Cross-beta nanostructures based on dinaphthylalanine Gd-conjugates loaded with doxorubicin

Abstract

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)2 is 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−1 s−1 at 20 MHz) and their capability to encapsulate doxorubicin suggest their potential application as supramolecular theranostic agents.

Structural Characterization of PEGylated Hexaphenylalanine Nanostructures Exhibiting Green Photoluminescence Emission

“…The coupling reaction of Fmoc‐Ahoh‐OH was achieved directly in the solid phase by carbodiimide activation. This synthetic method, largely used to prepare short PEG conjugates with molecular weights of 350–800, allows the preparation of PEGylated conjugates with monodisperse profiles.…”

Structural Characterization of Self‐Assembled Tetra‐Tryptophan Based Nanostructures: Variations on a Common Theme

“…A three‐dimensional model of W4 aggregates was generated following the procedure previously adopted for similar systems by Diaferia et al ,. The structure of the hexapeptide fragment KLVFFA embodied in the amyloid‐beta peptide II (Protein Data Bank entry 3OW9) was used to generate the monomer of the W4 peptide by replacing all side chains with Trp residues.…”

Wide Angle X-Ray Scattering to Study the Atomic Structure of Polymeric Fibers

“…Besides the cases of natural polymers here reported, novel studies have been reported on other materials, for example aromatic peptide-based materials that exhibit spontaneous phenomena of supramolecular organization into ordered nanostructures [59][60][61]. Here, the knowledge of their inner molecular organization was correlated to the design of novel molecules with enhanced and tunable properties for drug delivery or contrast agents.…”