Performance of cell-penetrating peptide-linked polymers physically mixed with poorly membrane-permeable molecules on cell membranes

Sakuma, Shinji; Suita, Masaya; Yamamoto, Takafumi; Masaoka, Yoshie; Kataoka, Makoto; Yamashita, Shinji; Nakajima, N.; Shinkai, Norihiro; Yamauchi, Hitoshi; Hiwatari, Ken‐ichiro; Hashizume, Akio; Tachikawa, Hiroyuki; Kimura, Ryoji; Ishimaru, Yuki; Kasai, Atsushi; Maeda, Shin

doi:10.1016/j.ejpb.2012.01.008

Cited by 22 publications

(42 citation statements)

References 40 publications

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“…GE-160 bearing D-octaarginine was previously prepared twice, and their grafting degrees were 11 and 17% [17,18,32]. In the present study, D-octaarginine was not also anchored to the polymeric platform with a stable grafting degree (Runs 1-3, Table 1).…”

Section: Discussionmentioning

confidence: 69%

“…We have addressed a unique strategy of penetration enhancement using cell-penetrating peptide-linked polymers [17,18]. Cell-penetrating peptides are cationic oligopeptides that are internalized into cells via macropinocytosis [19][20][21].…”

Section: Introductionmentioning

confidence: 99%

“…Poly(N-vinylacetamide-co-acrylic acid) (PNVA-co-AA) bearing 7 D-octaarginine, which is a typical cell-penetrating peptide, was first prepared to validate our strategy and its potential as a safe penetration enhancer ( Fig. 1) [17,18]. Mice experiments revealed that the polymers significantly enhanced peptide penetration through the nasal membrane without mucosal irritation.…”

Section: Introductionmentioning

confidence: 99%

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Cross-reactivity of immunoglobulin A secreted on the nasal mucosa in mice nasally inoculated with inactivated H1N1 influenza A viruses in the presence of d-octaarginine-linked polymers

Sakuma

Morimoto

Nishida

et al. 2015

European Journal of Pharmaceutics and Biopharmaceutics

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We evaluated cross-reactivity of immunoglobulin A (IgA) secreted on the nasal mucosa in mice that were nasally inoculated 4 times with a mixture of inactivated H1N1 influenza A viruses and poly(N-vinylacetamide-co-acrylic acid) (PNVA-co-AA) bearing d-octaarginine at 7-day intervals. Three viral strains (A/Puerto Rico/8/34, A/New Caledonia/20/99 IVR116, and A/Solomon Islands/03/2006) and D-octaarginine-linked polymers with different molecular weights were used as antigens and their carriers, respectively. Secretion of intranasal IgA was barely observed when the inactivated virus alone was administered. The polymer induced the production of intranasal IgA specific to the inoculated viruses, irrespective of the viral strain and molecular weight of the polymer. The respective antibodies cross-reacted to recombinant hemagglutinin proteins of not only the viral strain used for immunization but also other H1N1 strains, including A/Puerto Rico/8/34 strain whose hemagglutinin proteins are diverse from those of other strains. Mice with high reactivity of IgA to the inoculated viruses tended to acquire clear cross-reactivity to other viral strains. Notably, IgA induced by inactivated H1N1 A/New Caledonia/20/99 IVR116 strain with the strongest immunogenicity between 3 antigens in the presence of the polymer cross-reacted to recombinant hemagglutinin proteins of the A/Brisbane/10/2007 and A/Viet Nam/1194/2004 strains, which are categorized into H3N2 and H5N1, respectively. Our polymer is a potential candidate for an efficient antigen carrier that induces mucosal IgA having cross-reactivity to antigenically drifted variants, irrespective of the subtype of viral strains.

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Section: Discussionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cross-reactivity of immunoglobulin A secreted on the nasal mucosa in mice nasally inoculated with inactivated H1N1 influenza A viruses in the presence of d-octaarginine-linked polymers

Sakuma

Morimoto

Nishida

et al. 2015

European Journal of Pharmaceutics and Biopharmaceutics

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“…23 Anionic 5(6)-carboxyfluorescein (CF) was taken up into Caco-2 cells, which is a human colorectal adenocarcinoma cell line, through incubation with polymers. Polymer-induced CF uptake remained constantly high for the duration of a 120 min experiment, even though Zaro and Shen reported that cellular uptake of intact oligoarginines terminated within 15 min.…”

Section: ■ Discussionmentioning

confidence: 99%

Potential of d-Octaarginine-Linked Polymers as an in Vitro Transfection Tool for Biomolecules

Mohri¹,

Morimoto²,

Maruyama³

et al. 2015

Bioconjugate Chem.

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We have been investigating the potential use of cell-penetrating peptide-linked polymers as a novel penetration enhancer. Since previous in vivo studies demonstrated that poly(N-vinylacetamide-co-acrylic acid) bearing D-octaarginine, a typical cell-penetrating peptide, enhanced membrane permeation of biomolecules, its potential as an in vitro transfection tool was evaluated in this study. A plasmid DNA encoding green fluorescent protein (pGFP-C1), β-galactosidase, and bovine serum albumin (BSA) were used as model biomolecules. Anionic pGFP-C1 interacted electrostatically with cationic d-octaarginine-linked polymers. When the ratio of mass concentration of polymers to that of pGFP-C1 reached 2.5, complexes whose size and zeta potential were approximately 200 nm and 15 mV, respectively, were obtained. GFP expression was observed in cells incubated with complexes prepared under conditions in which the polymer/pDNA concentration ratio exceeded 2.5. The expression level elevated with an increase in the concentration ratio, but physicochemical properties of the complexes remained unchanged. Results suggested that free polymers contributed to pGFP-C1 internalization. Another cell study demonstrated that β-galactosidase premixed with polymers was taken up into cells in its active tetrameric form. Similar electrostatic interaction-driven complex formation was observed for BSA charged negatively in neutral solution. However, it appeared that the internalization processes of BSA differed from those of pGFP-C1. A mass concentration-dependent increase in internalized BSA was observed, irrespective of the polymer/protein concentration ratio. Due to frail interactions, polymers that were released from the complexes and subsequently immobilized on cell membranes might also contribute to membrane permeation of BSA.

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“…Secondly, owning to the positive zeta potential TMC coated liposomes could be close to the negative cell membrane and uptake by endocytosis pathways. Thirdly, it was reported that Arg8, as CPPs, was capable for promoting cellular internalization when modified on the nanocarriers surface (Sakuma et al, 2012). Compared with TMC-Lips all the results revealed that TMC-Arg8-Lips had a better permeation enhancement property.…”

Section: à6mentioning

confidence: 58%

Oral absorption enhancement of salmon calcitonin by using bothN-trimethyl chitosan chloride and oligoarginines-modified liposomes as the carriers

Huang

et al. 2013

Drug Delivery

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In this study both N-trimethyl chitosan chloride (TMC) and oligoarginine (Arg8) were utilized to modify liposomes as the multifunctional carriers (TMC-Arg8-Lips) for enhancing the oral absorption of salmon calcitonin. Two permeation enhancers with positive charges were sequentially adsorbed on the liposomal surface with negative charges by electrostatic interaction. Instead of salmon calcitonin, fluorescein isothiocyanate dextran (FD4) was loaded in TMC-Arg8-Lips for Caco-2 cell permeation test in vitro and penetration examination in rat intestinal tract in vivo. The results showed that the apparent permeability coefficient (P app ) of TMC-Arg8-Lips containing FD4 were 7.0-, 4.4-, 1.8-and 1.4-folds higher than FD4 solution, FD4-TMC solution, non-modified liposomes (Non-Lips) and TMC modified liposomes (TMC-Lips), respectively. A strong fluorescence was observed by confocal laser scanning microscope (CLSM) at rat intestinal wall isolated in different times after the FD4 loaded carriers were intragastrically administrated. Furthermore, the images revealed that TMC-Arg8-Lips could penetrate deeply inside the mucosal membrane. The pharmacodynamic study indicated that TMC-Arg8-Lips containing calcitonin were more efficient in enhancing the absorption and prolonging the reduction of blood calcemia in rats. The area above the plasma calcium concentration-time curve (AAC) of TMC-Arg8-Lips containing calcitonin was increased by more than 16.6-and 1.6-fold when compared to Non-Lips and TMC-Lips, respectively.

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Performance of cell-penetrating peptide-linked polymers physically mixed with poorly membrane-permeable molecules on cell membranes

Cited by 22 publications

References 40 publications

Cross-reactivity of immunoglobulin A secreted on the nasal mucosa in mice nasally inoculated with inactivated H1N1 influenza A viruses in the presence of d-octaarginine-linked polymers

Cross-reactivity of immunoglobulin A secreted on the nasal mucosa in mice nasally inoculated with inactivated H1N1 influenza A viruses in the presence of d-octaarginine-linked polymers

Potential of d-Octaarginine-Linked Polymers as an in Vitro Transfection Tool for Biomolecules

Oral absorption enhancement of salmon calcitonin by using bothN-trimethyl chitosan chloride and oligoarginines-modified liposomes as the carriers

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