METAL COMPLEXES AND THEIR BIOLOGICAL ACTIVITY IN VIVO

Luminescent transition metal complexes (TMCs) represent a class of compounds with remarkable photophysical and electrochemical properties, arising from their unique electronic structures. Complexes containing Pt(II), Ir(III), Ru(II), Cu(I) for example are characterized by the presence of partially filled d-orbitals, exhibit a range of fascinating phenomena including phosphorescence, long-lived excited states, and tuneable emission wavelengths. These features, in conjunction with their chemical versatility and stability, have rendered TMCs indispensable in numerous fields, spanning optoelectronics, sensing, and bioimaging. Within this diverse landscape of TMCs, platinum complexes have garnered particular attention owing to their exceptional luminescence properties and the pivotal role of supramolecular self-assembly in dictating their behaviour. Thanks to the square planar geometry, when the Pt(II) ion is coordinated to conjugated ligands self-assembly can occur leading to the creation of supramolecular structures. These complexes in the assemblies can exhibit strong metal-metal interactions that engender unique photophysical characteristics, including intense phosphorescence and long-lived excited states [8,9]. The self-assembly of these complexes is strongly medium dependent and can further modulates their electrochemical properties and modify their reactivities enabling the creation of stimuli-responsive materials and sophisticated functional systems. In Professor De Cola's research group, the behaviour of self-assembling platinum complexes has been extensively studied. The possibility of using water-soluble, self-assembling platinum complexes makes them ideal candidates for in vivo imaging applications. It is known that one of the major problems of classic luminescent markers is the presence of oxygen in biological systems, as this is a known quencher of long-lived luminescent states. However, self-assembled structures would protect the metal centre, thus preventing oxygen access. Although the self-assembly process has been extensively studied to evaluate its spectroscopic effects, its potential for modulation at the biological level has never been thoroughly investigated While many Pt(II) complexes are toxic and several anticancer drugs have been developed taking advantage of their toxicity, there is a wide variety of transition metals, in biological systems that play crucial roles in enzymatic function, protein transport and storage, oxygen transport, and photosynthesis. Deficiencies in metals can lead to various of diseases in humans, such as anemia, growth retardation, and heart disease in infants due to iron, zinc, and copper deficiencies. Amongst the enzyme that play an important role in maintaining the cell metabolism and healthy our body superoxide dismutase (SODs), which utilize copper and zinc to neutralize reactive oxygen species, and catalase, which employs manganese to decompose hydrogen peroxide are very relevant. The significance of these metalloenzymes has spurred intensive research in recent years, with a particular focus on the synthesis of artificial metalloenzymes that mimic the catalytic processes of their natural counterparts. To achieve the goal of mimicking enzymatic activity, it is crucial to simulate an environment that closely resembles the natural enzymatic task. One promising strategy involves confining these artificial metalloenzymes within nanostructures, thereby creating a controlled and restricted system. This approach aims to replicate the spatial constraints and microenvironment found within enzyme active sites, potentially enhancing the catalytic efficiency and selectivity of the artificial metalloenzymes. A promising approach for enhancing the stability of transition metal complexes (TMCs) in biological environments is the utilization of soft or hard porous nanomaterials as confinement systems. Nanotechnology has experienced a remarkable surge in research and development across various sectors, including medicine. Nanomaterials, owing to their nanoscale dimensions, exhibit unique properties that differ significantly from their bulk counterparts, making them attractive for biomedical applications. The potential of nanomaterials as drug delivery vehicles stems from their ability to protect drugs from degradation, facilitate targeted delivery, enable relatively straightforward manufacturing processes, demonstrate biocompatibility, and accommodate diverse drug types. Consequently, employing nanomaterials for the transport and protection of catalytic TMCs complexes offers a promising strategy to overcome the challenges associated with their instability in biological systems. In this field, transition metal complexes represent a valuable resource for therapeutic and diagnostic applications in modern medicine. Their diverse chemical interactions, encompassing redox processes and coordination chemistry, allow for the development of tailored approaches to disease treatment. Ongoing research endeavours to discover and optimize novel metal complexes, enhancing their efficacy, safety, and specificity for various medical applications. As such, transition metal complexes are poised to play an increasingly pivotal role in the future of pharmacology and therapeutic interventions. The aim of my research is to develop transition metal complexes able to self-assembly to achieve new functions or simple catalysis-mimic compounds. To enhance their stability in biological media, I have investigated soft and hard porous structures creating hybrid nanosystems. The first objective of my research focused on Pt(II) complexes, containing conjugated ligands, exploiting the high tendency of such square planar compounds, to self-assembly in supramolecular structures. The synthesized water-soluble Pt(II) complexes have been investigated to assess their assembly tendency and in a very complex media such as living organisms. The obtained results suggest that the self-assembly of the complexes, and in particular of a positively charged compound, modulate their photophysical properties, and, very interestingly, trigger important biological effects, suggesting a kind of antioxidant activity. For this reason, in the second objective I have designed and synthesized metallic complexes as mimic for the natural enzymes, containing Cu and Zn as metals. Artificial metalloenzymes have become increasingly important in the last decades as a promising approach to combine homogeneous catalysis and biocatalysis for therapeutical applications. In cell systems, the enzymes superoxide dismutase (SOD), catalase (CAT), oxidase (OXD) and peroxidase (POD) are involved in redox homeostasis. Therefore, artificial systems able to function as antioxidant under few pathological situations associated with an enhanced oxidative stress, such as diabetes, cancers, inflammatory bowel and neurodegenerative diseases are the basis of my ongoing research. In the last part, the third objective of my work, I have focused on the development of soft, non-lipid-based vesicle, i.e. Qs (QS), eventually covered with silica, and hard porous nanosystems such as organosilicates. The porous nanoparticles have been employed for the encapsulation of some of the complexes in order to confer water compatibility and to enhance their stability. In conclusion, this PhD research has yielded significant advancements in two key areas: i) understanding self-assembly in vivo and in particular the biological impact of redox active assemblies; ii) SOD mimic systems that can be used in biological samples due to the enhanced stability dictated by a nanocage and the water miscibility again promoted by the scaffold. These findings can open new venue on the design of systems in which the modulation of the redox activity can be tuned by molecule-molecule interaction as well as the novel way to protect unstable species.