Hydrophobic Amino Acid Tryptophan Shows Promise as a Potential Absorption Enhancer for Oral Delivery of Biopharmaceuticals.

Noriyasu Kamei,Kazuhiro Higashiyama,Hideyuki Ogino,Hideyuki Tamiwa,Serena Hirano,Mari Miyata,Mariko Takeda-Morishita,Yuta Haruna,Koyo Matsumura

doi:10.3390/pharmaceutics10040182

Noriyasu Kamei, Kazuhiro Higashiyama + Show 7 more

Open Access

https://doi.org/10.3390/pharmaceutics10040182

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Journal: Pharmaceutics	Publication Date: Oct 10, 2018
Citations: 17	License type: CC BY 4.0

Affiliation: Kobe Gakuin University

Abstract

Cell-penetrating peptides (CPPs) have great potential to efficiently deliver drug cargos across cell membranes without cytotoxicity. Cationic arginine and hydrophobic tryptophan have been reported to be key component amino acids for cellular internalization of CPPs. We recently found that l-arginine could increase the oral delivery of insulin in its single amino acid form. Therefore, in the present study, we evaluated the ability of another key amino acid, tryptophan, to enhance the intestinal absorption of biopharmaceuticals. We demonstrated that co-administration with l-tryptophan significantly facilitated the oral and intestinal absorption of the peptide drug insulin administered to rats. Furthermore, l-tryptophan exhibited the ability to greatly enhance the intestinal absorption of other peptide drugs such as glucagon-like peptide-1 (GLP-1), its analog Exendin-4 and macromolecular hydrophilic dextrans with molecular weights ranging from 4000 to 70,000 g/mol. However, no intermolecular interaction between insulin and l-tryptophan was observed and no toxic alterations to epithelial cellular integrity—such as changes to cell membranes, cell viability, or paracellular tight junctions—were found. This suggests that yet to be discovered inherent biological mechanisms are involved in the stimulation of insulin absorption by co-administration with l-tryptophan. These results are the first to demonstrate the significant potential of using the single amino acid l-tryptophan as an effective and versatile bioavailability enhancer for the oral delivery of biopharmaceuticals.

Highlights

During the past few decades, cell-penetrating peptides (CPPs) have been established as potential tools for delivering bioactive macromolecules and lipidic or polymeric particulate carriers into cells via mainly covalent conjugation [1,2]
Apart from the discussion regarding the effects of peptides with different numbers of amino acids, we recently found that the L-form of the amino acid arginine (L-arginine) could strongly enhance the intestinal absorption of insulin in its single amino acid form, its effectiveness was relatively less than peptide forms of arginine [13]
The plasma insulin concentration increased after administration of insulin with L-tryptophan in a concentration dependent manner and with a late onset of action 30–60 min after administration. This result suggests that L-tryptophan has the potential to strongly enhance the intestinal absorption of insulin as single amino acid form

Summary

Introduction

During the past few decades, cell-penetrating peptides (CPPs) have been established as potential tools for delivering bioactive macromolecules and lipidic or polymeric particulate carriers into cells via mainly covalent conjugation [1,2]. Other studies suggest that when hydrophobic moieties such as stearyl groups or hydrophobic amino acids such as tryptophan are found within the peptide structure they synergistically enhance the potential of the original arginine-rich peptides [14,15,16,17]. We demonstrated the stronger effect of penetratin over R8 on the intestinal and nasal absorption of various peptide and protein drugs [3,6,21,22]. These findings have shown the importance of the hydrophobic amino acid tryptophan for boosting the action of arginine-rich peptides in the facilitation of the intestinal absorption of insulin. Little is known about the ability of tryptophan to enhance the absorption of insulin

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