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Cancer chemotherapeutic agents using a nanotechnological approach

2021-09Tese de doutoramento Acesso aberto
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datacite.subject.fosCiências Médicas::Medicina Básicapt_PT
dc.contributor.advisorGaspar, Maria Manuela
dc.contributor.advisorSoveral, Graça
dc.contributor.advisorCasini, Angela
dc.contributor.authorPinho, Jacinta O.
dc.date.accessioned2021-12-13T15:08:49Z
dc.date.available2024-10-26T00:30:34Z
dc.date.issued2021-09
dc.date.submitted2021-06
dc.description.abstractThe complexity and aggressiveness of cancer, as well as its increasing incidence and mortality worldwide, prompts the search for novel and alternative therapeutic strategies with improved effectiveness and safety. In this sense, the identification of therapeutic targets, the discovery of new molecules with antitumor potential, and the design of drug delivery systems create opportunities for a successful cancer management. Among compounds with promising anticancer activity are metal-based complexes and hybrid molecules, with some already approved for clinical use and others undergoing clinical trials or in preclinical research. In the present work, two compounds with promising anticancer potential were studied, the Cu2+ complex Cuphen [Cu(phen)Cl2] and a dual acting hybrid molecule, HM, containing two moieties – a DNA alkylating triazene and a ʟ-tyrosine analogue, 4-S-CAP, with high specificity for tyrosinase. Cuphen may act through the modulation of aquaporins (AQPs), inhibiting AQP3-mediated glycerol transport and affecting cell migration. In turn, the dual acting HM demonstrated a superior antiproliferative activity compared to the clinically approved temozolomide. Also, HM significantly inhibited tyrosinase activity and arrested cell cycle in G0/G1 phase. Following these promising in vitro results, the next goal was to maximize the in vivo therapeutic efficacy of these compounds by exploring the versatility of the most successful lipid-based nanosystem, liposomes. Long circulating liposomal formulations, with suitable physicochemical properties for each molecule, were designed and evaluated in preclinical studies. In the case of Cuphen, liposomes with pH-sensitive properties were designed to promote a locally-triggered release at the slightly acidic tumor microenvironment. In vivo, liposomal Cuphen significantly reduced melanoma and colon cancer progression, compared to free form. Furthermore, Cuphen liposomes displaying magnetic properties were successfully developed for further increase their accumulation at tumor sites upon application of an external magnetic field. For HM, an efficient incorporation in long circulating liposomes was obtained. In a subcutaneous murine melanoma model, liposomal HM remarkably reduced tumor progression, compared to free HM. Moreover, in a syngeneic metastatic melanoma model, a reduction on the number of lung metastases was observed for liposomal HM compared to all groups, including the positive control temozolomide. Remarkably, in the subcutaneous melanoma model, biodistribution studies of LIP HM showed that, 48 h post-administration, 4% of the injected dose per gram of tumor was attained, correlating with the obtained therapeutic activity. Importantly, all developed nanoformulations, for both anticancer compounds, demonstrated to be safe for parenteral administration, in healthy animals, not eliciting hepatic toxic side effects neither hemolytic activity. Furthermore, the long-term stability of liposomes in lyophilized form was achieved using an appropriate cryoprotectant. In conclusion, these encouraging results demonstrate the advantages of exploring novel therapeutic targets and compounds, particularly when associated to liposomes as a delivery system, to potentiate their safety and therapeutic effectiveness for cancer management.pt_PT
dc.description.provenanceSubmitted by Paula Guerreiro (passarinho@reitoria.ulisboa.pt) on 2021-11-25T15:42:26Z No. of bitstreams: 1 ulsd737094_td_Jacinta_Pinho.pdf: 9327057 bytes, checksum: cb024fbaa1e456452b07bdacc998cc87 (MD5)en
dc.description.provenanceMade available in DSpace on 2021-12-13T15:08:49Z (GMT). No. of bitstreams: 1 ulsd737094_td_Jacinta_Pinho.pdf: 9327057 bytes, checksum: cb024fbaa1e456452b07bdacc998cc87 (MD5) Previous issue date: 2021-09en
dc.identifier.tid101617836pt_PT
dc.identifier.urihttp://hdl.handle.net/10451/50382
dc.language.isoengpt_PT
dc.relationSFRH/BD117586/2016pt_PT
dc.relationPTDC/MEDQUI/31721/2017pt_PT
dc.subjectcancropt_PT
dc.subjectcomplexo de cobrept_PT
dc.subjectmolécula híbridapt_PT
dc.subjectalvos terapêuticospt_PT
dc.subjectlipossomaspt_PT
dc.subjectcancerpt_PT
dc.subjectcopper-based complexpt_PT
dc.subjecthybrid moleculept_PT
dc.subjectnovel targetspt_PT
dc.subjectlong circulating liposomespt_PT
dc.titleCancer chemotherapeutic agents using a nanotechnological approachpt_PT
dc.typedoctoral thesis
dspace.entity.typePublication
oaire.awardNumberPTDC/BTM-SAL/28977/2017
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBTM-SAL%2F28977%2F2017/PT
oaire.fundingStream3599-PPCDT
person.familyNameO. Pinho
person.givenNameJacinta
person.identifier.ciencia-id3917-1B44-2048
person.identifier.orcid0000-0001-7725-4701
person.identifier.ridQ-7287-2017
person.identifier.scopus-author-id57205600024
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.contributor.authoremailrepositorio@reitoria.ulisboa.pt
rcaap.rightsopenAccesspt_PT
rcaap.typedoctoralThesispt_PT
relation.isAuthorOfPublicationeb27ba92-529f-43ff-b84b-640615431264
relation.isAuthorOfPublication.latestForDiscoveryeb27ba92-529f-43ff-b84b-640615431264
relation.isProjectOfPublicationd228a8b2-d247-4bcc-9db0-bcb2318aafc5
relation.isProjectOfPublication.latestForDiscoveryd228a8b2-d247-4bcc-9db0-bcb2318aafc5
thesis.degree.nameTese de doutoramento, Farmácia (Tecnologia Farmacêutica), Universidade de Lisboa, Faculdade de Farmácia, 2021pt_PT

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