title: Rational Design of a Transferrin-Binding Peptide Sequence Tailored to Targeted Nanoparticle Internalization.
abstract: The transferrin receptor (TfR) is a promising target in cancer therapy owing to its overexpression in most solid tumors and on the blood-brain barrier. Nanostructures chemically derivatized with transferrin are employed in TfR targeting but often lose their functionality upon injection in the bloodstream. As an alternative strategy, we rationally designed a peptide coating able to bind transferrin on suitable pockets not involved in binding to TfR or iron by using an iterative multiscale-modeling approach coupled with quantitative structure-activity and relationship (QSAR) analysis and evolutionary algorithms. We tested that selected sequences have low aspecific protein adsorption and high binding energy toward transferrin, and one of them is efficiently internalized in cells with a transferrin-dependent pathway. Furthermore, it promotes transferrin-mediated endocytosis of gold nanoparticles by modifying their protein corona and promoting oriented adsorption of transferrin. This strategy leads to highly effective nanostructures, potentially useful in diagnostic and therapeutic applications, which exploit (and do not suffer) the protein solvation for achieving a better targeting.
authors.affiliation: Center for Nanotechnology Innovation@NEST, Istituto Italiano di Tecnologia , Piazza San Silvestro 12, Pisa 56127, Italy.|NEST, Scuola Normale Superiore and Istituto Nanoscienze-CNR , Piazza San Silvestro 12, Pisa 56127, Italy.
authors.forename: Melissa
authors.initials: M
authors.lastname: Santi
authors.affiliation: Center for Nanotechnology Innovation@NEST, Istituto Italiano di Tecnologia , Piazza San Silvestro 12, Pisa 56127, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Maccari
authors.affiliation: Center for Nanotechnology Innovation@NEST, Istituto Italiano di Tecnologia , Piazza San Silvestro 12, Pisa 56127, Italy.
authors.forename: Paolo
authors.identifier: 0000-0001-6012-592X
authors.initials: P
authors.lastname: Mereghetti
authors.affiliation: Center for Nanotechnology Innovation@NEST, Istituto Italiano di Tecnologia , Piazza San Silvestro 12, Pisa 56127, Italy.
authors.forename: Valerio
authors.identifier: 0000-0003-1311-3349
authors.initials: V
authors.lastname: Voliani
authors.affiliation: Institute of Clinical Physiology-CNR , Via Giuseppe Moruzzi 1, Pisa 56124, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rocchiccioli
authors.affiliation: Institute of Clinical Physiology-CNR , Via Giuseppe Moruzzi 1, Pisa 56124, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Ucciferri
authors.affiliation: NEST, Scuola Normale Superiore and Istituto Nanoscienze-CNR , Piazza San Silvestro 12, Pisa 56127, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Luin
authors.affiliation: Center for Nanotechnology Innovation@NEST, Istituto Italiano di Tecnologia , Piazza San Silvestro 12, Pisa 56127, Italy.
authors.forename: Giovanni
authors.identifier: 0000-0002-0067-2240
authors.initials: G
authors.lastname: Signore
mesh_terms: D000327:Adsorption; D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D004705:Endocytosis; D006046:Gold / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D053758:Nanoparticles / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D000066970:Protein Corona / Q000737:chemistry / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D011990:Receptors, Transferrin / Q000378:metabolism; D014168:Transferrin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D010455:Peptides; D000066970:Protein Corona; D011990:Receptors, Transferrin; D014168:Transferrin; D006046:Gold