Safety of the Cell-Penetrating Peptide Penetratin as an Oral Absorption Enhancer

Abstract

Novel delivery technology using cell-penetrating peptides (CPPs) have recently shown their potential and are emerging as promising candidates for an oral protein and peptide delivery systems. As with for the development of any absorption enhancer that is meant to function across an epithelial layer covering a surface highly exposed to pathogens such as the intestines, concern arises about the safety of such enhancers. The purpose of this study was to investigate the effect of 7 d of consecutive oral administrations of CPPs and a typical enterotoxin, lipopolysaccharide (LPS) to mice to determine the degree, if any, of damage caused to the hepatic tissue. Following the 7-d dosing regimen, we could not detect significantly increased levels of the liver enzymes alanine aminotransferase and aspartate aminotransferase in plasma of mice treated with CPP and LPS compared to the controls, whereas heightened levels were observed in animals receiving the bile salt. In conclusion, the repeated use of CPPs as an oral absorption enhancer for macromolecules was found to be a safe strategy.

Intestinal permeation enhancers for oral peptide delivery

“…Chitosan nanoparticles opened TJs and increased intestinal permeability of insulin, but co-administration with LPS (5 mg/kg) to rats for 7 days did not lead to an increase in hepatic necrosis [476]. In a similar study, coadministration of penetratin (5mM) or C 10 (154 mM) with LPS for 7 days to mice had no effect on biomarkers of hepatic necrosis, however taurodeoxycholate (96 mM) increased plasma levels of aspartate transaminase and alanine transaminase [477]. It is noteworthy that uptake of LPS into the hepatic portal vein is not pathological as low level uptake is associated with maintaining a normal responsive kupffer cell population, but excessive levels may lead to hepatic dysfunction [478].…”

Application of Permeation Enhancers in Oral Delivery of Macromolecules: An Update

“…The surfactants hexadecylphosphocholine and octylphenol ethoxylate increase permeation of LPS across Caco-2 monolayers [125]. Co-delivery of C 10 (154 mM) or penetratin (2 mM) with LPS to mice for seven consecutive days did not cause LPS induced hepatic damage, as measured by plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) which are both released during hepatic necrosis [126]. A significant elevation in those enzymes was observed when LPS was co-delivered with taurodeoxycholate (96 mM) in the same study.…”

Safety concerns over the use of intestinal permeation enhancers: A mini-review

“…When penetratin was also orally co-administered with LPS daily for 7 days in mice, there was no significant increase levels in liver enzymes. 63 Although, one particular study demonstrated an increase in serum LPS after prolonged exposure to food-and pharmaceutical grade emulsifiers, carboxymethylcellulose (1% w/v) or polysorbate-80 (1% w/v) in wild type and IL-10 knock-out mice. 64 However, the foregoing is predicated on the risk for bystander entry solely according to a MW and molecular diameter-based argument.…”