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Desenvolvimento de sistemas inteligentes de metalofármacos de ruténio para a terapia seletiva do cancro da mama metastático
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Resumo(s)
Breast cancer remains the most common and lethal subtype of cancer among women worldwide,
tith more than 2.26 million cases were diagnosed only in 2020.Metastatic breast cancer (MBC)
represents the advanced stage of the disease and is considered incurable. Patients with MBC are typically
treated with drugs that are used in other types of cancer. Ruthenium-based compounds have emerged as
promising candidates to platinum-based drugs due to their unique chemical and pharmacological
properties, such as high antitumoral and antimetastatic activities. However, their intrinsic selectivity is
not sufficient, and they still exhibit some toxicity, limiting their clinical use.
To address these challenges, this master's thesis aims to develop novel ruthenium metallodrugs
that can provide a more efficient and less toxic therapeutic approach for the treatment of MBC. The
approach involves the development of smart ruthenium metallodrugs delivery systems that enable
controlled release of the cytotoxic complex specifically in the target, sparing healthy tissues and
reducing toxicity.
One strategy to achieve selective drug delivery involves the use of peptides as vectorization
systems. Peptides have shown selectivity and affinity for receptors that are overexpressed in tumor cells,
enabling preferential accumulation of the drug at the tumor site. The fibroblast growth factor receptor
(FGFR), which is often overexpressed in breast cancer, and is associated with metastasis and recurrence
of the disease, has been identified as an interesting target for the treatment of MBC.
The smart metallodrug delivery systems explored in this thesis consist of a cytotoxic rutheniumcyclopentadienyl (RuCp) complex conjugated to a peptide with high affinity for FGFR, through a pHsensitive linker. This design aims to exploit the small pH difference between the tumor
microenvironment (pH 6.8) and healthy tissues (pH 7.4) to achieve selective and controlled release of
the cytotoxic complex within tumor cells.
In this work were synthesized two new bipyridine ligands, four new RuCp complexes, two new
peptides, and two Ru-peptide conjugates (RuPC).
The new ruthenium complexes and the monofunctionalized bipyridines were characterized by
several spectroscopic techniques that allowed to confirm the proposed structures, such as Fouriertransform infrared spectroscopy (FT-IR), ultraviolet–visible spectrophotometry (UV-vis), proton
nuclear magnetic resonance (1H NMR), phosphorus nuclear magnetic resonance (31P NMR) and carbon
nuclear magnetic resonance (13C NMR) and by two-dimensional NMR techniques. Elemental analysis
of the complexes allowed to evaluate their purity. Complex 3 was also characterized by analytical
reversed phase high performance liquid chromatography (RP-HPLC) and electrospray ionization mass
spectrometry (ESI-MS). The stability of the complexes was evaluated by UV-Vis in 100% DMSO and
5% DMSO/95% DMEM solutions, over 24 or 48 hours. All complexes showed to be stable to proceed
to biological assays. The partition coefficient in n-octanol/water of the complexes was also determined
and the complexes showed to be lipophilic.
The new peptides were characterized by RP-HPLC and ESI-MS. The peptides and RuPCs were
obtained with a purity superior to 90%, except the peptide P2 that was not obtained pure.
The release profile of the RuPC1 was evaluated by analytical RP-HPLC over 48 h, at two pH
values (6,8 and 7,4). The results suggest that the RuPC doesn’t have a suitable for a controlled release
of the active complex.
The cytotoxic activity of the conjugate RuPC1 and its free complex and peptide was evaluated
in four cell lines with different expression of the FGFR, at two different pH values (6,8 and 7,4). The results obtained indicate that RuPC does not show selectivity for cells that overexpress FGFR and that
do not take advantage of differences in pH.
These results are a good starting point for future work.
Descrição
Tese de mestrado, Química (Química), 2023, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Cancro da mama metastático Complexos organometálicos de Ru(II) FGFR Sistemas inteligentes de entrega de fármacos Conjugados ruténio-péptido Teses de mestrado - 2023