Cross-beta nanostructures based on dinaphthylalanine Gd-conjugates loaded with doxorubicin.
Very recently we proposed novel di- and tetra-phenylalanine peptides derivatized with gadolinium complexes as potentials supramolecular diagnostic agents for applications in MRI (Magnetic Resonance Imaging). It was observed that in very short FF dipeptide building blocks, the propensity to aggregate decreases significantly after modification with bulky moiety such as Gd-complexes, thus limiting their potential as CAs. We hypothesized that the replacement of the Phe side chain with more extended aromatic groups could improve the self-assembling. Here we describe the synthesis, structural and relaxometric behavior of a novel water soluble self-assembled peptide CA based on 2-naphthylalanine (2Nal). The peptide conjugate Gd-DOTA-L6-(2Nal)2is able to self-assemble in long fibrillary nanostructures in water solution (up to 1.0 mg/mL). CD and FTIR spectroscopies indicate a β sheet secondary structure with an antiparallel orientation of single strands. All data are in good agreement with WAXS and SAXS characterizations that show the typical "cross-β pattern" for fibrils at the solid state. Molecular modeling indicates the three-dimensional structure of the peptide spine of aggregates is essentially constituted by extended β-sheet motifs stabilized by hydrogen bonds and hydrophobic interactions. The high relaxivity of nanoaggregates (12.3 mM-1s-1at 20 MHz) and their capability to encapsulate doxorubicin suggest their potential application as supramolecular theranostic agents.
Department of Pharmacy, Research Centre on Bioactive Peptides (CIRPeB), University of Naples "Federico II", Via Mezzocannone 16, 80134, Naples, Italy.
Carlo
C
Diaferia
Department of Molecular Biotechnologies and Health Science, University of Turin, Via Nizza 52, 10125, Turin, Italy.
Eliana
E
Gianolio
Institute of Crystallography (IC), CNR, Via Amendola 122, 70126, Bari, Italy.
Teresa
T
Sibillano
Institute of Biostructure and Bioimaging (IBB), CNR, via Mezzocannone 16, 80134, Naples, Italy.
Flavia Anna
FA
Mercurio
Institute of Biostructure and Bioimaging (IBB), CNR, via Mezzocannone 16, 80134, Naples, Italy.
Marilisa
M
Leone
Institute of Crystallography (IC), CNR, Via Amendola 122, 70126, Bari, Italy.
Cinzia
C
Giannini
Institute of Biostructure and Bioimaging (IBB), CNR, via Mezzocannone 16, 80134, Naples, Italy.
Nicole
N
Balasco
Institute of Biostructure and Bioimaging (IBB), CNR, via Mezzocannone 16, 80134, Naples, Italy.
Luigi
L
Vitagliano
Department of Pharmacy, Research Centre on Bioactive Peptides (CIRPeB), University of Naples "Federico II", Via Mezzocannone 16, 80134, Naples, Italy.
Giancarlo
G
Morelli
Department of Pharmacy, Research Centre on Bioactive Peptides (CIRPeB), University of Naples "Federico II", Via Mezzocannone 16, 80134, Naples, Italy. antonella.accardo@unina.it.
Antonella
A
Accardo
D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D002942:Circular Dichroism; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology*; D004337:Drug Carriers / Q000138:chemical synthesis*; D005682:Gadolinium / Q000737:chemistry; D008958:Models, Molecular; D049329:Nanostructures / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry; D017550:Spectroscopy, Fourier Transform Infrared
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D009842:Oligopeptides; D004317:Doxorubicin; D005682:Gadolinium