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Tetraoxane-based tumor-activated prodrug strategy to target intracellular labile ferrous iron

2022-09Tese de doutoramento Acesso restrito
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datacite.subject.fosCiências Médicas::Medicina Básicapt_PT
dc.contributor.advisorMoreira, Rui Ferreira Alves
dc.contributor.advisorLopes, Francisca da Conceição
dc.contributor.advisorRodrigues, Cecília Maria Pereira
dc.contributor.authorMagalhães e Silva, Diogo
dc.date.accessioned2023-06-28T11:18:24Z
dc.date.available2023-06-28T11:18:24Z
dc.date.issued2022-09
dc.date.submitted2022-07
dc.description.abstractIron is a critical component in many cellular functions including DNA replication and repair, essential for cell vitality. However, iron metabolism dysregulation is associated with infectious diseases and cancer. Despite clinical precedent for iron-dependent pharmacology in antimalarial therapy with endoperoxides, tumour targeting strategies designed to exploit changes in iron homeostasis remain poorly studied. In this work, two tetraoxane-based Fe(II)-activable drug conjugate (FeADC) systems were developed as targeted therapy. Type I FeADCs spontaneously releases the cytotoxic payload after reaction with Fe(II). Ten type I FeADCs were obtained with different cytotoxic payloads for malaria and cancer. Type I FeADCs coupled with antimalarials were potent on the nanomolar range in chloroquine-sensitive strain. Type I FeADCs conjugated with doxorubicin showed high efficiency in reducing cellular viability in Fe(II)-rich cancer cell lines. Importantly, this FeADC was significantly less toxic to non-tumorigenic cells than the parent drug. Type I FeADC activity against Fe(II)-rich cancer cell lines was abrogated when incubated with the iron chelator desferoxamine (DFO). Type II FeADCs, in addition to the Fe(II)-activable tetraoxane scaffold shared with the type I system, also contains an unique structural feature that enables reaction with another metabolite, which is elevated in cancer. This feature only becomes available after endoperoxide activation by Fe(II), thus increasing the potential for improved selectivity. We have prepared a type II FeADC that showed high efficiency in reducing cellular viability in Fe(II)-rich cancer cell lines. Type II FeADC selectivity was evaluated in AML12 cells, being 200-fold less toxic than the parent drug. Importantly, our results also demonstrate that type II FeADC induced cell death is iron-dependent. In summary, the tetraoxane scaffold was validated as a drug delivery system for diseases with iron metabolism dysregulation.pt_PT
dc.description.provenanceSubmitted by Paula Guerreiro (passarinho@reitoria.ulisboa.pt) on 2023-05-24T14:45:03Z No. of bitstreams: 1 scnd741213_td_Diogo_Silva.pdf: 9654888 bytes, checksum: fa060e41097ef2d13496d71166c867fc (MD5)en
dc.description.provenanceMade available in DSpace on 2023-06-28T11:18:24Z (GMT). No. of bitstreams: 1 scnd741213_td_Diogo_Silva.pdf: 9654888 bytes, checksum: fa060e41097ef2d13496d71166c867fc (MD5) Previous issue date: 2022-09en
dc.description.sponsorshipLISBOA-01-0145-FEDER-016405pt_PT
dc.description.sponsorshipLISBOA-01-0145-FEDER-402-022125pt_PT
dc.identifier.tid101622031pt_PT
dc.identifier.urihttp://hdl.handle.net/10451/58385
dc.language.isoengpt_PT
dc.relationTetraoxane-based tumor-activated prodrug strategy to target intracellular labile ferrous iron
dc.relationPRECISION ONCOLOGY BY INNOVATIVE THERAPIES AND TECHNOLOGIES
dc.relationResearch Institute for Medicines
dc.subjectmetabolismo do ferropt_PT
dc.subjectião ferroso lábilpt_PT
dc.subject1,2,4,5-tetraoxanospt_PT
dc.subjectentrega de fármacospt_PT
dc.subjectpró-fármacospt_PT
dc.subjectiron metabolismpt_PT
dc.subjectlabile iron poolpt_PT
dc.subject1,2,4,5-tetraoxanespt_PT
dc.subjectdrug deliverypt_PT
dc.subjectprodrugspt_PT
dc.titleTetraoxane-based tumor-activated prodrug strategy to target intracellular labile ferrous ironpt_PT
dc.typedoctoral thesis
dspace.entity.typePublication
oaire.awardNumberSFRH/BD/132341/2017
oaire.awardNumberPTDC/MED-QUI/30021/2017
oaire.awardNumberSAICTPAC/0019/2015
oaire.awardNumberUID/DTP/04138/2019
oaire.awardTitleTetraoxane-based tumor-activated prodrug strategy to target intracellular labile ferrous iron
oaire.awardTitlePRECISION ONCOLOGY BY INNOVATIVE THERAPIES AND TECHNOLOGIES
oaire.awardTitleResearch Institute for Medicines
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F132341%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FMED-QUI%2F30021%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/9471 - RIDTI/SAICTPAC%2F0019%2F2015/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FDTP%2F04138%2F2019/PT
oaire.fundingStreamOE
oaire.fundingStream3599-PPCDT
oaire.fundingStream9471 - RIDTI
oaire.fundingStream6817 - DCRRNI ID
person.familyNameTrindade Fonseca Magalhães e Silva
person.givenNameDiogo Maria
person.identifierhttps://scholar.google.pt/citations?user=FbyS9g4AAAAJ&hl=pt-PT&oi=ao
person.identifier.ciencia-id2512-3B09-A896
person.identifier.orcid0000-0001-7576-5719
person.identifier.scopus-author-id56708930300
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.contributor.authoremailrepositorio@reitoria.ulisboa.pt
rcaap.rightsrestrictedAccesspt_PT
rcaap.typedoctoralThesispt_PT
relation.isAuthorOfPublication84c9a5b7-ea1b-4d3a-8cc3-1cb4247d04ee
relation.isAuthorOfPublication.latestForDiscovery84c9a5b7-ea1b-4d3a-8cc3-1cb4247d04ee
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relation.isProjectOfPublication.latestForDiscoveryd077bdcf-8aba-4492-9206-290959cf8d68
thesis.degree.nameTese de doutoramento, Farmácia (Química Farmacêutica e Terapêutica), Universidade de Lisboa, Faculdade de Farmácia, 2022pt_PT

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