Biotechnology

QUADRUPLE-BONDED DIRHENIUM CLUSTERS AS A NEW ANTICANCER DRUG

The growing interest in transition-metal-containing drugs, starting from cisplatin discovery can be explained by wide opportunities that metal complexes have in the comparison with organic molecules, especially their versatile redox chemistry. Perspective platform for development of new antitumor pharmaceuticals is represented by dinuclear carboxylate complexes of rhodium, ruthenium and rhenium with so-called ‘Chinese lantern’ structure as species could bind to DNA, inhibit DNA replication and protein synthesis. Among this group, the dirhenium compounds may be recognized as the most promising candidates for clinical development due to their very low toxicity. This issue is especially important considering severe limitations for clinical use of some cytostatics as cisplatin originating in its neuro-, hemato-, hepato- and nephrotoxicity. Cisplatin, as a systemic anti-proliferative agent, preferentially kills dividing cells, primarily by attacking their DNA at some level (synthesis, replication or processing) and binds to non-DNA targets. It is not truly selective for cancer cells and damages also proliferating normal cells such as those in the bone marrow and gut epithelia. Also, the dirhenium compounds contain an unique quadruple bond that is absent in nature, in the molecules of common medicines plethora and represent a new type of δ â€‛ antioxidants in contrast to known Ï€-antioxidants. This quadruple bond due to significant unsaturation possesses mighty antiradical and antioxidant properties, that should be used in medical practice.

The main goal of the project is creating medicines (first of all anticancer agents) based on organometallic rhenium compounds with low toxicity, the action of wich is directed on tumor cells death and due to the antioxidant properties will posses antihemolytic, hepato- and nephroprotective and other valuable functions. We plan:
1. As our recent findings showed that nature of ligands play a significant role in DNA-interactions and in the antitumor activity of the dirhenium complexes, new antitumor dirhenium species with active ligands involving zwitterionic aminocarboxylate ligands, curcuminoid, indolylacetic, etc. ligands will be synthesized.
2. Anticancer activity of the newly synthesized species solely and together with cisplatin (Re-Pt antitumor system) will be investigated. The redox-activated strategy will be used and mechanism of redox depending interactions with biomolecules will be investigated during anticancer experiments.
3. Preparation and investigation of nanoliposomes and solid lipid nanoparticles containing rhenium compounds and Re-Pt antitumor system is planned as encapsulation of cluster rhenium compounds to lipid coating have not only protective but activation significance for the quadruple Reâ€‛Re bond; this approach has its own significance for nanobiotechnology; application of nanovesicules with mixed composition inside opens perspective to make control of drug release and to use nanobased combinational therapy.
4. Quadruple-bonded rhenium compounds will be used not only in anticancer treatment but in some diseases with depleted redox states as antihemolytics, hepato- and nephroprotectors.

NEW BIOMARKERS BASED ON RHENIUM COMPOUNDS

The project aims is creating biomarkers based on organometallic rhenium compounds with low toxicity, which will allow to carry out diagnostics of pathological processes in the body. Rhenium carbonyl complexes have a number of useful properties that make them excellent candidates for use in imaging. Absorption of this complexes mostly in the UV (320 - 400 nm) with high absorption coefficients and this makes the complexes easy to excite. Rhenium compounds have moderate to highly phosphorescent with λ > 500 nm, large Stokes shifts and very long emission life times.

This is highly favorable, as self-quenching processes are intrinsically minimized and cellular autofluorescence can be cut out easily with suitable filters. In addition rhenium compounds not prone to photobleaching, that highly important, as photobleaching leads to a significant reduction of signal intensity. The luminescence of rhenium carbonyl complexes is characterized by high intensity and lifetime, which allows the use of lower concentrations of substances. Furthermore these complexes are nontoxic to the organism which sets it apart on their background analogs that exist. The use of biomolecules as transport will allow to deliver the marker directly to the tissue that needs to explored.