Oligoarginine-linked polymers as a new class of penetration enhancers

Sakuma, Shinji; Suita, Masaya; Masaoka, Yoshie; Kataoka, Makoto; Nakajima, N.; Shinkai, Norihiro; Yamauchi, Hitoshi; Hiwatari, Ken‐ichiro; Tachikawa, Hiroyuki; Kimura, Ryoji; Yamashita, Shinji

doi:10.1016/j.jconrel.2010.08.022

Cited by 37 publications

(54 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Increased cellular penetration with oligoarginine conjugated to a polymer backbone have also been shown by Sakuma et al [36], where physically mixed insulin and polymer backbone conjugated with octa-arginine (R8) increased nasal absorption of insulin. The group also demonstrated increased penetration of fluorescent in Caco-2 cells and Calu-3 cells when the fluorescent probe was mixed with polymer conjugated with R8, while physical mixture with R8 alone did not improve the uptake of the fluorescent probe into the cells.…”

Section: Discussionmentioning

confidence: 63%

Arginine-tagging of polymeric nanoparticles via histidine to improve cellular uptake

Chiu

Tucker

McLeod

et al. 2015

European Journal of Pharmaceutics and Biopharmaceutics

View full text Add to dashboard Cite

Polyarginine, a cell-penetrating peptide, has been shown to aid cellular penetration of bioactives into cells. We utilized a novel approach of using a histidine linker to produce poly(ethyl-cyanoacrylate) (PECA) nanoparticles tagged with oligoarginine and investigated cellular uptake. MALDI TOF/TOF (tandem) analysis revealed that di-arginine-histidine (RRH) covalently bound to PECA nanoparticles to form cationic particles (+18 mV), while longer oligoarginine peptides did not co-polymerize with PECA nanoparticles. Although RRH-tagged nanoparticles had similar size and FITC-dextran entrapment efficiency compared to unmodified nanoparticles, RRH-tagging of nanoparticles resulted in a greater release of FITC-dextran. As the nanoparticles were found to aggregate in Hanks Balanced Salt Solution (HBSS), the effect of phosphate on the zeta-potential of nanoparticles was studied. Treating the nanoparticles with poloxamer-407 prevented aggregation. RRH-tagged PECA nanoparticles increased cellular uptake by a further 30% compared to unmodified PECA nanoparticles and was concentration dependent. We suggest that enhanced cell uptake can be achieved using a di-arginine-histidine construct as opposed to the previously published findings that a minimum of hexa-arginine is necessary. Further, the cationic zeta-potential of the cell-penetrating peptide may not be needed to enhance uptake.

show abstract

Section: Discussionmentioning

confidence: 63%

Arginine-tagging of polymeric nanoparticles via histidine to improve cellular uptake

Chiu

Tucker

McLeod

et al. 2015

European Journal of Pharmaceutics and Biopharmaceutics

View full text Add to dashboard Cite

show abstract

“…Results indicated that D-octaarginine-linked polymers remained on cell membranes while CF was continuously internalized into cells mainly via macropinocytosis repeated for the individual peptidyl branches in the polymer backbone, as originally hypothesized. 22 Internalization of cationic atenolol and nonionic FITC-dextran were also observed in Caco-2 cells incubated with Doctaarginine-linked polymers. The charge-independent cellular uptake indicated that electrostatic interactions between oligoarginine-linked polymers and bioactive molecules were not always required for our technology.…”

Section: ■ Discussionmentioning

confidence: 95%

“…Alternatively, we designed cell-penetrating peptide-linked polymers with a unique strategy in which penetration enhancement of biomolecules is not always concomitant with cellular uptake of the peptides bound to polymers. 22 −25 We hypothesized that recognition of peptidyl branches in the polymer backbone triggers macropinocytosis on the membrane surface of cells exposed to a mixture of biomolecules and cell-penetrating peptide-linked polymers. Since macropinocytosis proceeds extensively in the multiple peptide access points of the singlestranded polymers, cells fail in uptake of peptides anchored chemically to the polymeric platform.…”

Section: ■ Introductionmentioning

confidence: 99%

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

Mohri¹,

Morimoto²,

Maruyama³

et al. 2015

Bioconjugate Chem.

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Arginine oligomers have been widely studied to enhance the cellular uptake of poorly membrane-permeable bioactive molecules (Gonçalves et al, 2005;Sakuma et al, 2010). As an example, heptamer oligomer of arginine (R7) was first suggested as a potential PTD in transdermal delivery of cyclosporine A (CsA) for treatment of inflammatory skin diseases (Rothbard et al, 2000).…”

Section: Protein Transduction Domains-drug Complexmentioning

confidence: 99%

Biomaterials as novel penetration enhancers for transdermal and dermal drug delivery systems

2013

View full text Add to dashboard Cite

The highly organized structure of the stratum corneum provides an effective barrier to the drug delivery into or across the skin. To overcome this barrier function, penetration enhancers are always used in the transdermal and dermal drug delivery systems. However, the conventional chemical enhancers are often limited by their inability to delivery large and hydrophilic molecules, and few to date have been routinely incorporated into the transdermal formulations due to their incompatibility and local irritation issues. Therefore, there has been a search for the compounds that exhibit broad enhancing activity for more drugs without producing much irritation. More recently, the use of biomaterials has emerged as a novel method to increase the skin permeability. In this paper, we present an overview of the investigations on the feasibility and application of biomaterials as penetration enhancers for transdermal or dermal drug delivery systems.

show abstract

Oligoarginine-linked polymers as a new class of penetration enhancers

Cited by 37 publications

References 32 publications

Arginine-tagging of polymeric nanoparticles via histidine to improve cellular uptake

Arginine-tagging of polymeric nanoparticles via histidine to improve cellular uptake

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

Biomaterials as novel penetration enhancers for transdermal and dermal drug delivery systems

Contact Info

Product

Resources

About