Stearylated Arginine-Rich Peptides:  A New Class of Transfection Systems

Futaki, Shiroh; Ohashi, Wakana; Suzuki, Tadanao; Niwa, Mineo; Tanaka, Seigo; Ueda, Kunihiro; Harashima, Hideyoshi; Sugiura, Yukio

doi:10.1021/bc015508l

Cited by 437 publications

(340 citation statements)

References 29 publications

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“…To successfully deliver BCG-CWS, we incorporated STR-R8 in the CWS-NP/LEEL. The R8 peptide is a synthetic peptide that mimics the trans-activating transcriptional activator of the human immunodeficiency virus [19], and has a highly positive charge and a high cellular affinity. Nanoparticles modified with the R8 peptide have been successful in delivering several substances, such as low molecular drugs, proteins and nucleic acids, under in vitro and in vivo conditions [11].…”

Section: Discussionmentioning

confidence: 99%

Nanoparticulation of BCG-CWS for application to bladder cancer therapy

Nakamura

Fukiage

Higuchi

et al. 2014

Journal of Controlled Release

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The Mycobacterium bovis Bacille Calmett-Guerin cell wall skeleton (BCG-CWS) could be used to replace live BCG as a bladder cancer drug. However, because BCG-CWS is poorly soluble, has a strong-negative charge, very high molecular weight and heterogeneity in size of tens of μm, it cannot be used in such an application. We report herein on the development of a novel packaging method that permits BCG-CWS to be encapsulated into 166 nm-sized lipid particles. The BCG-CWS encapsulated nano particle (CWS-NP) has a high uniformity and can be easily dispersed. Thus, it has the potential for use as a packaging method that would advance the scope of applications of BCG-CWS as a bladder cancer drug. In a functional evaluation, CWS-NP was efficiently taken up by mouse bladder tumor cells (MBT-2) in vitro and inhibited tumor growth in mice bearing MBT-2 tumors. Moreover, intravesically administered CWS-NP showed significant antitumor effects in a rat model with in naturally developed bladder cancer. An enhancement in Th1 differentiation by CWS-NP was also confirmed in human T cells. In conclusion, CWS-NP represents a promising delivery system for BCG-CWS for clinical development as a potent bladder cancer drug.

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Section: Discussionmentioning

confidence: 99%

Nanoparticulation of BCG-CWS for application to bladder cancer therapy

Nakamura

Fukiage

Higuchi

et al. 2014

Journal of Controlled Release

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“…Stearyl octaarginine (STR-R8) was synthesized as described previously [5]. The pDNAs pCMV-luc (7037 bp) encoding luciferase and pCMV-EGFP (6199 bp) encoding the enhanced green fluorescent protein (EGFP) were prepared by EndFree Plasmid Mega Kit (Qiagen GmbH, Hilden, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…A STR-R8 solution (5 mol % of lipids) was added to the suspension to attach the R8 peptide to the envelope of the MEND (R8-MEND), and the mixture was incubated for 30 min at room temperature. 5 Empty R8-modified liposomes were prepared by the same procedure except for the condensation and packaging of pDNA. …”

Section: Preparation Of R8-modified Multifunctional Envelope-type Nanmentioning

confidence: 99%

Non-linear pharmacodynamics in a non-viral gene delivery system: Positive non-linear relationship between dose and transfection efficiency

Moriguchi

Kogure

Iwasa

et al. 2006

Journal of Controlled Release

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“…It has recently been shown that octaarginine (R8) peptide was able to transfect cells with a luciferasecoding plasmid as efficiently as polyarginine and polylysine. 17 Furthermore, the introduction of hydrophobic moieties into the N-terminus of the R8 peptide improved the transfection efficiency by two orders of magnitude. 17 In this study, we attempted to understand the reasons behind the improved transfection efficiency of stearylated-octaarginine.…”

Section: Introductionmentioning

confidence: 99%

“…17 Furthermore, the introduction of hydrophobic moieties into the N-terminus of the R8 peptide improved the transfection efficiency by two orders of magnitude. 17 In this study, we attempted to understand the reasons behind the improved transfection efficiency of stearylated-octaarginine. We examined whether the mechanism by which the R8 peptide is internalized is similar to other virus-derived arginine-rich peptides such as the Tat peptide (ie a seemingly endocytosis-independent) or not.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of improved gene transfer by the N-terminal stearylation of octaarginine: enhanced cellular association by hydrophobic core formation

et al. 2004

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The internalization mechanisms associated with octaarginine and stearyl-octaarginine were investigated using confocal laser microscopy and flow cytometric analysis. Octaarginine is able to translocate through cell membranes in a manner that does not exactly involve the classical endocytic pathways of internalization. However, when a stearyl moiety is attached to the N-terminus of octaarginine, the internalization shifts mainly to an endocytosis-dependent pathway. The transfection efficiency of stearyl-octaarginine was significantly higher than that of octaarginin. To understand the mechanism of the improved gene transfer by the N-terminal stearylation of octaarginine, the gene transfer processes mediated by octaarginine or stearyl-octaarginine were compared. Both octaarginine and stearyl-octaarginine are able to carry plasmid DNA into cells. The amount of plasmid DNA internalized as well as that delivered to the nucleus was higher in the case of stearyl-octaarginine. Even though the internalization mechanisms of octaarginine and stearyl-octaarginine were different, their complexes with plasmid DNA were internalized via the same pathway, presumably, the clathrin-mediated pathway of endocytosis. The results of the atomic force microscopy revealed that stearyl-octaarginine, but not octaarginine, can completely condense the DNA into stable complexes that can be highly adsorbed to the cell surface and subsequently highly internalized. Therefore, using stearylated-octaarginine provided higher internalization of plasmid DNA into cells, due to enhanced cellular association, as well as higher nuclear delivery. The results presented in this study provide a better understanding of the mechanisms of improved transfection using stearylated-octaarginine. The concept of using stearylated peptides may aid in the development of more efficient nonviral gene vectors.

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Stearylated Arginine-Rich Peptides: A New Class of Transfection Systems

Cited by 437 publications

References 29 publications

Nanoparticulation of BCG-CWS for application to bladder cancer therapy

Nanoparticulation of BCG-CWS for application to bladder cancer therapy

Non-linear pharmacodynamics in a non-viral gene delivery system: Positive non-linear relationship between dose and transfection efficiency

Mechanism of improved gene transfer by the N-terminal stearylation of octaarginine: enhanced cellular association by hydrophobic core formation

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