title: Arginine-tagging of polymeric nanoparticles via histidine to improve cellular uptake.
abstract: 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.
authors.affiliation: School of Pharmacy, University of Otago, Dunedin, New Zealand.
authors.forename: Jasper Z S
authors.initials: JZ
authors.lastname: Chiu
authors.affiliation: School of Pharmacy, University of Otago, Dunedin, New Zealand.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Tucker
authors.affiliation: School of Pharmacy, University of Otago, Dunedin, New Zealand.
authors.forename: Bernie J
authors.initials: BJ
authors.lastname: McLeod
authors.affiliation: School of Pharmacy, University of Otago, Dunedin, New Zealand. Electronic address: arlene.mcdowell@otago.ac.nz.
authors.forename: Arlene
authors.initials: A
authors.lastname: McDowell
mesh_terms: D001120:Arginine / Q000737:chemistry / Q000494:pharmacology*; D018938:Caco-2 Cells; D002412:Cations / Q000737:chemistry; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000494:pharmacology; D003487:Cyanoacrylates / Q000737:chemistry / Q000494:pharmacology; D003911:Dextrans / Q000737:chemistry / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry / Q000494:pharmacology; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D006639:Histidine / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D058105:Polymerization; D011108:Polymers / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002412:Cations; D057846:Cell-Penetrating Peptides; D003487:Cyanoacrylates; D003911:Dextrans; D004337:Drug Carriers; D010455:Peptides; D011108:Polymers; C015219:fluorescein isothiocyanate dextran; C558475:poly(ethylcyanoacrylate); C015462:polyarginine; D006639:Histidine; D001120:Arginine; D016650:Fluorescein-5-isothiocyanate
keywords: Cationic; Cell uptake; Cell-penetrating peptides; MALDI-TOF; Poly(ethyl-cyanoacrylate) nanoparticles; Polyarginine