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Dive into the research topics where Noriyasu Kamei is active.

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Featured researches published by Noriyasu Kamei.


Journal of Controlled Release | 2008

Usefulness of cell-penetrating peptides to improve intestinal insulin absorption

Noriyasu Kamei; Mariko Morishita; Yoshimi Eda; Nobuo Ida; Reiji Nishio; Kozo Takayama

Cell-penetrating peptides (CPPs) are a useful tool for delivering therapeutic macromolecules across cell membranes. We previously devised an approach using CPPs without intermolecular cross-linking and showed the efficient delivery of insulin from the intestine to the systemic circulation using a typical CPP, oligoarginine. However, this approach required relatively high doses of the CPP. Therefore, this study aimed to identify CPPs that are more effective for the delivery of insulin and do not induce toxic effects on the intestine. In this study, we examined the effects of various types of CPPs including arginine-rich peptides and amphipathic peptides that aid insulin absorption from rat ileal segments. Among these peptides, coadministration of insulin with R8, penetratin, pVEC, and RRL helix significantly increased ileal insulin absorption compared with insulin administration alone. In the case of R8, the D-form of the peptide had stronger absorption enhancing ability than the L-form. In contrast, the other three peptides exerted a more significant effect when the L-forms were applied, and L-penetratin had the strongest ability to enhance intestinal insulin absorption. Meanwhile, in a physical mixture of CPP and insulin, aggregates formed in the solution when high concentrations of CPPs were present. L-penetratin enhanced insulin absorption even when administered in an aggregated solution. We then showed that aggregates of L-penetratin and insulin were broken down in the presence of intestinal degradation enzymes. Thus, among CPPs used in this study, L-penetratin had the strongest ability to improve insulin intestinal absorption.


Journal of Controlled Release | 2009

Importance of intermolecular interaction on the improvement of intestinal therapeutic peptide/protein absorption using cell-penetrating peptides

Noriyasu Kamei; Mariko Morishita; Kozo Takayama

Our previous reports showed that the absorption of therapeutic peptides and proteins was significantly improved by coadministration of cell-penetrating peptides (CPPs) as the physical mixture. However, the mechanisms for this improvement are not clear. In the present study, we verified the hypothesis that the electrostatic interaction between drug and CPP is related to the enhancing effect of the CPP on the intestinal absorption of therapeutic peptides and proteins. In this study, the intermolecular binding was analyzed by surface plasmon resonance (SPR)-based binding assay, and the effect of CPPs on the intestinal absorption of peptide drugs was examined by in situ absorption study using a rat intestinal loop. Among the 16 peptide drugs possessing different isoelectric points, it was observed that only gastrin, insulin and glucagon-like peptide-1 (GLP-1) bound to D-R8 (D-form arginine octamer, a typical CPP), and subsequently their intestinal absorption increased by coadministration of D-R8. In contrast, the intestinal absorption of other peptide drugs that did not bind to D-R8 was not affected in the presence of D-R8. Thus, this study suggests that intermolecular binding between drug and CPP is an important factor governing the enhancing effect of the CPP on the intestinal absorption of therapeutic peptides and proteins.


International Journal of Pharmaceutics | 2009

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

El-Sayed Khafagy; Mariko Morishita; Noriyasu Kamei; Yoshimi Eda; Yohei Ikeno; Kozo Takayama

The purpose of our study was to investigate the potential of cell-penetrating peptides; penetratin as novel delivery vector, on the systemic absorption of therapeutic peptides and proteins across different mucosal administration sites. The absorption-enhancing feasibility of l- and d-penetratin (0.5mM) was used for glucagon-like peptide-1 (GLP-1), and exendin-4 as novel antidiabetic therapy, in addition to interferon-beta (IFN-beta) as protein biotherapeutic model from nasal and intestinal route of administration was evaluated as first time in rats. Nasal route is the most feasible for the delivery of therapeutic peptides coadministered with penetratin whereas the intestinal route appears to be more restricted. The absolute bioavailability (BA (%)) values depend on the physichochemical characters of drugs, stereoisomer character of penetratin, and site of administration. Penetratin significantly increased the nasal more than intestinal absorption of GLP-1 and exendin-4, as the BA for nasal and intestinal administration of GLP-1 was 15.9% and 5%, and for exendin-4 were 7.7% and 1.8%, respectively. Moreover, the BA of IFN-beta coadministered with penetratin was 11.1% and 0.17% for nasal and intestinal administration, respectively. From these findings, penetratin is a promising carrier for transmucosal delivery of therapeutic peptides and macromolecules as an alternative to conventional parenteral routes.


Journal of Controlled Release | 2014

In vivo proof of concept of oral insulin delivery based on a co-administration strategy with the cell-penetrating peptide penetratin.

Ebbe Juel Bech Nielsen; Shinya Yoshida; Noriyasu Kamei; Ruisha Iwamae; El-Sayed Khafagy; Jørgen Olsen; Ulrik Lytt Rahbek; Betty Lomstein Pedersen; Kozo Takayama; Mariko Takeda-Morishita

Oral delivery of insulin is blocked by low intestinal absorption caused by the poor permeability of insulin across cellular membranes and the susceptibility to enzymatic degradation in the gastrointestinal tract. Cell-penetrating peptides (CPPs) have been investigated for a number of years as oral absorption enhancers for hydrophilic macromolecules. Penetratin, a cationic and amphipathic CPP, effectively enhances insulin absorption and we were able to alleviate the enzymatic barrier by using the enzymatic resistant D-form of penetratin. In this study, mice were dosed orally with a physical mixture of insulin and penetratin. Blood glucose concentrations were measured and a pharmacological availability (PA) of 18.2% was achieved in mice dosed with insulin and D-penetratin. Following the promising data, we investigated the degradation parameters of insulin and penetratin in rat intestinal fluid. As expected, L-penetratin was degraded rapidly whereas D-penetratin had a halflife of 67±7min in 10-fold diluted gastrointestinal fluid. Insulin degradation was slowed by the presence of penetratin in intestinal fluid. The half-life of insulin increased from 24.9±4.5min to 55.6±14min and 90.5±11.8min in the presence of L- and D-penetratin respectively. In conclusion, both Land D-penetratin acted as oral absorption enhancers at select CPP concentrations for insulin and the current study is the first solid evidence of pharmacological activity of oral insulin delivery systems based on non-covalent intermolecular interactions with penetratin.


Journal of Controlled Release | 2009

Complexation hydrogels for intestinal delivery of interferon β and calcitonin

Noriyasu Kamei; Mariko Morishita; Hitomi Chiba; Nikhil J. Kavimandan; Nicholas A. Peppas; Kozo Takayama

Recent studies have suggested that complexation hydrogels poly(methacrylic acid-g-ethylene glycol) (henceforth designated as P(MAA-g-EG)) exhibit high insulin incorporation efficiency, rapid insulin release in the intestine based on their pH-dependent complexation properties, enzyme-inhibiting effects and mucoadhesive characteristics. Therefore, they are promising carriers for insulin delivery via an oral route. As we designed these hydrogels as carriers suitable for oral administration of various peptide/protein drugs, in this study we aimed at investigating the applicability of P(MAA-g-EG) hydrogels to improving the intestinal absorption of various peptide/protein drugs. High loading efficiency into hydrogels was observed for insulin, calcitonin, and interferon beta. In addition, polymer microparticles loaded with calcitonin and interferon beta exhibited complexation/decomplexation and pH-sensitive release behavior. The molecular weight and chemical structure appeared to affect the efficiency of loading and release depending on the peptides and proteins. Furthermore, a drastic reduction of plasma calcium concentration accompanied by calcium absorption and a dose-dependent enhancement of plasma interferon beta concentration were observed after the administration of particles loaded with calcitonin or interferon beta into closed rat ileal segments. These findings indicate that P(MAA-g-EG) hydrogels are promising carriers for administration of various peptides and proteins via an oral route.


Journal of Controlled Release | 2008

Permeation characteristics of oligoarginine through intestinal epithelium and its usefulness for intestinal peptide drug delivery.

Noriyasu Kamei; Mariko Morishita; Jumpei Ehara; Kozo Takayama

Cell-penetrating peptides such as HIV-1 Tat and oligoarginine are attractive tools for the intracellular delivery of therapeutic macromolecules. Although we have found that oligoarginine enhances the intestinal absorption of therapeutic peptides, especially insulin, the mechanism underlying the ability of oligoarginine to increase intestinal drug absorption is unclear. In addition, there is no information about the permeation characteristics of these functional peptides through the biological intestinal membrane. Therefore, in this study the permeation characteristics of oligoarginine itself across the intestinal membrane were first determined to obtain the information about absorption enhancement mechanisms. Incubation at low temperature and coincubation with heparin reduced the tissue distribution and permeation of fluorescein-labeled oligoarginine (FL-d-R6) through the rat ileal membrane. These results suggest that the attachment of FL-d-R6 to cell-surface proteoglycans and energy-dependent endocytosis are involved in its permeation through the ileal epithelial membrane. Based on the characteristics of oligoarginine, we attempted to facilitate the intestinal permeation of the peptide drug, leuprolide, using the function of oligoarginine. However, leuprolide permeation was not achieved when leuprolide was applied with oligoarginine to mucosal side of rat ileal sheets or when a leuprolide-oligoarginine conjugate was administered. These findings emphasize that any strategy using oligoarginine to improve intestinal drug permeation requires an intermolecular interaction, such as an electrostatic interaction, and a covalent linkage between the macromolecular drug and oligoarginine may hamper the ability of oligoarginine to enhance intestinal epithelial permeation of therapeutic peptides and proteins.


Journal of Pharmaceutical Sciences | 2013

Mechanistic Study of the Uptake/Permeation of Cell-Penetrating Peptides Across a Caco-2 Monolayer and Their Stimulatory Effect on Epithelial Insulin Transport

Noriyasu Kamei; Yoshinori Onuki; Kozo Takayama; Mariko Takeda-Morishita

Our recent studies have demonstrated the potential of cell-penetrating peptides (CPPs) to significantly stimulate the intestinal absorption of therapeutic peptides and proteins. This study examined the mechanisms underlying the intestinal epithelial uptake and permeation of CPPs and their contribution to the enhanced absorption of insulin. Fluorescein-tagged octaarginine (R8) and penetratin were used as the promising CPPs, and in vitro uptake and permeation assays were conducted using Caco-2 cell monolayer. The assay conducted under low temperature conditions revealed that energy-dependent pathways are not involved in d-form arginines (d-R8) uptake or its stimulatory effect on insulin uptake. The Km value (3.82 μM), calculated from the dose dependence of d-R8 uptake, suggested that a part of the d-R8 uptake was saturated at the functional concentration (60 μM d-R8). An analysis based on the binding parameters of insulin and d-R8 also showed an increase in the uptake clearance of the insulin/d-R8 complex, even at a saturated concentration of d-R8, implying that this complex is taken up by Caco-2 cells via pathways that differ from those that take up unbound d-R8. Thus, this study suggests that CPPs such as oligoarginines stimulate the intestinal epithelial transport of peptide and protein drugs via energy-independent unsaturable internalization.


Journal of Controlled Release | 2010

Molecular imaging analysis of intestinal insulin absorption boosted by cell-penetrating peptides by using positron emission tomography

Noriyasu Kamei; Mariko Morishita; Yousuke Kanayama; Koki Hasegawa; Mie Nishimura; Emi Hayashinaka; Yasuhiro Wada; Yasuyoshi Watanabe; Kozo Takayama

Molecular imaging technique by use of positron emission tomography (PET) is a noninvasive tool that allows one to quantitatively analyze the function of endogenous molecules and the pharmacokinetics of therapeutic agents in vivo. This technique is expected to be useful for evaluating the effectiveness of diverse drug delivery systems. We demonstrated previously that intestinal insulin absorption is increased significantly by coadministration of cell-penetrating peptides (CPPs), which are taken up effectively by several cells. However, the distribution behavior of insulin whose absorption is increased by CPPs is not clear. We used PET imaging and quantitatively analyzed the intestinal absorption and subsequent distribution of insulin and the effect of CPPs on its absorption and distribution. An unlabeled insulin solution containing tracer insulin, (68)Ga-DOTA-insulin, was administered with or without CPPs into a rat ileal closed loop. PET imaging showed that the CPPs, particularly D-R8 and L-penetratin, significantly increased the (68)Ga-DOTA-insulin level in the liver, kidney, and circulation. After absorption from the intestine, the (68)Ga-DOTA-insulin passed rapidly through the liver and accumulated in the kidney. The increase in the hepatic and renal distribution of (68)Ga-DOTA-insulin by each CPP coadministration was similar manner as that in intestinal absorption, suggesting that the increased accumulation of insulin in the liver and kidney induced by coadministration of CPPs was associated with the increased intestinal absorption of insulin. This is the first study to show that PET imaging enables one to quantitatively analyze the distribution behavior of intestinally absorbed insulin in several organs. This imaging methodology is likely to be useful for developing effective drug delivery systems targeted to specific organs.


Journal of Controlled Release | 2015

Brain delivery of insulin boosted by intranasal coadministration with cell-penetrating peptides.

Noriyasu Kamei; Mariko Takeda-Morishita

Intranasal administration is considered as an alternative route to enable effective drug delivery to the central nervous system (CNS) by bypassing the blood-brain barrier. Several reports have proved that macromolecules can be transferred directly from the nasal cavity to the brain. However, strategies to enhance the delivery of macromolecules from the nasal cavity to CNS are needed because of their low delivery efficiencies via this route in general. We hypothesized that the delivery of biopharmaceuticals to the brain parenchyma can be facilitated by increasing the uptake of drugs by the nasal epithelium including supporting and neuronal cells to maximize the potentiality of the intranasal pathway. To test this hypothesis, the CNS-related model peptide insulin was intranasally coadministered with the cell-penetrating peptide (CPP) penetratin to mice. As a result, insulin coadministered with l- or d-penetratin reached the distal regions of the brain from the nasal cavity, including the cerebral cortex, cerebellum, and brain stem. In particular, d-penetratin could intranasally deliver insulin to the brain with a reduced risk of systemic insulin exposure. Thus, the results obtained in this study suggested that CPPs are potential tools for the brain delivery of peptide- and protein-based pharmaceuticals via intranasal administration.


Journal of Pharmaceutical Sciences | 2013

Determination of the Optimal Cell-Penetrating Peptide Sequence for Intestinal Insulin Delivery Based on Molecular Orbital Analysis with Self-Organizing Maps

Noriyasu Kamei; Shingo Kikuchi; Mariko Takeda-Morishita; Yoshiaki Terasawa; Akihito Yasuda; Shuichi Yamamoto; Nobuo Ida; Reiji Nishio; Kozo Takayama

Our recent work has shown that the intestinal absorption of insulin can be improved significantly by coadministration of cell-penetrating peptides (CPPs), especially penetratin. However, a relatively high dose of penetratin is required to adequately stimulate the intestinal absorption of insulin. Therefore, in this study, we sought to determine the CPP that most effectively enhanced intestinal insulin absorption. An in situ loop absorption study using 26 penetratin analogues suggested that the chain length, hydrophobicity, and amphipathicity of the CPPs, as well as their basicity, contribute to their absorption-enhancing efficiency. Moreover, a molecular orbital method with self-organizing maps (SOMs) classification suggested that multiple factors, including the molecular weight, basicity, the lowest unoccupied molecular orbital energy, absolute hardness, and chemical potential of CPPs, are associated with their effects on intestinal insulin absorption. Furthermore, the new CPPs proposed by SOM clustering had a marked capacity to interact with insulin, and their ability to enhance insulin absorption was much stronger than that of the original penetratin. Therefore, the peptide sequence that optimally enhances intestinal insulin absorption could be defined by SOM with the molecular orbital method, and our present work emphasizes the utility of such methodologies in the development of effective drug delivery systems.

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Nicholas A. Peppas

University of Texas at Austin

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