One-month subchronic toxicity study of cell-penetrating peptides for insulin nasal delivery in rats

Khafagy, El-Sayed; Kamei, Noriyasu; Nielsen, Ebbe Juel Bech; Nishio, Reiji; Takeda‐Morishita, Mariko

doi:10.1016/j.ejpb.2013.09.014

Cited by 55 publications

(38 citation statements)

References 37 publications

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“…Thus, L-penetratin showed a greater increase in intestinal insulin absorption, and this is consistent with our former results obtained by in situ absorption study (13). Next, we used the CPPs assessed in our previous studies to examine the differences between the abilities of different CPPs to increase insulin absorption (12)(13)(14)(15)22,23). The time profiles for plasma insulin concentration after ileal coadministration of insulin with penetratin, R8, or PenetraMax, and the pharmacokinetic parameters are shown in Fig.…”

Section: Discussionsupporting

confidence: 74%

“…We recently reported our findings of an in silico analysis in which we found that an innovative CPP, "PenetraMax," developed by sequence modification of penetratin, had a superior insulin absorption-enhancing efficiency over the parent penetratin (21,22). A subchronic study of nasal administration of insulin with PenetraMax at two selected concentrations (0.5 and 2.0 mM), which significantly increased the systemic bioavailability of insulin reaching almost 100% relative to subcutaneous insulin administration, found no increase in the risk of detectable local or systemic inflammation and immunogenicity and without causing detectable epithelial membrane damage (23).…”

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: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

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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“…As we know, cell penetration and cargo delivery properties of penetratin are well-known facts to scientists involved in the fields of cell permeation and peptide delivery. [12][13][14][15][16][17] According to the promising results reported for a special analog of penetratin in an intranasal insulin delivery (a physical mixture formulation), 18 this 16-amino-acid peptide sequence was synthesized in our peptide laboratory in Khaje Nasir University and purified to more than 95% purity. Table 1 provides the amino acid sequence of penetratin and the newly developed analog of penetratin (PenetraMax) investigated in this study.…”

Section: Methodsmentioning

confidence: 99%

A novel nanoemulsion-based method to produce ultrasmall, water-dispersible nanoparticles from chitosan, surface modified with cell-penetrating peptide for oral delivery of proteins and peptides

Barbari¹,

Dorkoosh²,

Amini³

et al. 2017

IJN

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A simple and reproducible water-in-oil (W/O) nanoemulsion technique for making ultrasmall (<15 nm), monodispersed and water-dispersible nanoparticles (NPs) from chitosan (CS) is reported. The nano-sized (50 nm) water pools of the W/O nanoemulsion serve as “nano-containers and nano-reactors”. The entrapped polymer chains of CS inside these “nano-reactors” are covalently cross-linked with the chains of polyethylene glycol (PEG), leading to rigidification and formation of NPs. These NPs possess excessive swelling properties in aqueous medium and preserve integrity in all pH ranges due to chemical cross-linking with PEG. A potent and newly developed cell-penetrating peptide (CPP) is further chemically conjugated to the surface of the NPs, leading to development of a novel peptide-conjugated derivative of CS with profound tight-junction opening properties. The CPP-conjugated NPs can easily be loaded with almost all kinds of proteins, peptides and nucleotides for oral delivery applications. Feasibility of this nanoparticulate system for oral delivery of a model peptide (insulin) is investigated in Caco-2 cell line. The cell culture results for translocation of insulin across the cell monolayer are very promising (15%–19% increase), and animal studies are actively under progress and will be published separately.

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“…Although they have primarily been explored for intracellular drug delivery of, e.g., oligonucleotides (1) or antibodies (2), they may also be suitable candidates for transepithelial drug delivery involving non-covalent complexation with biopharmaceuticals (3). The primary sequence of a CPP is of great importance for its cellpenetrating efficiency.…”

Section: Introductionmentioning

confidence: 99%

Penetratin-Mediated Transepithelial Insulin Permeation: Importance of Cationic Residues and pH for Complexation and Permeation

Kristensen

Franzyk

Klausen

et al. 2015

AAPS J

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ABSTRACT. Penetratin is a widely used carrier peptide showing promising potential for mucosal delivery of therapeutic proteins. In the present study, the importance of specific penetratin residues and pH was investigated with respect to complexation with insulin and subsequent transepithelial insulin permeation. Besides penetratin, three analogues were studied. The carrier peptide-insulin complexes were characterized in terms of size and morphology at pH 5, 6.5, and 7.4 by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. At pH 7.4 mainly very large complexes were present, while much smaller complexes dominated at pH 5. Presence of arginine residues in the carrier peptide proved to be a prerequisite for complexation with insulin as well as for enhanced transepithelial insulin permeation in vitro. Rearrangement of tryptophan residues resulted in significantly increased insulin permeation as compared to that of the parent penetratin. In general, precomplexation with penetratin and its analogues at pH 5 gave rise to increased insulin permeation as compared to that observed at pH 7.4; this finding was further supported by a preliminary in vivo study using the parent penetratin.

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One-month subchronic toxicity study of cell-penetrating peptides for insulin nasal delivery in rats

Cited by 55 publications

References 37 publications

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

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

A novel nanoemulsion-based method to produce ultrasmall, water-dispersible nanoparticles from chitosan, surface modified with cell-penetrating peptide for oral delivery of proteins and peptides

Penetratin-Mediated Transepithelial Insulin Permeation: Importance of Cationic Residues and pH for Complexation and Permeation

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