ANTITUMOR NANOSCALE TRANSITION METAL DENDRIMERS TO TARGET APOPTOSIS SIGNALLING PATHWAYS

Duration of project: June 24th 2016-December 31st, 2017
Granted by the Romanian Executive Agency for Higher Education, Research, Development and Innovation Funding (UEFISCDI)
Project Code PNIII-P3-116 / 24.06.2016, contract no. 9BM/2016
Acronym: AFROMET

Host institution:
Institute of Oncology “Prof. Dr. Ion Chiricuta” Cluj Napoca,
34-36 Republicii, 400015 Cluj Napoca, Romania
Project director: CSII. Eva Fischer-Fodor, Ph.D., senior researcher

Romanian partner institution:
University of Medicine and Pharmacy “Iuliu Hatieganu”
8 Victor Babes, 400012 Cluj-Napoca, Romania
Romanian co-director: Assoc.Prof.Alma Maniu, MD, PhD

South African partner institution: Department of Chemistry,
University of Cape Town, PD Hahn Building, Upper Campus,
Rondebosch, South Africa
South African project director: Prof. Gregory S. Smith

Romanian research team:
Assoc.Prof. Calin Cainap. MD., PhD
Lect. Catalin Vlad, MD., PhD
CSIII. Ciprian Tomuleasa, MD, Ph.D

South African research team:
Nadia Baartzes, B.Sc., B.Sc. (Hons), M.Sc.
Laa-iqa Rylands, B.Sc., B.Sc.(Hons)
Irwin Cassells, B.Sc., B.Sc.(Hons)

The present project aims to establish scientific connections between the Institute of Oncology "Prof.Dr.I.Chiricuta" in Cluj (IOCN) and the University of Cape Town (UCT).

The purpose of the consortium is to strengthen the cooperation with the UCT team headed by Prof. Gregory Smith, having common interests in metallomics, in the development of new materials with potential therapeutic use and publishing of research studies. The project aim is to develop nanomaterials, transition metal complexes with functionalized dendrimers. The importance of metal-based drugs and dendrimer-type structures is recognized in cancer therapy, and the consortium proposes to study the molecular aspects of the activity of newly synthesized substances that combine cytotoxic properties of transition metal with intracellular transport properties of nanovectors.

The activities of the two partners will be complementary partner UCT will develop structures in silico, will perform synthesis and physico-chemical characterization of nanostructures type dendrimer with platinum group metals and IOCN ensure their assessment biological in order to elucidate the cytotoxicity, the molecular basis of death programmed cell signaling pathways and extrinsic and intrinsic mechanisms of cell mediated and humoral immune modulation. Through these assessments we aim to achieve the molecular design for complexes able to reduce the growth inhibition and to interfere with molecular targets in malignant cells.

General objectives of the project
The project proposes to develop nanomaterials of transitional metals and dendrimer macromolecules of platinum group metals (PGM) for biomedical applications.

Phase I: June 24th , 2016 – December 31st , 2016
I.1. Synthesis of metal complexes (UCT)
I.2. In vitro studies on nanodendrimers antitumor activity, apoptosis, DNA lesions and their effect on immune system (IOCN)

Phase II: January 1st, 2017- December 31st, 2017
II.1. Fine tuning of metal complexes synthesis to optimize their biologic activity (UCT)
II.2. Identification of signaling pathways and molecular targets in cancer cells treated with the novel synthesized metal compounds (IOCN)


Preliminary results of project- phase I, 2016

At present the first phase of the project was implemented, implicating the in vitro assessment of antiproliferative activity of novel synthesized ferrocene, ruthenium and palladium complexes against various tumor cell lines using cytotoxicity, and molecular methods.

The Romanian team hosted 2 South African researchers and has completed 2 exchange visits during the first phase of the project. In September 2016, two researchers from UCT: N. Baartzes and L. Rylands visited the Institute of Oncology “I.Chiricuta”. Two oral presentations were held in the Research Department of IOCN by the South-African guests. During their visit, the Tumor Biology Department launched the biologic testing on 10 new compounds, synthesized by the UCT team. The testing on one series of 3 polynuclear ferrocenyl complexes with thiosemicarbazone ligands was accomplished in the first phase of the project.

In October 2016, and November 2017, respectively, the Romanian team members Assoc. Prof.A. Maniu (UMF) and Lect. C. Vlad (IOCN) accomplished two visits to the partner institution from Cape Town.

In 2016 the team published a paper indexed by Thomson Reuters Web of Science core collection, with the title:

Cytotoxic activity of palladium(II) complexes of (1E,6E)-1,7-bis(4-(dimethylamino) phenyl) hepta-1,6-diene-3,5-dione against human colon carcinoma. Natalia Mijklasova, Roman Miklas, Piroska Virag, Corina Bianca Tatomir, Cristina Szalontai, Diana Cenariu, Ferdinand Devisky, Eva Fischer-Fodor. STUDIA UBB CHEMIA, 61, 3, Tom I, 2016, pages 109-116.
The above paper has mentioned in the Acknowledgements section the project code 9BM/2016.

We elaborated the manuscript with the title:
Polynuclear ferrocenylthiosemicarbazones inhibitory effect against colon tumor cells in vitro, authors: Nadia Baartzes,Mihai Cenariu, Cristina Szalontai, Florica Imre-Lucaci, Sorin Aurel Dorneanu, Alma Maniu, Eva Fischer-Fodor, Gregory Smith.
The paper will be submitted to a journal indexed by Thomson Reuters Web of Science.

Other studies, focusing the biologic activity of two ruthenium-based complexes are ongoing, with expected results in 2017.

Based on the results obtained in the first phase of the project, the Romanian and the South-African team members plan to submit an oral presentation to the 6th International Symposium on Metallomics, which will be held in 2017.


Contact person: CSII. Dr. Eva Fischer-Fodor
Tumor Biology Laboratory, Research Department
Institute of Oncology “Prof.Dr.I.Chiricuta”
34-36 Republicii Street, 400015 Cluj Napoca, Romania
Phone/Fax: 0264-439260, E-mail: fischer.eva@iocn.ro