title: Transport of surface-modified nanoparticles through cell monolayers.
abstract: We synthesized three peptides, a D-polyarginyl peptide (r8(FITC)), a Tat peptide (Tat(FITC)), and a control peptide (Cp(FITC)) and attached each to amino-CLIO, a nanoparticle 30 nm in diameter. We then examined the effective permeability, Peff, of all six materials through CaCo-2 monolayers. The transport of peptide-nanoparticles was characterized by a lag phase (0-8 h) and a steady-state phase (9-27 h). The steady-state Peff values for peptides were in the order r8(FITC)>Tat(FITC)=Cp(FITC). When r8(FITC) and Tat(FITC) peptides were attached to the nanoparticle, they conferred their propensity to traverse cell monolayers onto the nanoparticle, whereas Cp(FITC) did not. Thus, when the r8(FITC) peptide was attached to the amino-CLIO nanoparticle, the resulting peptide-nanoparticle had a Peff similar to that of this poly-D-arginyl peptide alone. The Peff of r8(FITC)-CLIO (MW approximately 1000 kDa) was similar to that of mannitol (MW=182 Da), a poorly transported reference substance, with a far lower molecular weight. These results are the first to indicate that the modification of nanoparticles by attachment of membrane-translocating sequence-based peptides can alter nanoparticle transport through monolayers. This suggests that the surface modification of nanoparticles might be a general strategy for enhancing the permeability of drugs and that high-permeability nanoparticle-based therapeutics can be useful in selected pharmaceutical applications.
authors.affiliation: Department of Chemistry and Applied BioSciences, Drug Formulation and Delivery, Swiss Federal Institute of Technology Zürich (ETH Zürich), Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Annette M
authors.initials: AM
authors.lastname: Koch
authors.forename: Fred
authors.initials: F
authors.lastname: Reynolds
authors.forename: Hans P
authors.initials: HP
authors.lastname: Merkle
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Lee
authors.initials: L
authors.lastname: Josephson
mesh_terms: D001692:Biological Transport / Q000502:physiology*; D018938:Caco-2 Cells; D002478:Cells, Cultured; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry / Q000378:metabolism; D005456:Fluorescent Dyes / Q000737:chemistry / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D049329:Nanostructures; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D013499:Surface Properties
chemical_list: D005456:Fluorescent Dyes; D010455:Peptides; D016650:Fluorescein-5-isothiocyanate