d‐Polyarginine Lipopeptides as Intestinal Permeation Enhancers

Abstract

An estimated 285 million people were living with diabetes in 2010, and this number is expected to reach 440 million by 2030. Current treatment of this disease involves the intradermal injection of insulin analogues. Many alternative administration routes have been proposed, the oral route being the most widely studied. One of the most interesting approaches for insulin delivery is the use of permeation enhancers to increase its transport across the gastrointestinal tract (GIT). Cell-penetrating peptides (CPPs) are a remarkable example of this family of compounds. Another alternative is the use of medium-chain fatty acids (MCFAs) to temporally disrupt the tight junctions of the GIT, thereby allowing greater drug transport. A combination of both strategies can provide a synergistic way to increase drug transport through the GIT. In this study we evaluated the complexation of insulin glulisine, an insulin analogue administered subcutaneously or intravenously in clinical practice, with a well-known CPP modified with the MCFA lauric acid. We prepared several formulations, examined their stability, and tested the best candidates in an intestinal cell-based model. In particular, two compounds (C -r and C -r ) were found to significantly increase the transport of insulin, and therefore show promise as a new delivery system worthy of further evaluation.

Combinatory Therapy Antimicrobial Peptide-Antibiotic to Minimize the Ongoing Rise of Resistance

“…Conjugation of CPPs with clinically relevant molecules was reported. Examples include the combination of lipo-polyarginine with insulin that was shown to enhance the transport through Caco-2/HT-29 cells almost two-fold (Garcia et al, 2018). Moreover, the conjugation or co-administration of TAT and polynonaarginin with the parathyroid hormone has sharply increased the transport through Caco-2 cells (Kristensen et al, 2015).…”

Barriers to the Intestinal Absorption of Four Insulin-Loaded Arginine-Rich Nanoparticles in Human and Rat

“…However, some studies indicate that poly- l -arginine can act as a permeation enhancer and transiently increase epithelial permeability by opening paracellular tight junctions. 15 Salmon protamine ( M w 372 Da) included in PrNC and PSA-PrNC as well as in approved insulin formulations has been reported to act as a cell-penetrating peptide (CPP), 27 and as a permeation enhancer. 28 This can be explained by arginine-rich sequences in the protamine peptide sharing homology to the canonical cell-penetrating peptide, Trans-Activator of Transcription (TAT).…”

“… 17 ENCP ( Figure 2 ) included C12-R8, octarginine (R8) linked to lauric acid (C12), a medium chain fatty acid. 15 R8 is a cell-penetrating peptide derived from the TAT sequence that has been reported to aid insulin intestinal permeability when complexed with it. 29 C12 is also an intestinal epithelial permeation enhancer, and it was included to aid R8-mediated epithelial permeation.…”

“… 11 − 13 All four NP contained arginine-rich oligopeptides or polypeptides with potential to interact with cell membranes and possibly to enable NP penetration through the plasma membrane. 11 − 15 This presents a delicate balance: the positive charge of the arginine-containing peptides is essential for membrane interaction and penetration, but an NP with a high positive charge will likely be immobilized in the mucus layer. 1 , 16 − 18 When the arginine-rich peptides form complexes with the negatively charged insulin, the net charge will be reduced.…”

Oligoarginine Peptide Conjugated to BSA Improves Cell Penetration of Gold Nanorods and Nanoprisms for Biomedical Applications

“…Accordingly, arginine-rich CPPs, (minimum amount of six Arg) are well known for their ability to cross biological barriers [ 49 , 50 ]. Although other studies have reported the conjugation of nanoparticles with internalization peptides in a direct way [ 51 , 52 , 53 , 54 ], it is also well known that the presence of BSA improves the circulation time of nanoparticles and controls the composition of the protein corona in physiological media, hence the importance of the inclusion of albumin in nanoparticles [ 37 , 55 , 56 ]. Therefore, we functionalized the BSA protein with r 8 to facilitate cell penetration of the AuNPs.…”