Projects / Programmes
Synthesis, characterisation and use of novel ruthenium compounds in electrochemotherapy of tumors
| Code |
Science |
Field |
Subfield |
| 1.04.03 |
Natural sciences and mathematics |
Chemistry |
Inorganic chemistry |
| Code |
Science |
Field |
| P360 |
Natural sciences and mathematics |
Inorganic chemistry |
| Code |
Science |
Field |
| 1.04 |
Natural Sciences |
Chemical sciences |
ruthenium compounds; anticancer metallodrugs; electroporation; in vivo tests
Researchers (23)
Organisations (4)
Abstract
The proposed interdisciplinary project brings together experts from fields of chemistry, electrical engineering, biology and medicine with the aim to work in synergy on developing electrochemotherapy with ruthenium compounds. Electrochemotherapy is an efficient local treatment for solid tumors which is in clinical use since 2006 and has excellent response results. In addition, clinical tests for some of ruthenium compounds as potential anticancer agents are also already in progress. The main aims of this work are:
Chemical synthesis and characterization. Synthesis of new ruthenium compounds and their characterization by different physico-chemical methods. We will use various ligands (triazoles, quinolones, N,N-ligands) to get the new potential antitumor metallodrugs with requested properties for electrochemotherapy.
In vitro electrochemotherapy. Screening of ruthenium compounds in vitro for their antitumor activity. Compounds will be tested alone and in combination with electroporation on different mammalian and human cell lines. The influence of electrochemotherapy with selected ruthenium compounds on metastatic potential of cells will be studied in order to evaluate the antimetastatic activity of ruthenium compounds in electrochemotherapy and the safety of the treatment. In addition, the influence of hypoxic environment on activity of ruthenium compounds will be studied. On the basis of obtained results we will select the best candidates for further electrochemotherapy experiments in vivo.
In vivo electrochemotherapy. In the last phase of the project in vivo tests on mouse tumor models will be performed. Selected ruthenium compounds from the in vitro experiments will be tested in electrochemotherapy for their antitumor activity. Assuming that in vivo tests confirm novel ruthenium compound as effective and safe antitumor or/and antimetastatic compound for electrochemotherapy treatment further development of the compound will be conducted. In addition, we will compare the results of in vitro and in vivo experiments to evaluate the influence of hypoxia on predictivity of results in vivo. We will try to optimize the tests in vitro in order to follow the 3R strategy for replacement, reduction and refinement of experiments on animals.
Note: We would like to stress that all formulae and schemes that are marked as Fig. i in the text are collected in the file that was attached to the project documentation!
Significance for science
The structure-property (biological, physical, chemical, etc.) relationships are crucial for understanding different natural processes. On the long run, the research on synthesis and structure of metal complexes may well enable us to actually predict the topology of molecules. This can ideally, lead to the rational design of materials for specific applications (e.g. new drugs). On the other hand the structure studies can also help in elucidating drugs mechanisms of action - which in many cases are only partially explained. The relationship between the chemical and three-dimensional structure of a molecule and its biological activity is called structure-activity relationship (SAR). With this method we are able to determine the chemical groups that are responsible for evoking a target biological effect in the organism. In our study we inserted new chemical groups into analogous ruthenium complexes and tested how this affected their biological effects. We believe our results may bring new insights in structure-activity relationships of ruthenium anticancer compounds. Our results of biological tests (enzyme inhibition, cytotoxicity) for our tested compounds are not ideal. Still they gave us first indications about the relation between the structure of compounds and biological activity, which was (and still is) our important goal. From the collected results we have acquired important information which will help us to modify the structures of ligands with which better results might be obtained. In the case of successful single-crystal preparation the structures of compounds in the solid state was analyzed in detail. All new inorganic-organic structural data are stored in the Cambridge Structural Database (CSDB) and are thus available to other researchers all over the world, so that they can use the information in their own research. In this way we will indirectly contribute also to the development of other basic sciences. We have also determined how the tested ruthenium compounds interact with cellular components (such as nucleic acids and proteins), as well as with their potential targets outside the cells, with the aim of understanding their mechanisms of action. We have confirmed that such interactions occured which is also important for better view of the mode of action of metallodrugs. We would again like to stress that 3R strategy (replacement, reduction and refinement of experiments on animals) was used during this project. With this we would like to show that we take seriously public concern about the use of animals in science and also the request to reduce cost of experiments. As a part of pharmacokinetics investigation of ruthenium compounds, our partners from IJS developed speciation analysis to investigate its distribution in human serum among un-bound species and those bound to major serum proteins. The method will be very useful also for similar studies that we plan in the future but also for the researchers dealing with similar systems.
Significance for the country
The described project was not important only for the development of basic science but allowed also to involve undergraduate and postgraduate students in the research work and to transfer the knowledge and experiences to the younger researchers. All these could later be used in their professional careers. In addition, this research is directly related to a number of subjects of the programs of undergraduate and postgraduate study at participating faculties of the University of Ljubljana. During the project several exchanges of researchers between the international labs involved in this project occured (e.g. COST "Short term scientific missions"; visits within the bilateral projects). This is especially useful for younger researchers. Such cross-disciplinary training visits are of benefit in the career development of early stage researchers and also enables them to use knowledge and facilities of foreign partners that are not available in Slovenia. We are also proud that two doctoral theses were successfully finished on the project topics. After finishing her Ph.D. Rosana Hudey was employed in a company BIA whereas Jakob Kljun obtained a postdoctoral ARRS project and continues with his work in the labs of Prof. I. Turel. Due to the involvement of particular foreign researchers, this project is important for further development of regional cohesion and cooperation within CEI (Central European Initiative) countries and AAD (Alps Adria Danube) region. The results generated and collaboration further advanced within the proposed project clearly increases our possibilities to sucessfully participate in competitive calls of the European Commission but also in other international project calls.
Most important scientific results
Annual report
2011,
2012,
2013,
final report,
complete report on dLib.si
Most important socioeconomically and culturally relevant results
Annual report
2011,
2012,
2013,
final report,
complete report on dLib.si
