Peptidomimetic ligands for tuning integrin-mediated signalling: rational design, synthesis and theranostic applications

Anselmi, Michele (2020) Peptidomimetic ligands for tuning integrin-mediated signalling: rational design, synthesis and theranostic applications, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Chimica, 32 Ciclo.
Documenti full-text disponibili:
[img] Documento PDF (English) - Accesso riservato fino a 17 Febbraio 2023 - Richiede un lettore di PDF come Xpdf o Adobe Acrobat Reader
Disponibile con Licenza: Creative Commons Attribution Non-commercial No Derivatives 4.0 (CC BY-NC-ND 4.0) .
Download (14MB) | Contatta l'autore

Abstract

Integrins are α/β-heterodimeric transmembrane adhesion receptors that mediate cell-cell and cell-ECM interactions. Integrins are bidirectional signalling receptors that respond to external signals (“outside-in” signalling) and in parallel, transduce internal signals to the matrix (“inside-out” signalling), to regulate vital cellular functions including migration, survival, growth and differentiation. Therefore, dysregulation of these tightly regulated processes often results in uncontrolled integrin activation and abnormal tissue expression that is responsible for many diseases. Because of their important roles in physiological and pathological events, they represent a validated target for therapeutic and diagnostic purposes. The aim of the present Thesis was focused on the development of peptidic ligands for α4β1 and αvβ3 integrin subtypes, involved in inflammatory responses (leukocytes recruitment and extravasation) and cancer progression (angiogenesis, tumor growth, metastasis), respectively. Following the peptidomimetic strategy, we designed and synthesized a small library of linear and cyclic hybrid α/β-peptidomimetics based on the phenylureido-LDV scaffolds for the treatment of chronic inflammatory autoimmune diseases. In order to implement a fast and non-invasive diagnostic method for monitoring the course of the inflammatory processes, a flat glass-surface of dye-loaded Zeolite L-crystal nanoparticles was coated with bioactive α4β1-peptidomimetics to detect specific integrin-expressing cells as biomarkers of inflammatory diseases. Targeted drug delivery has been considered a promising alternative to overcome the pharmacokinetic limitations of conventional anticancer drugs. Thus, a novel Small-Molecule Drug Conjugate was synthesized by connecting the highly cytotoxic Cryptophycin to the tumor-targeting RGDfK-peptide through a protease-cleavable linker. Finally, in view to making the peptide synthesis more sustainable and greener, we developed an alternative method for peptide bonds formation employing solvent-free mechanochemistry and ultra-mild minimal solvent-grinding conditions in common, inexpensive laboratory equipment. To this purpose, standard amino acids, coupling agents and organic-green solvents were used in the presence of nanocrystalline hydroxyapatite as a reusable, bio-compatible inorganic basic catalyst.

Abstract
Tipologia del documento
Tesi di dottorato
Autore
Anselmi, Michele
Supervisore
Co-supervisore
Dottorato di ricerca
Ciclo
32
Coordinatore
Settore disciplinare
Settore concorsuale
Parole chiave
Integrin, antagonists, agonists, inflammatory diseases, hybrid α/β-peptidomimetics, cyclopeptides, antitumor agents, drug delivery, cryptophycin, β-glucuronidase, small-molecule drug conjugate, nanostructured materials, Zeolite-L nanoparticles, diagnostic devices, green chemistry, mechanochemistry, liquid-assisted grinding
URN:NBN
Data di discussione
20 Marzo 2020
URI

Altri metadati

Gestione del documento: Visualizza la tesi

^