{"id":1354,"date":"2018-03-13T21:20:30","date_gmt":"2018-03-13T21:20:30","guid":{"rendered":"http:\/\/qfm.uc.pt\/?page_id=1354"},"modified":"2018-03-13T21:20:30","modified_gmt":"2018-03-13T21:20:30","slug":"bioimpact","status":"publish","type":"page","link":"https:\/\/qfm.uc.pt\/index.html\/language\/en\/projects\/bioimpact\/","title":{"rendered":"Biochemical Impact of Platinum and Palladium-based Anticancer Agents – BioIMPACT"},"content":{"rendered":"

Cisplatin is one of the most widely used antineoplastic compounds, since its serendipitous discovery in the 1960\u00b4s. However, its severe side effects and acquired resistance have led to an intense search for new generation Pt(II) and Pd(II) agents, aiming at an improved cytotoxic profile coupled to a lower toxicity. Polynuclear chelates with polyamines (PAs) as bridging ligands are one such group of compounds, known to act through covalent binding to DNA (their main pharmacological target), through an interplay not available to conventional Pt-drugs that leads to an enhanced antineoplastic effect. Nevertheless, the exact nature of the mechanisms involved, at a molecular level, is still unknown, thus highlighting the relevance of relating structure and conformational preferences of this kind of systems to their antitumour activity and biochemical impact.
\nThe PI and several partners of the present team (QFM-UC) have long been involved in the study of cisplatin-like Pt and Pd polynuclear complexes with aliphatic amines (including putrescine, spermidine and spermine, also previously investigated by the team), aiming at their thorough conformational characterisation and evaluation of anticancer activity towards human neoplastic cell lines. This work has been developed within several funded R&D projects: PBIC\/C\/QUI\/2219\/95 (JNICT, Portugal, LABC as PI); POCTI\/33199\/QUI\/00 (MPM as PI), POCTI\/QUI\/47256\/2002 (MPM as PI), PTDC\/QUI\/66701\/2006 (MPM as PI); POCI\/SAU-BEB\/66896\/2006 (FCT, Portugal); European COST Actions 922 and BM1401 (http:\/\/bit.ly\/1vTAp8A); EU\/IHP Programme for ISIS Neutrons (MPM and LABC group leaders). Reliable Structure-Activity Relationships (SAR\u00b4s) were established for these systems and quite promising results have been obtained for a Pd(II) agent. The present project thus comes as a natural follower of this line of research, with a view to extend the information available on the metal chelates to their pharmacokinetic and pharmacodynamic profiles, particularly regarding: (i) cellular and tissue bioavailability; (ii) cyto- and histological effects; (iii) induced metabolic changes.
\nAccordingly, several methodologies are chosen as the most suitable for attaining the proposed goals: Vibrational spectroscopy (Raman, Fourier Transform Infrared (FTIR), Inelastic Neutron Scattering (INS)) and synchrotron-based Extended X-ray Absorption Fine Structure (EXAFS), for a thorough characterisation of the metal\u00b4s coordination pattern and the conformational preferences of the complexes and their DNA adducts. Quantification of the intracellular complex concentration by LC-MS\/MS (liquid chromatography\/tandem mass spectrometry), and bioavailability assessment by atomic absorption and scintillation counting methods. Raman microspectroscopy and synchrotron radiation infrared microspectroscopy (SR-IRMS), yielding 3D-chemical images of living cells, for monitoring biodistribution and metabolic changes. These are state-of-the-art techniques for obtaining high resolution information at the cellular (and sub-cellular) level, particularly useful for cyto- and histopatological analysis upon drug administration. 1<\/sup>H High Resolution Magic Angle Spinning Nuclear Magnetic Resonance (HRMAS-NMR) spectroscopy, to assess the impact of the chelates on intracellular metabolism, followed by cell extracts analysis by liquid state 1<\/sup>H and 31<\/sup>P-NMR. NMR characterisation of selected chelate\/cell line combinations will yield specific information on the changing metabolites. Ex vivo<\/em> and in vivo<\/em> assays for pre-clinical evaluation of the complexes\u00b4 tumour inhibition potency and histologic induced effects, using the chorioallantoic membrane (CAM) as a model for tumour growth, as well as mouse xenografts of human cells. The influence of dietary antioxidants on the activity of these potential chemotherapeutic agents will also be addressed.
\nIn summary, the present project aims at filling the gap between the measured anticancer activity of Pt(II) and Pd(II) polyamine chelates (in the light of their previously established SAR\u00b4s) and their biodistribution and biochemical impact (metabolic and histopathological effects). Furthermore, the effect of common dietary phytochemicals on the pharmacodynamics of the complexes will be investigated, with a view to begin to understand the influence of the daily diet on chemotherapy intervention. The success of this multidisciplinary study is ensured by the recognised expertise of the team members in the different approaches to be used, in a close scientific collaboration between six research institutions (national and international).<\/p>\n

State<\/b>
\nFinished
\nPeriod<\/b>
\n2016 to 2019
\nFunding<\/b>
\n198.690,00 \u20ac
\nProject code<\/b>
\nPTDC\/QEQ-MED\/1890\/2014
\nFunding Entity<\/b>
\nPortuguese Foundation for Science and Technology (FCT), Portugal<\/p>\n

Members<\/b>
\nMaria Paula Matos Marques Catarro<\/a>\u00a0(Principal Investigator)
\nLu\u00eds Alberto Esteves Batista de Carvalho<\/a>
\nAna Margarida Amado Roque Batista
\nAna L\u00facia Marques Batista de Carvalho<\/a>
\nAdriana Maria Pires Mamede<\/a><\/p>\n

Publications<\/b>
\nImpact of the Pd2<\/sub>Spermine Chelate on Osteosarcoma Metabolism: an NMR Metabolomics Study<\/a>
\nI. Lamego, M.P.M. Marques, I.F. Duarte, A.S. Martins, H. Oliveira e A.M. Gil
\nJournal of Proteome Research\u00a016<\/strong>, 1773-1783 (2017)<\/p>\n

Intracellular Water \u2013 an Overlooked Drug Target? Cisplatin\u00b4s Impact in Cancer Cells Probed by Neutrons<\/a>
\nM.P.M. Marques, A.L.M. Batista de Carvalho, V. Garcia-Sakai, L. Hatter e L.A.E. Batista de Carvalho
\nPhysical Chemistry Chemical Physics\u00a019<\/b>, 2702-2713 (2017)<\/p>\n

Anti-invasive and Anti-proliferative Synergism Between Docetaxel and a Polynuclear Pd-Spermine Agent<\/a>
\nA.L.M. Batista de Carvalho, P.S.C. Medeiros, F.M. Costa, V.P. Ribeiro, J.B. Sousa, C. Diniz e M.P.M. Marques
\nPLoS ONE\u00a011<\/strong>, e0167218 (2016).<\/p>\n

Chemotherapeutic Response to Cisplatin-like Drugs in Human Breast Cancer Cells Probed by Vibrational Microspectroscopy<\/a>
\nA.L.M. Batista de Carvalho, M. Pilling, P. Gardner, J. Doherty, G. Cinque, K. Wehbe, C. Kelley, L.A.E. Batista de Carvalho, M.P.M. Marques
\nFaraday Discussions\u00a0187<\/strong>, 273-298 (2016)<\/p>\n","protected":false},"excerpt":{"rendered":"

Cisplatin is one of the most widely used antineoplastic compounds, since its serendipitous discovery in the 1960\u00b4s. However, its severe side effects and acquired resistance have led to an intense search for new generation Pt(II) and Pd(II) agents, aiming at an improved cytotoxic profile coupled to a lower toxicity. Polynuclear chelates with polyamines (PAs) as […]<\/p>\n","protected":false},"author":1,"featured_media":0,"parent":596,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"footnotes":""},"class_list":["post-1354","page","type-page","status-publish","hentry"],"_links":{"self":[{"href":"https:\/\/qfm.uc.pt\/index.html\/wp-json\/wp\/v2\/pages\/1354","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/qfm.uc.pt\/index.html\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/qfm.uc.pt\/index.html\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/qfm.uc.pt\/index.html\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/qfm.uc.pt\/index.html\/wp-json\/wp\/v2\/comments?post=1354"}],"version-history":[{"count":0,"href":"https:\/\/qfm.uc.pt\/index.html\/wp-json\/wp\/v2\/pages\/1354\/revisions"}],"up":[{"embeddable":true,"href":"https:\/\/qfm.uc.pt\/index.html\/wp-json\/wp\/v2\/pages\/596"}],"wp:attachment":[{"href":"https:\/\/qfm.uc.pt\/index.html\/wp-json\/wp\/v2\/media?parent=1354"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}