Desenvolvimento de sistemas inteligentes de metalofármacos de ruténio para a terapia seletiva do cancro da mama metastático

Detalhes bibliográficos
Autor(a) principal: Sá, Marco Alexandre Pina de
Data de Publicação: 2023
Tipo de documento: Dissertação
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10451/58786
Resumo: Tese de mestrado, Química (Química), 2023, Universidade de Lisboa, Faculdade de Ciências
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spelling Desenvolvimento de sistemas inteligentes de metalofármacos de ruténio para a terapia seletiva do cancro da mama metastáticoCancro da mama metastáticoComplexos organometálicos de Ru(II)FGFRSistemas inteligentes de entrega de fármacosConjugados ruténio-péptidoTeses de mestrado - 2023Departamento de Química e BioquímicaTese de mestrado, Química (Química), 2023, Universidade de Lisboa, Faculdade de CiênciasBreast 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.Morais, Tânia Sofia Ferreira, 1980-Repositório da Universidade de LisboaSá, Marco Alexandre Pina de2023-07-28T09:23:23Z202320232023-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10451/58786engmetadata only accessinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T17:07:44Zoai:repositorio.ul.pt:10451/58786Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:08:55.885352Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Desenvolvimento de sistemas inteligentes de metalofármacos de ruténio para a terapia seletiva do cancro da mama metastático
title Desenvolvimento de sistemas inteligentes de metalofármacos de ruténio para a terapia seletiva do cancro da mama metastático
spellingShingle Desenvolvimento de sistemas inteligentes de metalofármacos de ruténio para a terapia seletiva do cancro da mama metastático
Sá, Marco Alexandre Pina de
Cancro da mama metastático
Complexos organometálicos de Ru(II)
FGFR
Sistemas inteligentes de entrega de fármacos
Conjugados ruténio-péptido
Teses de mestrado - 2023
Departamento de Química e Bioquímica
title_short Desenvolvimento de sistemas inteligentes de metalofármacos de ruténio para a terapia seletiva do cancro da mama metastático
title_full Desenvolvimento de sistemas inteligentes de metalofármacos de ruténio para a terapia seletiva do cancro da mama metastático
title_fullStr Desenvolvimento de sistemas inteligentes de metalofármacos de ruténio para a terapia seletiva do cancro da mama metastático
title_full_unstemmed Desenvolvimento de sistemas inteligentes de metalofármacos de ruténio para a terapia seletiva do cancro da mama metastático
title_sort Desenvolvimento de sistemas inteligentes de metalofármacos de ruténio para a terapia seletiva do cancro da mama metastático
author Sá, Marco Alexandre Pina de
author_facet Sá, Marco Alexandre Pina de
author_role author
dc.contributor.none.fl_str_mv Morais, Tânia Sofia Ferreira, 1980-
Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Sá, Marco Alexandre Pina de
dc.subject.por.fl_str_mv Cancro da mama metastático
Complexos organometálicos de Ru(II)
FGFR
Sistemas inteligentes de entrega de fármacos
Conjugados ruténio-péptido
Teses de mestrado - 2023
Departamento de Química e Bioquímica
topic Cancro da mama metastático
Complexos organometálicos de Ru(II)
FGFR
Sistemas inteligentes de entrega de fármacos
Conjugados ruténio-péptido
Teses de mestrado - 2023
Departamento de Química e Bioquímica
description Tese de mestrado, Química (Química), 2023, Universidade de Lisboa, Faculdade de Ciências
publishDate 2023
dc.date.none.fl_str_mv 2023-07-28T09:23:23Z
2023
2023
2023-01-01T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/masterThesis
format masterThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10451/58786
url http://hdl.handle.net/10451/58786
dc.language.iso.fl_str_mv eng
language eng
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eu_rights_str_mv openAccess
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dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
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collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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