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Smart Bioinorganic Hybrids for Nanomedicine

Periodic Reporting for period 3 - BIOINOHYB (Smart Bioinorganic Hybrids for Nanomedicine)

Reporting period: 2019-02-01 to 2020-07-31

The use of bioinorganic nanohybrids (nanoscaled systems based on an inorganic and a biological component) is currently a revolutionary approach for drug delivery, therapeutics, imaging, diagnosis and biocompatibility. One of the most promising and desired societal impacts of nanotechnology is indeed in the field of nanomedicine. The ultimate target is a personalized health care, where innovative rational approaches are applied to minimize adverse side effects of medical therapies. However, researchers still know relatively little about the structure, function and mechanism of these innovative nanodevices. BIOINOHYB project aims at achieving a comprehensive understanding and control of a novel class of bioinorganic nanohybrids, based on photosensitive and magnetic metal oxides, by means of advanced quantum chemical calculations, with the final goal of providing the design principles for smart multifunctional systems with a strong impact potential on medical applications (see Figure 1).
We first worked on the preparation and on the study of models of nanostructures for a photosensitive semiconducting oxide: titanium dioxide (TiO2). We first prepared 2D slab (surface and thin film) and OD (nanoparticles) models. We investigated nanoparticles of increasing size (up to a diameter of 4.4 nm: about 4000 atoms, see Figure 2) and considered different shapes: decahedral (exposing facet and edges) and spherical shaped nanoparticles. This activity required a careful design for chemically stable stoichiometric systems and the recourse to some simulated thermal annealing through molecular dynamics runs, as a suitable approach to global optimization of such complex and large systems. The final optimized structures were fully relaxed at a quantum chemical level. We then investigated structural and electronic properties for comparison among different sized and shaped nanoparticles, with respect to bulk and available experimental data.
This work is published on:
G. Fazio, L. Ferrighi, C. Di Valentin; Spherical versus faceted anatase TiO2 nanoparticles: a model study of structural and electronic properties. Journal of Physical Chemistry C 2015, 119, 20735−20746.
D. Selli, G. Fazio, C. Di Valentin; Modelling Realistic TiO2 Nanospheres: a Benchmark Study of SCC-DFTB against Hybrid DFT. Journal of Chemical Physics 2017, 147, 164701.

Since nanoparticles typically experience water environments or biological aqueous media, as a next step we investigated the oxide/water interface, for both flat and curved TiO2 surfaces (faceted and spherical nanoparticles). This work was done in collaboration with the group of Prof. Yoshiyasu Matsumoto in Kyoto (Japan), who are capable of preparing nanoparticles of different shape and of small size (comparable to that we can simulate with first-principles calculations) and to gradually control the water partial pressure, going smoothly from ultra-high vacuum to high water partial pressure. Comparison between experimental and simulated infrared spectra and definition of the water species on the nanoparticles surface are the two main outcomes of this computational/experimental combined study.
This work is published on:
K. Shirai, G. Fazio, T. Sugimoto, D. Selli, L. Ferraro, K. Watanabe, M. Haruta, B. Ohtani, H. Kurata, C. Di Valentin, Y. Matsumoto; Water-assisted hole trapping at the highly curved surface of nano-TiO2 photocatalyst. Journal of the American Chemical Society 2018, 140, 1415-1422.

To make our studies more realistic, we aim at increasing the nanoparticle size (in terms of number of atoms) and the number of water layers around the nanoparticles. However, calculations become very demanding. For this reason, we made an effort to provide an accurate benchmark of a computationally cheaper method (Density Functional Tight Binding, DFTB) with respect to reference Density Functional Theory (DFT) calculations for water multilayers on TiO2 slab models, as described by both static and dynamic simulations. The assessment of the validity of DFTB method for this type of investigations, derived from our study, in collaboration with Prof. Gotthard Seifert from the University of Dresden, is an extremely important result for this project and for all the scientific community. With this powerful tool, we could address large nanoparticles in a multilayer of water. On top of that, we also developed a QM/MM interface to include the presence of surrounding bulk water.
This work is published on:
D. Selli, G. Fazio, G. Seifert, C. Di Valentin; Water Multilayers on TiO2 (101) Anatase Surface: Assessment of a DFTB-Based Method. Journal of Chemical Theory and Computation 2017, 13, 3862−3873.
G. Fazio, D. Selli, L. Ferraro, G. Seifert, C. Di Valentin; Curved TiO2 Nanoparticles in Water: Short (Chemical) and Long (Physical) Range Interfacial Effects. ACS Applied Materials & Interfaces 2018, 10, 29943-29953.

Since “naked” nanoparticles are not always stable in water (at neutral pH) or in physiological fluids, their stabilization through functionalization is required. For this reason we studied surface coating with polyethyleneglycol (PEG), see Figure 3.
This work is published on:
D. Selli, C. Di Valentin; Ab initio investigation of polyethylene glycol coating of TiO2 surfaces. Journal of Physical Chemistry C 2016, 120, 29190−29201.
As a further important step, we investigated the effect of light on the bare nanoparticles (both faceted and spherical) and on the nanoparticles in the presence of some adsorbed water molecules.
In the case of bare nanoparticles, we computed the electronic transitions (excitation and emission) and the EPR parameters for the trapped charged carriers, we also investigated the singlet and triplet excitons and defined the electron/hole preferential localization sites.
This work is published on:
G. Fazio, L. Ferrighi, C. Di Valentin; Photoexcited carriers recombination and trapping in spherical vs faceted TiO2 nanoparticles. Nano Energy 2016, 27, 673–689.

When adsorbed on the surface, water molecules may play a role in the photoinduced processes and especially in the charge carrier trapping. This aspect was investigated in collaboration with Prof. Yoshiyasu Matsumoto’s group that performed some transient absorption experiments on photoirradiated faceted and spherical nanoparticles.
This work is published on:
K. Shirai, G. Fazio, T. Sugimoto, D. Selli, L. Ferraro, K. Watanabe, M. Haruta, B. Ohtani, H. Kurata, C. Di Valentin, Y. Matsumoto; Water-assisted hole trapping at the highly curved surface of nano-TiO2 photocatalyst. Journal of the American Chemical Society 2018, 140, 1415-1422.

Titania nanoparticles can be coated or functionalized to modify the absorption properties and to activate their tethering ability towards biologically active molecules. In this respect, we investigated both graphene coating and enediol binding.
This work is published on:
M. Datteo, H. Liu, C. Di Valentin; Water on Graphene-coated TiO2: Role of atomic Vacancies. ACS Applied Materials & Interfaces 2018, 10, 5793-5804.
C. Ronchi, D. Selli, W. Pipornpong, C. Di Valentin. Proton Transfers at a Dopamine-Functionalized TiO2 Interface. Journal of Physical Chemistry 2018, DOI: 10.1021/acs.jpcc.8b04921.

In parallel to the above-mentioned work on TiO2, we also worked on a magnetic metal oxide of extremely high interest for nanomedical applications: magnetite (Fe3O4). We have investigated the proper methodology to describe the delicate electronic and magnetic properties of this system, the correct model for the (001) surface at the interface with water. Existing literature is based on non-proper methodologies and approaches leading to an incorrect picture.
This work is published on:
H. Liu, C. Di Valentin; Band gap in magnetite above the Verwey temperature induced by symmetry breaking. Journal of Physical Chemistry C 2017, 121, 25736-25742.
H. Liu, C. Di Valentin; Bulk-terminated or reconstructed Fe3O4(001) surface: water makes the difference. Nanoscale 2018, 10, 11021-11027.
The results of the work performed so far are beyond the state of the art on various aspects. We have modelled extremely large semiconducting oxide nanoparticles (up to 4000 atoms) at an advanced quantum mechanical level (DFT), being able to provide accurate structural details and correct electronic properties. On a more fundamental level, we have provided clear evidence for the validity of the DFTB, as a computational cheaper approach, for studying titanium dioxide/water interface. On a more practical side, we have been able to investigate the interaction of realistic and variously shaped nanoparticles with light, even in the presence of water. Our work in collaboration with prominent experimental partners proves that our models are representative of real experimental conditions. With this premises, the project is expected to provide a valuable contribution to make further important steps beyond the state of the art on the modelling of metal oxide nanoparticles for medical application.
The impact of our work on the scientific community is proven by the citation statistics of our recently published articles, by the invitations that the PI constantly receives to present keynote or plenary lectures at international conferences and by the acceptance of oral contributions from the other members of the group.
Our studies will have a socio-economic impact and implications for a wider society in the medium-long run, because, on one side, accurate modelling of nanosized systems may allow to substitute or avoid expensive and time-consuming experiments and, on the other, the knowledge achieved with this project may allow improving current strategies in nanomedicine.
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