1. Transition Metal Cluster Complexes for Biological Applications

Contact persons: Kaplan Kirakci, Kamil Lang

We investigate transition metal cluster complexes (Mo, W, Re, Cu, etc.) as biomaterials with photodynamic and radiodynamic properties. We proposed that such cluster complexes constitute versatile theranostic tools with desirable features such as high luminescence quantum yields, production of singlet oxygen, and radioluminescence properties attractive for photodynamic/radiodynamic therapy, scintillators, bacterial photoinactivation, or photocatalytic degradation.

1.1. Singlet Oxygen

Singlet oxygen O₂(¹Δ_g) is a potent mediator of phototoxicity and is typically generated by energy transfer from the excited triplet states of a photosensitizer to molecular oxygen (Fig. 1). This feature, coupled with the limited diffusion length of the O₂(¹Δ_g) in cells (~ 150-190 nm) due to its short lifetime, leads to a high selectivity in the destruction of targeted cells. In addition, O₂(¹Δ_g) has strong bactericidal and virucidal properties, which are the bases for a promising method for fighting microorganisms (often resistant) - antimicrobial photodynamic inactivation. Singlet oxygen interacts with cell structures and interferes with different metabolic pathways, preventing the development of resistance of microorganisms towards photodynamic treatment.

Figure 1: Production of O₂(¹Δ_g) by energy transfer from the excited triplet states of a photosensitizer to molecular oxygen. Typical photosensitizers: octahedral molybdenum or tungsten clusters, porphyrins, phthalocyanines.

References:

K. Lang, J. Mosinger, D. M. Wagnerová: Photophysical properties of porphyrinoid sensitizers noncovalently bound to host molecules; models for photodynamic therapy. Coord. Chem. Rev. 2004, 248, 321-350.
K. Lang, J. Mosinger, P. Kubát: Nanofibers and nanocomposite films for singlet oxygen-based applications. Chapter 15, pp. 305 – 321. Singlet Oxygen: Applications in Biosciences and Nanosciences (Vol. 1), S. Nonell, C. Flors (Eds.), European Society for Photobiology 2016. The Royal Society of Chemistry, Cambridge, UK

1.2. Octahedral Molybdenum Clusters

The octahedral molybdenum clusters (Mo6) are nanometer sized metallic aggregates of Mo(II) atoms stabilized by eight strongly bonded inner ligands, usually halogen atoms, and six labile inorganic/organic apical ligands (Fig. 2). These complexes display red phosphorescence and can produce singlet oxygen O₂(¹Δ_g) in high quantum yields. As opposed to organic dyes/photosensitizers such as porphyrins, they are less prompt to photobleaching due to their inorganic nature and do not experience self-quenching of their excited states at high concentrations or in the solid state. Being made of abundant elements they represent a sustainable alternative to noble metals- or rare-earth-based phosphors.

Figure 2: Structure of Mo₆ cluster with possible inorganic/organic apical ligands (dark yellow). Mo atoms are in blue, inner ligands, usually halogen atoms, are in magenta.

1.2.1. Photophysical and Photochemical Properties of Mo₆

Excitable by UV-blue light.
Ultrafast intersystem crossing, e.g., 1.7 ps for [Mo₆I₈(CF₃COO)₆]^2-.
Long lived triplet states (hundreds of µs) in solids (in contrast to aromatic organics, e.g., porphyrins) and in solutions. External environment in the solid state (molecular packing, counter-anions) has an effect on the relaxation processes in the triplet states.
Phosphorescence in the red/near-IR region, high phosphorescence quantum yields, large Stokes shifts (metal-metal distortions in the geometry relaxation of the first triplet state), efficient quenching of phosphorescence by O₂.
Triplet states energy is ~1.9 eV, i.e., > 0.98 eV of O₂(¹Δ_g).
High quantum yields of O₂(¹Δ_g) formation.

Figure 3 Left: Water solution of Mo6 in a vial and its phosphorescence under UV light. Right: Time-resolved phosphorescence of cluster 1 in the absence of oxygen (a), air-saturated (b) and oxygen-saturated (c) water solution.

1.2.2. Photodynamic and Radiodynamic Activity of Mo₆

Photodynamic therapy (PDT) is a minimally invasive modality for the treatment of several malignancies. Its principle lies in the production of reactive oxygen species (ROS), mostly singlet oxygen O₂(¹Δ_g), by a photosensitiser upon visible light irradiation (Fig. 2). Still, the conventional PDT treatment is limited because of the limited penetrability of visible light through tissues. We reported on in vitro testing of Mo₆ compounds in 2016 for the first time.
In order to overcome the limited penetrability of light, several alternative ways of excitation have been employed such as infrared irradiation exciting two-photon absorbing photosensitisers, chemiluminescent nanoparticles able to excite photosensitisers in-situ, or X-ray irradiation to activate ROS-producing radiosensitizers. The latter-named alternative of activation is promising because X-rays can reach deep-seated tumours and the clinical translation of this modality is facilitated by available equipment originally developed for the radiotherapy treatment. Radiodynamic therapy (RDT) was first introduced in the form of a complex system composed of scintillating nanoparticles and an attached photosensitizer. Recently, our group simplified the nanoparticle system for radiodynamic therapy. We demonstrated that Mo₆ clusters produce O₂(¹Δ_g) directly upon X-ray irradiation.

Our approach

Novel apical ligands (stability, active targeting). Some examples of photodynamic therapy towards Hela cells are bellow (irradiation at 460 nm).

Nanocarriers - protection against hydrolysis, good dispersability, while keeping intact the photophysical properties, improving biodistribution: e.g., copolymer poly(lactic-co-glycolic acid), water-soluble copolymers based on N-(2-hydroxypropyl)methacryl-amide, water-soluble polymers, e.g., PEG, chitosan.
Excitation by X-rays, i.e., Mo₆ clusters as radiosensitizers for radiodynamic therapy (Fig. 4).

Figure 4. Radiotoxicity of nanoparticles made of [Mo₆I₈(OPOPh₂)₆]^2- and X-ray irradiation (blue bars), *significant difference (p < 0.05) between control experiments and radiotoxic effects of the nanoparticles. In control experiments (black bars), cells were treated with saline only and irradiated.

• Composites – e.g., nanoceria/Mo6 cluster composites for environmental remediation.

Key references:

T. Přibyl, M. Rumlová, R. Mikyšková, M. Reiniš, A. Kaňa, K. Škoch, J. Zelenka, K. Kirakci, T. Ruml, K. Lang: PEGylated Molybdenum-Iodine Nanocluster as a Promising Radiodynamic Agent against Prostatic Adenocarcinoma. Inorg. Chem. 2024, 63, 9, 4419–4428.
K. Kirakci, M. A. Shestopalov, K. Lang: Recent developments on luminescent octahedral transition metal cluster complexes towards biological applications. Coord. Chem. Rev. 2023, 481, 215048.
R. Guégan, X. Cheng, X. Huang, Z. Němečková, M. Kubáňová, J. Zelenka, T. Ruml, F. Grasset, Y. Sugahara, K. Lang, K. Kirakci: Graphene oxide sheets decorated with octahedral molybdenum cluster complexes for enhanced photoinactivation of Staphylococcus aureus. Inorg. Chem. 2023, 62, 14243-14251.
K. Kirakci, R. Pola, M. Rodrigues Tavares, M. Pechar, T. Přibyl, I. Křížová, J. Zelenka, T. Ruml, T. Etrych, K. Lang: Radiosensitizing molybdenum-iodide nanoclusters conjugated with a biocompatible N-(2-hydroxypropyl)methacrylamide copolymer: a step towards radiodynamic therapy. Mater. Adv., 2023, 4, 6389-639.
K. Kirakci, M. Kubáňová, T. Přibyl, M. Rumlová, J. Zelenka, T. Ruml, K. Lang: A Cell Membrane Targeting Molybdenum-Iodine Nanocluster: Rational Ligand Design toward Enhanced Photodynamic Activity. Inorg. Chem. 2022, 61, 5076–5083.
K. Kirakci, T. K. N. Nguyen, F. Grasset, T. Uchikoshi, J. Zelenka, P. Kubát, T. Ruml, K. Lang: Electrophoretically Deposited Layers of Octahedral Molybdenum Cluster Complexes: A Promising Coating for Mitigation of Pathogenic Bacterial Biofilms under Blue Light. ACS Appl. Mater. Interfaces 2020, 12, 52492−52499.
K. Kirakci, J. Zelenka, M. Rumlová, J. Cvačka, T. Ruml, K. Lang: Cationic octahedral molybdenum cluster complexes functionalized with mitochondria-targeting ligands: photodynamic anticancer and antibacterial activity. Biomater. Sci. 2019, 7, 1386 – 1392.
K. Kirakci, P. Kubát, K. Fejfarová, J. Martinčík, M. Nikl, K. Lang: X-ray-Inducible Luminescence and Singlet Oxygen Sensitization by an Octahedral Molybdenum Cluster Compound: A New Class of Nanoscintillators. Inorg. Chem. 2016, 55, 803−809.

2. Atomically Precise Metal Clusters

Contact person: Tomáš Baše

Our research on metal clusters builds upon the successful functionalization of (car)borane cluster molecules and the investigation of their interactions with gold and other metals (Ag, Cu) across their various dimensional levels. A key focus in this research is on the preparation of atomically precise metal clusters, a novel class of molecules that provide unique insights into the transition of properties from a single metal atom to its bulk form. When functionalized with (car)borane clusters, these metal nanoclusters exhibit enhanced thermal and chemical stability compared to those stabilized solely by organic ligands.
Atomically precise metal clusters open up diverse research opportunities, including the development of new cluster types and the exploration of phenomena such as their luminescent behavior. These advancements hold promise for broadening our understanding of their unique properties as well as potential applications in many areas.