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Polymer-metal based compounds to target (non)hormone-responsive cancers : synthesis and mechanistic evaluation
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Cancer is the second leading cause of death worldwide being responsible for 9.6 million deaths of a total of 18.1 million new cases in 2018. In particular, breast cancer is the most commonly diagnosed and the leading cause of death in women. Among the several types of breast cancers, the triple negative breast cancer, which is estrogen receptor negative (ER-), progesterone receptor negative (PR-) and human epidermal growth factor receptor 2 negative (HER2-) is known for its typical highly metastatic profile, with inferior prognosis and for which there is still no available effective targeted therapy. Thus, the investment in the research of new chemotherapeutic agents in this area is crucial and imperative. Within this PhD project, six new organic ligands and eighteen new ruthenium(II) cyclopentadienyl compounds were synthesized and fully characterized. These complexes were divided in three different families with the general formula [Ru(Cp)(P)(bipy)]+, where cyclopentadienyl (Cp), phosphane (P) and bipyridyl (bipy) moieties were functionalized with different groups in order to include a macromolecular ligand (polylactide - PLA and/or polyethylene glycol - PEG) and a biomolecule (biotin or curcumin) to enhance the selectivity of compounds to cancer cells, exploring both passive and active cancer targeting strategies. To assess the biological potential of the new compounds an array of in vitro studies aiming at establishing structure-activity relations was performed. The studies in hormone and nonhormone-responsive cancer cell lines encompassed the assessment of cytotoxicity, cell death, intracellular distribution (drug internalization) and anti-metastatic ability (colony formation assay) of compounds. Multidrug resistance for selected compounds on the main ABC transporters was also studied by flow cytometry. Finally, compounds’ toxicity was assessed using a zebrafish model and the lead compounds were subjected to preliminary in vivo studies using a nude mice animal model bearing triple negative breast cancer orthotopic tumors where their toxicity and efficacy on primary tumors and metastases was evaluated.
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Anticancer agents Ruthenium(II) cyclopentadienyl complexes Targeted therapies Polymer-metal conjugates Triple negative breast cancer