Efficiency of cell-penetrating peptides on the nasal and intestinal absorption of therapeutic peptides and proteins

Khafagy, El-Sayed; Morishita, Mariko; Kamei, Noriyasu; Eda, Yoshimi; Ikeno, Yohei; Takayama, K.

doi:10.1016/j.ijpharm.2009.07.022

Cited by 85 publications

(64 citation statements)

References 43 publications

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“…CPPs comprise short polycationic peptides based on hydrophobic sequences derived from signal peptides, viral peptides, or other sources (29), and are recognized as promising tools for the intracellular delivery of macromolecular medicines (30)(31)(32)(33). Our recent study has shown that the absorption of insulin and other medicinal peptides and proteins across the epithelial mucosal membrane can be improved significantly by the coadministration of new CPPs with biodrug cargos (13)(14)(15).…”

Section: Discussionmentioning

confidence: 99%

“…The proteolytic stability of CPPs is a critical requirement for their therapeutic application, and it is essential that they can (13,15,49). In addition to this proteolytic stability, we should consider another factor.…”

Section: Discussionmentioning

confidence: 99%

“…In our previous reports, we showed that, by using a noncovalent cargo-interaction strategy, cell-penetrating peptides (CPPs) can successfully deliver the most challenging peptide and protein cargos, including insulin, through the intestinal and nasal mucosae with highly effective bioavailability (12)(13)(14)(15). Penetratin, which is derived from the Drosophila Antennapedia homeoprotein (16)(17)(18), was most successful in overcoming the barrier to the permeability of peptides and proteins through the epithelial mucosal membrane and increased the enteral insulin bioavailability by up to 35% (13).…”

Section: Introductionmentioning

confidence: 99%

“…Our strategy of using new CPPs to increase oral insulin absorption is based on their ability to increase the permeation of insulin across the intestinal mucosal membrane (13,15,22). Insulin absorption appears to differ between intestinal regions because the protease content is much higher in the upper small intestine than in the descending small intestine (24).…”

Section: Introductionmentioning

confidence: 99%

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Region-Dependent Role of Cell-Penetrating Peptides in Insulin Absorption Across the Rat Small Intestinal Membrane

Khafagy

Iwamae

Kamei

et al. 2015

AAPS J

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Abstract. We have reported that the cell-penetrating peptide (CPP) penetratin acts as a potential absorption enhancer in oral insulin delivery systems and that this action occurs through noncovalent intermolecular interactions. However, the region-dependent role of CPPs in intestinal insulin absorption has not been clarified. To identify the intestinal region where CPPs have the most effect in increasing insulin absorption, the region-dependent action of penetratin was investigated using in situ closed intestinal loops in rats. The order of the insulin area under the insulin concentration-time curve (AUC) increase effect by L-penetratin was ileum>jejunum>duodenum>colon. By contrast, the AUC order after coadministration of insulin with D-penetratin was colon>duodenum≥jejunum and ileum. We also compared the effects of the L-and D-forms of penetratin, R8, and PenetraMax on ileal insulin absorption. Along with the CPPs used in this study, L-and D-PenetraMax produced the largest insulin AUCs. An absorption study using ilea pretreated with CPPs showed that PenetraMax had no irreversible effect on the intestinal epithelial membrane. The degradation of insulin in the presence of CPPs was assessed in rat intestinal enzymatic fluid. The half-life (t 1/2 ) of insulin increased from 14.5 to 23.7 and 184.7 min in the presence of L-and D-PenetraMax, respectively. These enzymatic degradation-resistant effects might contribute partly to the increased ileal absorption of insulin induced by D-PenetraMax. In conclusion, this study demonstrated that the ability of the L-and D-forms of penetratin to increase intestinal insulin absorption was maximal in the ileum and the colon, respectively, and that D-PenetraMax is a powerful but transient enhancer of oral insulin absorption.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Region-Dependent Role of Cell-Penetrating Peptides in Insulin Absorption Across the Rat Small Intestinal Membrane

Khafagy

Iwamae

Kamei

et al. 2015

AAPS J

Self Cite

View full text Add to dashboard Cite

show abstract

“…Polioviral receptor binding ligand: A novel and safe peptide drug carrier from polioviral capsid cargo (peptides or proteins) into cells without the need of receptor binding (Khafagy et al, 2009). Tat, one of the widely studied CPP, was discovered in 1988 as a membrane shuttling protein.…”

Section: Original Articlementioning

confidence: 99%