Diaferia, Carlo (2017) Design and development of new nanosystem based on self-assembly peptides for nanomedicine applications. [Tesi di dottorato]

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Tipologia del documento:	Tesi di dottorato
Lingua:	English
Titolo:	Design and development of new nanosystem based on self-assembly peptides for nanomedicine applications
Autori:	Autore Email Diaferia, Carlo carlo.diaferia@unina.it
Data:	11 Dicembre 2017
Numero di pagine:	361
Istituzione:	Università degli Studi di Napoli Federico II
Dipartimento:	dep05
Dottorato:	phd071
Ciclo di dottorato:	30
Coordinatore del Corso di dottorato:	nome email D'Auria, Maria Valeria mariavaleria.dauria@unina.it
Tutor:	nome email Morelli, Giancarlo [non definito]
Data:	11 Dicembre 2017
Numero di pagine:	361
Parole chiave:	Self-assembly peptides, bioimaging, nanomedicine
Settori scientifico-disciplinari del MIUR:	Area 03 - Scienze chimiche > CHIM/03 - Chimica generale e inorganica Area 03 - Scienze chimiche > CHIM/08 - Chimica farmaceutica Area 03 - Scienze chimiche > CHIM/09 - Farmaceutico tecnologico applicativo
Depositato il:	19 Dic 2017 13:07
Ultima modifica:	19 Mar 2019 11:37
URI:	http://www.fedoa.unina.it/id/eprint/12228

Abstract

Peptide-based materials (PBMs) generate by the aggregation of amphiphilic monomers represent a rapidly growing tool within materials science. They have been considered for several applications in different fields from electronic to nanomedicine. According to an appropriate design, amphiphilic peptides can spontaneously assemble in well-structured supramolecular materials as result of an intricate network of inter- and/or intra-molecular interactions between hydrophobic and hydrophilic portions. The interaction manner can strongly influence both morphology and properties of the final supramolecular materials. Aromaticity is the terms used to describe the particular molecular stability associated to a cyclic shaped and planar chemical entity with a ring of resonance bonds. The peculiar electronic structure of aromatics molecules arouses their interesting physicochemical properties. All the classes of intermolecular forces known as the aromatic interaction give raise from it. The knowledge and the study of aromatic interaction contaminated peptide based material field too. To this day, using self-assembly as instrument of bottom-up nano-plenning, it is a clear evidence that aromatic peptide sequences, containing phenylalanine (Phe), tyrosine (Tyr) or tryptophan (Trp), can be opportunely modulated to the aim of generate the required supramolecular architecture. The forefather of this new class of peptide monomers is the well-known diphenylalanine (FF) homopeptide. Through a combination of π-π staking and hydrogen-bonding, different method of preparation, specific pH values or solvent, FF is able to self-organize in different kinds of nano- and macro- morphologies (hollow nanotubes, fibers, vesicles, metastable hydrogels or organogels). By this evidence, many structural analogues of diphenylalanine were studied and peptide nanostructures containing the FF motif or more extended aromatic sequences have been investigated for their mechanical, electrochemical and optical properties, and more recently for some nanomedicine applications. Nevertheless, the majority of studies reported in literature are principally focused on clarifying the physicochemical aspects responsible for array stability in FF based nanostructures, whereas only few studies have been devoted in the investigation of FF aggregates for biomedical applications. This essentially because of the intrinsic low water solubility of these peptide sequences. According to these considerations, during the three years of the PhD project, novel poly-phenylalanine self-assembling conjugates were carefully designed, synthetized and fully characterized. The final peptide materials were evaluated for potential applications in bio-imaging field (with particular bearing to Magnetic Resonance Imaging and fluorescence imaging). It was also appreciate as the chemical modification of the aromatic framework with chelating agents, gadolinium (Gd) complexes, and polyethylene glycol (PEG) fragments with different length can affect the structural organization and the supramolecular behavior of the nanomaterial. The result produced on the hierarchical organization by the chemical replacement of the Phe with others aromatic amino acids (such as tryptophan, tyrosine and 2-naphthylalanine) was also investigated. The entirety of collected data during this PhD project permits to highlight the possible relationship existing between the chemical structure of the proposed building blocks, the final supramolecular nanostructure, and their functional features. In order to simplify the comprehension and the discussion of the results (Chapter III), they will be argued in three separate sections: • Section I: PBMs as supramolecular contrast agents for MRI. • Section II: PBMs as photoluminescent supramolecular probes. • Section III: PBMs obtained by punctual chemical modifications of homophenylalanine sequences. In Section I, an innovative class of supramolecular CAs for MRI, based on peptide self-assembly monomers, is described and analyzed. Different design strategies were applied to obtain and improve the aggregation phenomenon. The structural and relaxometric properties of each self-assembling system are discussed and mutually compared. The improved values of relaxivity and the exanimated capability to encapsulate the doxorubicin anticancer drug suggest a potential use of the proposed nanostructures as new theranostic platform. Photoluminescent (PL) phenomena in peptide-based materials are the subject of Section II. A class of novel PEGylated homo-phenylalanine was synthetized and, due to the high content of β-sheet, the final self-assembled systems show blue PL emission. A red-shift of the fluorescence was actualized by FRET phenomena between the nanostructure and a internalized NBD dye. Committing to the hydrogen bonding hypothesis, a relationship between observed PL and the number of interaction sites in nanostructures was developed. In Section III the effect of a punctual chemical modification on peptide primary sequence will be elucidated. Hetero- and homo-sequences were derived simply by the replacement of Phe residues with tyrosine and tryptophan ones. Characteristic gelification behavior was found for peptides containing Tyr. WAXS/SAXS studies and molecular dynamic simulations supported the structural analysis of the new peptide-based materials. The experimental protocols are totally collected in the dedicated Experimental section. The full characterization of synthetized peptides, conjugates and derivatives is reported in Appendix I, meanwhile additional information, Tables and Figures are gather together in Appendix II.

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