Kamei Noriyasu, Tamiwa Hideyuki, Miyata Mari, Haruna Yuta, Matsumura Koyo, Ogino Hideyuki, Hirano Serena, Higashiyama Kazuhiro, Takeda-Morishita Mariko
Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan.
Pharmaceutics. 2018 Oct 10;10(4):182. doi: 10.3390/pharmaceutics10040182.
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.
细胞穿透肽（CPPs）具有高效递送药物货物穿过细胞膜且无细胞毒性的巨大潜力。据报道，阳离子精氨酸和疏水性色氨酸是CPPs细胞内化的关键组成氨基酸。我们最近发现，L-精氨酸能以其单一氨基酸形式增加胰岛素的口服递送。因此，在本研究中，我们评估了另一种关键氨基酸色氨酸增强生物药物肠道吸收的能力。我们证明，与L-色氨酸共同给药显著促进了给予大鼠的肽类药物胰岛素的口服和肠道吸收。此外，L-色氨酸表现出极大增强其他肽类药物肠道吸收的能力，如胰高血糖素样肽-1（GLP-1）、其类似物艾塞那肽-4以及分子量范围为4000至70,000 g/mol的大分子亲水性右旋糖酐。然而，未观察到胰岛素与L-色氨酸之间的分子间相互作用，也未发现对上皮细胞完整性有任何毒性改变，如细胞膜变化、细胞活力或细胞旁紧密连接的改变。这表明，与L-色氨酸共同给药刺激胰岛素吸收涉及尚未发现的内在生物学机制。这些结果首次证明了使用单一氨基酸L-色氨酸作为生物药物口服递送的有效且通用的生物利用度增强剂的巨大潜力。
