Novos Rumos para Metalofármacos Anticancerígenos

Drug2Target aims at achieving improved chemotherapeutic approaches against cancer, via a twofold strategy: (i) screening of new polynuclear Pt/Pd/Ni compounds in different types of human cancers; (ii) search for new therapeutic targets. It comes as a natural progression of previous FCT Projects (PTDC/QUI/66701/2006, POCI/SAU-BEB/66896/2006, PTDC/QEQ-MED/1890/2014), and encompasses: in vitro/in vivo screening for anticancer activity, cyto-/histopathological spectroscopic analysis; metabolomics. The innovative concept is to couple cutting-edge vibrational spectroscopy techniques (synchrotron-FTIR, Raman microspectroscopy and neutron scattering) to NMR-metabolomics and biological/pharmacological approaches, with a view to elucidate the effectiveness of new Pt/Pd/Ni-drugs (at a molecular level) and to unveil new therapeutic targets – profiting from an interdisciplinary international team with recognised proficiency. The compounds yielding the best results are foreseen to be assessed in prospective clinical trials, and technological transfer to the pharmaceutical industry is anticipated, with a possible patent in a near future. Homo- and heteronuclear Pt(II), Pd(II) and Ni(II) complexes with putrescine, spermidine and spermine, with or without hydrolysable ligands such as chlorides, will be probed. Synthesis, already ongoing, is based on published procedures optimised at UC. Upon full characterisation of the novel complexes (by elemental analysis, and NMR, FTIR, Raman and INS spectroscopies), their antitumour activity will be assessed: in vitro, in human cancer cell lines (both 2D and 3D-cultures, e.g. triple-negative breast cancer, lung, prostate, osteosarcoma); in vivo for the most promising compounds, in tumour-bearing mice. Particular emphasis will be placed on: (i) metabolic changes in cells and tissues probed by FTIR/Raman (spectral cyto-/histopathology) and by untargeted NMR metabolomics; (ii) in vivo anticancer activity (assessed in xenograft mouse models). Identification of new, non-conventional, chemotherapeutic targets will be pursued, specifically focusing on intracellular water – both in the cytoplasm and in biomolecules ́ hydration layers. The proposed multidisciplinary (Fig. 1, annexes) and interdisciplinary (Fig. 2, annexes) workplan relies on the team ́s recognised expertise in the wide range of methodologies to be used. UC will host the optical vibrational spectroscopy measurements (Raman and FTIR). The in vitro biological screening of the complexes will be performed both at UC and REQUIMTE. Upon completion of these initial tasks, bioavailability/biodistribution in cells will be investigated, and new targets will be searched for, at UC and REQUIMTE. For the most promising agents, in vivo assays followed by histopathological analysis and metabolic profiling will be implemented at UC, REQUIMTE and UA (Fig. 1). The INS, QENS, SR-FTIR, SR-AFM-FTIR and XAS experiments will be carried out by the UC team at ISIS and DLS, supported by the expertise of the team elements VGS (from ISIS), and GC and DG (from DLS). This is a pioneer approach for the design of multitarget metallodrugs, i.e. acting simultaneously on more than one molecular target, which is expected to lead to an enhanced therapeutic efficacy.