476
DOI:	10.1016/j.ijpharm.2022.121519