Argenziano, Rita (2023) Complex bioinspired organic systems and hybrids: green chemistry solutions for surface functionalization, biomedicine, and nanotechnology. [Tesi di dottorato]

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Abstract

The core of this PhD thesis is the exploitation, the manipulation, and the mimicking of natural phenolic systems as functional biocompatible components for use in hydrogels, sensors, surface coating, underwater adhesion, drug delivery and interfaces in technological and biomedical applications. Use of green chemistry methodologies, based on mechanochemical treatments, solvent free reaction, deep eutectic solvents, for preparation/manipulation of these materials or their extraction from natural sources represents a main approach pursued in this research activity. The synergistic effect stemming from combination of these compounds, exhibiting unique intrinsic features, with inorganic materials, resulting in tuning of their chemical, optical, and even electrical properties was also investigated. In detail, the main outcomes of this PhD research activity can be summarized as follows: -A versatile dip-coating technology widely applied in the case of polydopamine (PDA) for surface functionalization of various materials was applied to the methyl ester of the melanin precursor 5,6-dihydroxyindole-2-carboxylic acid (DHICA) in combination with hexamethylenediamine (HMDA) capable of imparting adhesive properties. For the investigation of the redox activity and morphology of the resulting film, voltammetric and AFM/SEM techniques were used. Chemical characterization was performed using HPLC, MALDI-MS, and 1H-NMR. Using chemical assays and a model of UV-stressed human immortalized keratinocytes (HaCat) cells, the film reducing activity was assessed and compared to PDA based film. The hypothesized film deposition mechanism is the spontaneous assembly of self-organized networks held together primarily by electrostatic interactions of MeDHICA in the anion form and HMDA as the dication. The film exhibited considerable oxidative stress protection on HaCaT cells and showed strong reducing properties. -The synthesis of new eumelanin precursors such as the amide/diamide derivatives of 5,6-dihydroxyindole-2-carboxylic acid was developed, based on the use of N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b] pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU) as coupling agent and requiring the protection of the catechol function by easily removable acetyl groups. Satisfactorily high yields (>85%) were obtained for all amides. The melanin-like pigments prepared by the amide derivatives by oxidative polymerization in air in aqueous buffer at pH 9, exhibited chromophores resembling those of DHICA-derived pigments. In the case of the carboxybutanamide, analysis of the pigment by EPR, ATR FT IR and MALDI MS indicated a substantial structural similarity to DHICA melanin, while investigation of the early intermediates confirmed unchanged regiochemistry of the oxidative coupling. The pigment exhibited a UVA-visible absorption even more intense than that of DHICA melanin, and a noticeable solubility in polar solvents of dermocosmetic relevance together with optimum antioxidant and lipid peroxidation inhibition properties. -Phenolic compounds deriving from agri-food by-products or synthetic conjugates of caffeic acid such as 2-S-lipoylcaffeic acid butanamide were exploited as active compounds for the inhibition of tyrosinase. Preliminary analysis of these compounds on dopa or tyrosine oxidase activity of mushroom tyrosinase showed potent inhibitory effects. Overall, these results hint to the use of these compounds as a valuable option in the treatment of pigmentation disorders associated with an overproduction of melanin by the action of tyrosinase. -An alternative strategy for the implementation of bio-inspired glues by proper combination of polyphenols or waste materials including proteins with in-situ generated catechol polymers was developed. The hydrogels proved to be biocompatible, hemocompatible, not harmful to skin, displayed durable adhesiveness and exhibited good water vapour permeability. Additionally, they demonstrated excellent contact-active antibacterial properties and in some cases a favourable wound healing activity on dermal fibroblasts. -A green deep eutectic solvent (DES) based protocol coupled with a ball milling pre-treatment for the recovery of lignins from edible nuts was developed. In particular, the extracted materials were recovered in satisfactory yields (19-27% w/w). A completely spectroscopic and chromatographic characterization allowed to conclude that the majority of the samples consisted of lignins with remarkable antioxidant properties. -A low-cost, scalable and straightforward solid-state mechanochemical protocol for the synthesis of silver nanoparticles (AgNP) based on the use of the highly reducing agri-food by-product Pecan Nut Shell (PNS) or lignin was developed. In addition, lignin or mechanochemical prepared Lignin/AgNPs were incorporated into poly (lactic acid) electrospun fibers, providing materials with enhanced antioxidant and antimicrobial properties for use in the biomedical sector. Finally, as part of the PhD project carried out during a training period carried out at the Institute of Bioscience and Biotechnology, University of Maryland (College Park, USA) under the supervision of Professor Gregory Payne the following research activities were developed: -A top-down reverse engineering mediators-based approach for the study of a chitosan hydrogel embedded with 5,6-dihydroxyindole (DHI) and the corresponding carboxyl acid (DHICA) melanins was implemented. This approach coupled with a spectroelectrochemical analysis highlighted the change in terms of antioxidant activity of DHICA and DHI melanin before and after metal binding. -A facile reverse engineering method was applied to fully characterize new functional hybrids catechol-graphene composite hydrogels, showing synergistic properties such as metal-like conductivity, redox activity and charge-storage through an electrical double as demonstrated by spectroelectrochemical measurements. Conducting and redox-active components enable distinctly different mechanisms for charge-storage and electron-transfer; these components act synergistically, and mediators provide unique opportunities to extend the capabilities of electronic materials.

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