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Intracellularly-Targeted Nanoplatform to Target Dendritic Cells and for Immunomodulation

2020-05Tese de doutoramento Acesso aberto
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datacite.subject.fosCiências Médicas::Medicina Básicapt_PT
dc.contributor.advisorFlorindo, Helena F.
dc.contributor.advisorGraça, Luís
dc.contributor.advisorPréat, Véronique
dc.contributor.authorPeres, Carina Sofia Gonçalves
dc.date.accessioned2020-12-14T11:54:45Z
dc.date.available2023-06-01T00:33:06Z
dc.date.issued2020-05
dc.date.submitted2019-12
dc.description.abstractTriple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Immunotherapy, notably cancer vaccines and immune checkpoint modulators, has emerged as a promising alternative therapy. However, limited efficacy has been obtained for cancer vaccines and severe immune-mediated side effects have been related to immune checkpoint inhibitors under clinical development. Thus, to overcome the main disadvantages presented by these two therapeutic options when used individually, and considering the heterogeneity of TNBC, combination therapies are under clinical development to treat this specific breast cancer subtype. We hypothesized that the development of a multifunctional nanovaccine could re-shape the tumour microenvironment (TME), sensitizing TNBC to the agonist immune checkpoint OX40, and thus, improving the overall anti-tumour immune response. For this purpose, a poly(lactic acid) (PLA) nanoparticle (NP)-based nanovaccine was designed and synthesized to target dendritic cells (DC) and the TME by incorporating TNBC-associated antigens, toll-like receptor ligands CpG and Poly(I:C), and siRNA to downregulate the potent immunosuppressive cytokine transforming growth factor-β (TGF-β). NP surface was modified by hyaluronic acid to promote DC activation, but also to potentiate their delivery to the TME by targeting CD44 receptor, overexpressed in TNBC cells. NPs presented a spherical-shape with an average diameter close to 200 nm, displaying narrow polydispersity index, near-neutral surface charge, and entrapment efficiencies (EE) superior to 85%. NPs were extensively taken up by both DC and TNBC cells, without affecting their viability. In addition, NPs induced DC activation and maturation, increasing significantly the expression of the surface markers. 4T1 tumour-bearing animals treated with the multifunctional nanovaccine combined with αOX40 showed a noteworthy tumour remission, with a higher overall survival and a tumour volume 4-fold lower than those obtained for αOX40-treated mice. The nanovaccine re-shaped the immune profiling within the TME, which correlated with the overall anti-tumour effect obtained in this combinatorial scheme. This study revealed the synergy between a multi-targeting nanovaccine and αOX40 in TNBC, providing important insights for the establishment of novel combination regimens against this tumour.pt_PT
dc.description.provenanceSubmitted by Paula Guerreiro (passarinho@reitoria.ulisboa.pt) on 2020-12-03T11:07:18Z No. of bitstreams: 1 ULSD897323_td_Carina_Peres.pdf: 3333360 bytes, checksum: e96e34b8f41ff4b7477bff451dbfd2cc (MD5)en
dc.description.provenanceMade available in DSpace on 2020-12-14T11:54:45Z (GMT). No. of bitstreams: 1 ULSD897323_td_Carina_Peres.pdf: 3333360 bytes, checksum: e96e34b8f41ff4b7477bff451dbfd2cc (MD5) Previous issue date: 2020-05en
dc.description.sponsorshipResearch project ENMed/0003/2015 under the framework of EuroNanoMed-Ipt_PT
dc.description.sponsorshipResearch project ENMed/0051/2016 under the framework of EuroNanoMed-IIpt_PT
dc.identifier.tid101460830pt_PT
dc.identifier.urihttp://hdl.handle.net/10451/45275
dc.language.isoengpt_PT
dc.relationSFRH/BD/ 87591 /2012pt_PT
dc.relationTherMelVac- dendritic cell-targeted peptide vaccine against melanoma by ligand-modified nanoparticles
dc.relationPRECISION ONCOLOGY BY INNOVATIVE THERAPIES AND TECHNOLOGIES
dc.relationStrategic Project - UI 4013 - 2011-2012
dc.subjectvaccinept_PT
dc.subjecttriple-negative breast cancerpt_PT
dc.subjectnanomedicinept_PT
dc.subjecttumour microenvironmentpt_PT
dc.subjectimmune checkpointspt_PT
dc.titleIntracellularly-Targeted Nanoplatform to Target Dendritic Cells and for Immunomodulationpt_PT
dc.typedoctoral thesis
dspace.entity.typePublication
oaire.awardNumberPTDC/SAU-FAR/119389/2010
oaire.awardNumberUTAP-ICDT/DTP-FTO/0016/2014
oaire.awardNumberSAICTPAC/0019/2015
oaire.awardNumberUID/DTP/04138/2013
oaire.awardNumberPEst-OE/SAU/UI4013/2011
oaire.awardTitleTherMelVac- dendritic cell-targeted peptide vaccine against melanoma by ligand-modified nanoparticles
oaire.awardTitlePRECISION ONCOLOGY BY INNOVATIVE THERAPIES AND TECHNOLOGIES
oaire.awardTitleStrategic Project - UI 4013 - 2011-2012
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FSAU-FAR%2F119389%2F2010/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/UTAP-ICDT%2FDTP-FTO%2F0016%2F2014/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/9471 - RIDTI/SAICTPAC%2F0019%2F2015/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FDTP%2F04138%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/PEst-OE%2FSAU%2FUI4013%2F2011/PT
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
oaire.fundingStream9471 - RIDTI
oaire.fundingStream5876
oaire.fundingStream6817 - DCRRNI ID
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.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
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.contributor.authoremailrepositorio@reitoria.ulisboa.pt
rcaap.rightsopenAccesspt_PT
rcaap.typedoctoralThesispt_PT
relation.isProjectOfPublication31cdfbc1-952c-45c2-a626-93d1a7fecf93
relation.isProjectOfPublication99c84e8c-54c7-4a87-b2e4-f6a0da220b9e
relation.isProjectOfPublication7a25b129-19f8-47b3-a119-0c46d8e0bc70
relation.isProjectOfPublication3ea9d46e-a653-42ed-aa04-6630ede070cc
relation.isProjectOfPublicationafe1e2c4-bb23-4b69-bb0d-dc960c217226
relation.isProjectOfPublication.latestForDiscovery3ea9d46e-a653-42ed-aa04-6630ede070cc
thesis.degree.nameTese de doutoramento, Farmácia (Tecnologia Farmacêutica), Universidade de Lisboa, Faculdade de Farmácia, 2020pt_PT

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