Publicação
Porphyrinoid functionalized carbon nanomaterials for cancer therapies
| Resumo: | The quest for more effective cancer therapies is an ongoing and pressing challenge, as cancer remains one of the leading causes of mortality worldwide. This thesis explores the anticancer potential of new systems comprising carbon nanomaterials (as graphene oxide, GO, and graphene quantum dots, GQDs) and porphyrinoids (as porphyrins or phthalocyanines, Pcs). The new hybrid materials were characterized and tested in photodynamic therapy (PDT) or in deoxyribonucleic acid (DNA) G-quadruplex (G4) sensing and stabilization. Therefore, a comprehensive review of the state of the art was carried out initially, to understand the synthetic routes used to functionalize GO/GQDs with organic molecules (namely porphyrins and Pcs) through covalent and non-covalent bonds. The application of these systems in different cancer therapies was also summarized. The reported potential alongside with the detected gap in the knowledge allowed to define and justify the objectives of this thesis. Several porphyrins were synthesized, bearing structural features considered to be adequate to functionalize carbon nanomaterials. On a first approach, symmetric tetracationic porphyrins, such as 5,10,15,20-tetrakis(1-methyl-pyridinium-4-yl)porphyrin (TMPyP), its Zn(II) complex (Zn-TMPyP) and a dibenzoporphyrin (P1-C5), were successfully obtained through conventional synthetic pathways involving, for example, Rothemund and Heck reactions and cationization through N-alkylation. On a second approach, several attempts were explored to functionalize the meso position of porphyrins’ macrocycle with terpyridine (tpy) units through Vilsmeier-Haack formylation, Suzuki-Miyaura coupling and Kröhnke-type reactions, among others. The synthesized tetracationic porphyrins (TMPyP, Zn-TMPyP and P1-C₅) were loaded onto GO/GQDs and the resulting hybrids were characterized by several spectroscopic techniques and electron microscopy. The new systems showed photo-antiproliferative activity in T24 human bladder cancer cells. Within this research context, Zn-TMPyP@GQDs were found to be the most promising hybrid nanomaterials. In a different application, four Zn(II) complexes of cationic Pcs (ZnPcs) were assembled on GO to develop multifunctional G4 optical sensors, based on a “turn-off-on” effect of their fluorescence properties. When compared with non-immobilized ZnPcs, ZnPcs@GO allowed to detect and stabilize G4s for longer periods, through a progressive release of ZnPcs from GO platforms and concomitant fluorescence recovery. A novel approach was developed to synthesize functional hybrid nanomaterials, in which blue- or aqua green-emitting GQDs (GQDs-B/AG) were covalently attached to DNA sequences with the potential to fold as G4s. GQDs induced the luminescence and shaped the folding properties of the new arrays. The GQDs-DNA bioconjugates showed a higher potential to carry the porphyrin TMPyP, in comparison to the affinity between non-immobilized DNA sequences and TMPyP. Lastly, this thesis describes frontier research about more complex hybrid nanomaterials, comprising GO sheets functionalized with 5,10,15,20-tetra(pyridin-4-yl)porphyrin (TPyP) and gold nanoparticles (AuNPs). Despite its exploratory character, the presented research suggests that the porphyrin TPyP allows a higher organization of AuNPs over the GO sheets. Overall, the results obtained and discussed throughout this thesis highlight the potential of carbon nanomaterials to stabilize different types of porphyrinoids and boost their action in cancer therapies related to PDT or G4s. The as-found synergies show that this type of hybrid materials deserves further exploration towards future biomedical applications. |
|---|---|
| Autores principais: | Monteiro, Ana Rita Rodrigues Vilares Cabral |
| Assunto: | Cancer therapies Carbon nanomaterials DNA G-quadruplex Gold nanoparticles Graphene oxide Graphene quantum dot Photodynamic therapy Phthalocyanine Porphyrin |
| Ano: | 2023 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Aveiro |
| Idioma: | inglês |
| Origem: | RIA - Repositório Institucional da Universidade de Aveiro |
| _version_ | 1877769332211056640 |
|---|---|
| author | Monteiro, Ana Rita Rodrigues Vilares Cabral |
| author_facet | Monteiro, Ana Rita Rodrigues Vilares Cabral |
| author_role | author |
| country_str | PT |
| creators_json_txt | [{\"Person.name\":\"Monteiro, Ana Rita Rodrigues Vilares Cabral\"}] |
| datacite.creators.creator.creatorName.fl_str_mv | Monteiro, Ana Rita Rodrigues Vilares Cabral |
| datacite.date.Accepted.fl_str_mv | 2023-05-09T00:00:00Z |
| datacite.date.available.fl_str_mv | 2025-06-13T10:45:10Z |
| datacite.date.embargoed.fl_str_mv | 2025-06-13T10:45:10Z |
| datacite.rights.fl_str_mv | http://purl.org/coar/access_right/c_abf2 |
| datacite.subjects.subject.fl_str_mv | Cancer therapies Carbon nanomaterials DNA G-quadruplex Gold nanoparticles Graphene oxide Graphene quantum dot Photodynamic therapy Phthalocyanine Porphyrin |
| datacite.titles.title.fl_str_mv | Porphyrinoid functionalized carbon nanomaterials for cancer therapies |
| dc.creator.none.fl_str_mv | Monteiro, Ana Rita Rodrigues Vilares Cabral |
| dc.date.Accepted.fl_str_mv | 2023-05-09T00:00:00Z |
| dc.date.available.fl_str_mv | 2025-06-13T10:45:10Z |
| dc.date.embargoed.fl_str_mv | 2025-06-13T10:45:10Z |
| dc.description.none.fl_str_mv | A investigação em terapias de cancro mais efetivas é um importante desafio atual, uma vez que o cancro continua a ser uma das principais causas de mortalidade a nível global. Esta tese explora o potencial anticancerígeno de novos sistemas envolvendo nanomateriais de carbono como óxido de grafeno (GO) e pontos quânticos de grafeno (GQDs), com porfirinas ou ftalocianinas (Pcs). Os novos materiais foram caracterizados e testados em terapia fotodinâmica (PDT) e na deteção e estabilização de estruturas G-quadruplex (G4) de ácido desoxirribonucleico (ADN). Assim, a compreensão deste tópico envolveu uma avaliação inicial do estado da arte sobre as rotas sintéticas usadas para funcionalizar GO/GQDs com moléculas orgânicas (nomeadamente porfirinas e Pcs) através de ligações covalentes ou não-covalentes. Foi também sumariada a aplicação destes sistemas em diversas terapias de cancro. O potencial que está reportado para estes sistemas e as lacunas de conhecimento na área ajudaram a definir e a justificar, de modo integrador, os objetivos desta tese. Foram sintetizadas diversas porfirinas com características estruturais consideradas adequadas para a interação com nanomateriais de carbono. Em primeiro lugar, foram obtidas porfirinas tetracatiónicas simétricas, como a 5,10,15,20-tetraquis-(1-metilpiridínio-4-il)porfirina (TMPyP), o respetivo complexo de Zn(II) (Zn-TMPyP) e uma dibenzoporfirina (P1-C₅), através de rotas sintéticas que envolveram reações de Rothemund, Heck e cationizações através de N-alquilações. Seguidamente, foram exploradas estratégias para funcionalizar as posições meso de macrociclos porfirínicos com unidades de terpiridina (tpy), onde se recorreu, entre outras, a reações de formilação de Vilsmeier-Haack, Suzuki-Miyaura e do tipo-Kröhnke. As porfirinas tetracatiónicas sintetizadas (TMPyP, Zn-TMPyP, P1-C5) foram conjugadas com GO/GQDs e os híbridos resultantes foram caracterizados por diferentes técnicas espectroscópicas e por microscopia eletrónica. Os novos sistemas demonstraram atividade antiproliferativa em células de cancro da bexiga humana T24. Neste contexto de investigação, os nanomateriais híbridos Zn-TMPyP@GQDs revelaram-se os mais promissores. Numa aplicação diferente, quatro complexos de Zn(II) de Pcs catiónicas (ZnPcs) foram conjugados com GO, tendo-se desenvolvido sensores óticos de G4s baseados num efeito “turn-off-on” das suas propriedades de fluorescência. Quando comparados com complexos não-imobilizados, os híbridos ZnPcs@GO favoreceram a deteção e a estabilização de G4s por períodos mais longos, através da libertação progressiva das plataformas de GO, com concomitante recuperação de fluorescência do sistema. Desenvolveu-se uma nova abordagem para sintetizar nanomateriais híbridos funcionais, explorando-se a ligação covalente de GQDs (com emissão azul ou verde-azulada, GQDs-B/AG) a sequências de ADN, correspondentes a diferentes topologias de G4s. Obtiveram-se supraestruturas fluorescentes nas quais foram identificadas conformações de ADN distintas. Os bioconjugados de GQDs-ADN demonstraram maior potencial para transportar a porfirina TMPyP, em relação à afinidade demonstrada entre as sequências de ADN (não-imobilizadas) para TMPyP. Por último, descreve-se a investigação em nanomateriais híbridos mais complexos, constituídos por folhas de GO funcionalizadas com 5,10,15,20-tetra-(4-piridil)porfirina (TPyP) e nanopartículas de Au (AuNPs). Não obstante o seu caráter exploratório, os resultados obtidos sugerem que a porfirina TPyP permite uma maior organização das AuNPs nas folhas de GO. No geral, os resultados obtidos e discutidos ao longo desta tese salientam o potencial dos nanomateriais de carbono para estabilizarem diferentes porfirinóides e potenciarem a sua ação em terapias de cancro, relacionadas com PDT ou G4s. As sinergias encontradas demonstram que este tipo de materiais híbridos deve continuar a ser explorado para futuras aplicações biomédicas. |
| dc.format.none.fl_str_mv | application/pdf |
| dc.identifier.none.fl_str_mv | http://hdl.handle.net/10773/39109 |
| dc.language.none.fl_str_mv | eng |
| dc.rights.none.fl_str_mv | http://purl.org/coar/access_right/c_abf2 |
| dc.subject.none.fl_str_mv | Cancer therapies Carbon nanomaterials DNA G-quadruplex Gold nanoparticles Graphene oxide Graphene quantum dot Photodynamic therapy Phthalocyanine Porphyrin |
| dc.title.fl_str_mv | Porphyrinoid functionalized carbon nanomaterials for cancer therapies |
| dc.type.none.fl_str_mv | http://purl.org/coar/resource_type/c_db06 |
| description | The quest for more effective cancer therapies is an ongoing and pressing challenge, as cancer remains one of the leading causes of mortality worldwide. This thesis explores the anticancer potential of new systems comprising carbon nanomaterials (as graphene oxide, GO, and graphene quantum dots, GQDs) and porphyrinoids (as porphyrins or phthalocyanines, Pcs). The new hybrid materials were characterized and tested in photodynamic therapy (PDT) or in deoxyribonucleic acid (DNA) G-quadruplex (G4) sensing and stabilization. Therefore, a comprehensive review of the state of the art was carried out initially, to understand the synthetic routes used to functionalize GO/GQDs with organic molecules (namely porphyrins and Pcs) through covalent and non-covalent bonds. The application of these systems in different cancer therapies was also summarized. The reported potential alongside with the detected gap in the knowledge allowed to define and justify the objectives of this thesis. Several porphyrins were synthesized, bearing structural features considered to be adequate to functionalize carbon nanomaterials. On a first approach, symmetric tetracationic porphyrins, such as 5,10,15,20-tetrakis(1-methyl-pyridinium-4-yl)porphyrin (TMPyP), its Zn(II) complex (Zn-TMPyP) and a dibenzoporphyrin (P1-C5), were successfully obtained through conventional synthetic pathways involving, for example, Rothemund and Heck reactions and cationization through N-alkylation. On a second approach, several attempts were explored to functionalize the meso position of porphyrins’ macrocycle with terpyridine (tpy) units through Vilsmeier-Haack formylation, Suzuki-Miyaura coupling and Kröhnke-type reactions, among others. The synthesized tetracationic porphyrins (TMPyP, Zn-TMPyP and P1-C₅) were loaded onto GO/GQDs and the resulting hybrids were characterized by several spectroscopic techniques and electron microscopy. The new systems showed photo-antiproliferative activity in T24 human bladder cancer cells. Within this research context, Zn-TMPyP@GQDs were found to be the most promising hybrid nanomaterials. In a different application, four Zn(II) complexes of cationic Pcs (ZnPcs) were assembled on GO to develop multifunctional G4 optical sensors, based on a “turn-off-on” effect of their fluorescence properties. When compared with non-immobilized ZnPcs, ZnPcs@GO allowed to detect and stabilize G4s for longer periods, through a progressive release of ZnPcs from GO platforms and concomitant fluorescence recovery. A novel approach was developed to synthesize functional hybrid nanomaterials, in which blue- or aqua green-emitting GQDs (GQDs-B/AG) were covalently attached to DNA sequences with the potential to fold as G4s. GQDs induced the luminescence and shaped the folding properties of the new arrays. The GQDs-DNA bioconjugates showed a higher potential to carry the porphyrin TMPyP, in comparison to the affinity between non-immobilized DNA sequences and TMPyP. Lastly, this thesis describes frontier research about more complex hybrid nanomaterials, comprising GO sheets functionalized with 5,10,15,20-tetra(pyridin-4-yl)porphyrin (TPyP) and gold nanoparticles (AuNPs). Despite its exploratory character, the presented research suggests that the porphyrin TPyP allows a higher organization of AuNPs over the GO sheets. Overall, the results obtained and discussed throughout this thesis highlight the potential of carbon nanomaterials to stabilize different types of porphyrinoids and boost their action in cancer therapies related to PDT or G4s. The as-found synergies show that this type of hybrid materials deserves further exploration towards future biomedical applications. |
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| person_str_mv | Monteiro, Ana Rita Rodrigues Vilares Cabral |
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| spelling | pt_PTThe quest for more effective cancer therapies is an ongoing and pressing challenge, as cancer remains one of the leading causes of mortality worldwide. This thesis explores the anticancer potential of new systems comprising carbon nanomaterials (as graphene oxide, GO, and graphene quantum dots, GQDs) and porphyrinoids (as porphyrins or phthalocyanines, Pcs). The new hybrid materials were characterized and tested in photodynamic therapy (PDT) or in deoxyribonucleic acid (DNA) G-quadruplex (G4) sensing and stabilization. Therefore, a comprehensive review of the state of the art was carried out initially, to understand the synthetic routes used to functionalize GO/GQDs with organic molecules (namely porphyrins and Pcs) through covalent and non-covalent bonds. The application of these systems in different cancer therapies was also summarized. The reported potential alongside with the detected gap in the knowledge allowed to define and justify the objectives of this thesis. Several porphyrins were synthesized, bearing structural features considered to be adequate to functionalize carbon nanomaterials. On a first approach, symmetric tetracationic porphyrins, such as 5,10,15,20-tetrakis(1-methyl-pyridinium-4-yl)porphyrin (TMPyP), its Zn(II) complex (Zn-TMPyP) and a dibenzoporphyrin (P1-C5), were successfully obtained through conventional synthetic pathways involving, for example, Rothemund and Heck reactions and cationization through N-alkylation. On a second approach, several attempts were explored to functionalize the meso position of porphyrins’ macrocycle with terpyridine (tpy) units through Vilsmeier-Haack formylation, Suzuki-Miyaura coupling and Kröhnke-type reactions, among others. The synthesized tetracationic porphyrins (TMPyP, Zn-TMPyP and P1-C₅) were loaded onto GO/GQDs and the resulting hybrids were characterized by several spectroscopic techniques and electron microscopy. The new systems showed photo-antiproliferative activity in T24 human bladder cancer cells. Within this research context, Zn-TMPyP@GQDs were found to be the most promising hybrid nanomaterials. In a different application, four Zn(II) complexes of cationic Pcs (ZnPcs) were assembled on GO to develop multifunctional G4 optical sensors, based on a “turn-off-on” effect of their fluorescence properties. When compared with non-immobilized ZnPcs, ZnPcs@GO allowed to detect and stabilize G4s for longer periods, through a progressive release of ZnPcs from GO platforms and concomitant fluorescence recovery. A novel approach was developed to synthesize functional hybrid nanomaterials, in which blue- or aqua green-emitting GQDs (GQDs-B/AG) were covalently attached to DNA sequences with the potential to fold as G4s. GQDs induced the luminescence and shaped the folding properties of the new arrays. The GQDs-DNA bioconjugates showed a higher potential to carry the porphyrin TMPyP, in comparison to the affinity between non-immobilized DNA sequences and TMPyP. Lastly, this thesis describes frontier research about more complex hybrid nanomaterials, comprising GO sheets functionalized with 5,10,15,20-tetra(pyridin-4-yl)porphyrin (TPyP) and gold nanoparticles (AuNPs). Despite its exploratory character, the presented research suggests that the porphyrin TPyP allows a higher organization of AuNPs over the GO sheets. Overall, the results obtained and discussed throughout this thesis highlight the potential of carbon nanomaterials to stabilize different types of porphyrinoids and boost their action in cancer therapies related to PDT or G4s. The as-found synergies show that this type of hybrid materials deserves further exploration towards future biomedical applications.pt_PTA investigação em terapias de cancro mais efetivas é um importante desafio atual, uma vez que o cancro continua a ser uma das principais causas de mortalidade a nível global. Esta tese explora o potencial anticancerígeno de novos sistemas envolvendo nanomateriais de carbono como óxido de grafeno (GO) e pontos quânticos de grafeno (GQDs), com porfirinas ou ftalocianinas (Pcs). Os novos materiais foram caracterizados e testados em terapia fotodinâmica (PDT) e na deteção e estabilização de estruturas G-quadruplex (G4) de ácido desoxirribonucleico (ADN). Assim, a compreensão deste tópico envolveu uma avaliação inicial do estado da arte sobre as rotas sintéticas usadas para funcionalizar GO/GQDs com moléculas orgânicas (nomeadamente porfirinas e Pcs) através de ligações covalentes ou não-covalentes. Foi também sumariada a aplicação destes sistemas em diversas terapias de cancro. O potencial que está reportado para estes sistemas e as lacunas de conhecimento na área ajudaram a definir e a justificar, de modo integrador, os objetivos desta tese. Foram sintetizadas diversas porfirinas com características estruturais consideradas adequadas para a interação com nanomateriais de carbono. Em primeiro lugar, foram obtidas porfirinas tetracatiónicas simétricas, como a 5,10,15,20-tetraquis-(1-metilpiridínio-4-il)porfirina (TMPyP), o respetivo complexo de Zn(II) (Zn-TMPyP) e uma dibenzoporfirina (P1-C₅), através de rotas sintéticas que envolveram reações de Rothemund, Heck e cationizações através de N-alquilações. Seguidamente, foram exploradas estratégias para funcionalizar as posições meso de macrociclos porfirínicos com unidades de terpiridina (tpy), onde se recorreu, entre outras, a reações de formilação de Vilsmeier-Haack, Suzuki-Miyaura e do tipo-Kröhnke. As porfirinas tetracatiónicas sintetizadas (TMPyP, Zn-TMPyP, P1-C5) foram conjugadas com GO/GQDs e os híbridos resultantes foram caracterizados por diferentes técnicas espectroscópicas e por microscopia eletrónica. Os novos sistemas demonstraram atividade antiproliferativa em células de cancro da bexiga humana T24. Neste contexto de investigação, os nanomateriais híbridos Zn-TMPyP@GQDs revelaram-se os mais promissores. Numa aplicação diferente, quatro complexos de Zn(II) de Pcs catiónicas (ZnPcs) foram conjugados com GO, tendo-se desenvolvido sensores óticos de G4s baseados num efeito “turn-off-on” das suas propriedades de fluorescência. Quando comparados com complexos não-imobilizados, os híbridos ZnPcs@GO favoreceram a deteção e a estabilização de G4s por períodos mais longos, através da libertação progressiva das plataformas de GO, com concomitante recuperação de fluorescência do sistema. Desenvolveu-se uma nova abordagem para sintetizar nanomateriais híbridos funcionais, explorando-se a ligação covalente de GQDs (com emissão azul ou verde-azulada, GQDs-B/AG) a sequências de ADN, correspondentes a diferentes topologias de G4s. Obtiveram-se supraestruturas fluorescentes nas quais foram identificadas conformações de ADN distintas. Os bioconjugados de GQDs-ADN demonstraram maior potencial para transportar a porfirina TMPyP, em relação à afinidade demonstrada entre as sequências de ADN (não-imobilizadas) para TMPyP. Por último, descreve-se a investigação em nanomateriais híbridos mais complexos, constituídos por folhas de GO funcionalizadas com 5,10,15,20-tetra-(4-piridil)porfirina (TPyP) e nanopartículas de Au (AuNPs). Não obstante o seu caráter exploratório, os resultados obtidos sugerem que a porfirina TPyP permite uma maior organização das AuNPs nas folhas de GO. No geral, os resultados obtidos e discutidos ao longo desta tese salientam o potencial dos nanomateriais de carbono para estabilizarem diferentes porfirinóides e potenciarem a sua ação em terapias de cancro, relacionadas com PDT ou G4s. As sinergias encontradas demonstram que este tipo de materiais híbridos deve continuar a ser explorado para futuras aplicações biomédicas.application/pdfengpt_PTPorphyrinoid functionalized carbon nanomaterials for cancer therapiesMonteiro, Ana Rita Rodrigues Vilares CabralHandlehttp://hdl.handle.net/10773/391092025-06-13T10:45:10Z2023-05-09T00:00:00Z2023-05-09http://purl.org/coar/access_right/c_abf2open accesspt_PTCancer therapiespt_PTCarbon nanomaterialspt_PTDNA G-quadruplexpt_PTGold nanoparticlespt_PTGraphene oxidept_PTGraphene quantum dotpt_PTPhotodynamic therapypt_PTPhthalocyaninept_PTPorphyrin42074489 byteshttp://purl.org/coar/access_right/c_abf2application/pdffulltexthttps://ria.ua.pt/bitstream/10773/39109/1/Documento_Ana_Rita_Monteiro.pdfother research producthttp://purl.org/coar/resource_type/c_db06doctoral thesis |
| spellingShingle | Porphyrinoid functionalized carbon nanomaterials for cancer therapies Monteiro, Ana Rita Rodrigues Vilares Cabral Cancer therapies Carbon nanomaterials DNA G-quadruplex Gold nanoparticles Graphene oxide Graphene quantum dot Photodynamic therapy Phthalocyanine Porphyrin |
| status | SINGLETON |
| subject.fl_str_mv | Cancer therapies Carbon nanomaterials DNA G-quadruplex Gold nanoparticles Graphene oxide Graphene quantum dot Photodynamic therapy Phthalocyanine Porphyrin |
| title | Porphyrinoid functionalized carbon nanomaterials for cancer therapies |
| title_full | Porphyrinoid functionalized carbon nanomaterials for cancer therapies |
| title_fullStr | Porphyrinoid functionalized carbon nanomaterials for cancer therapies |
| title_full_unstemmed | Porphyrinoid functionalized carbon nanomaterials for cancer therapies |
| title_short | Porphyrinoid functionalized carbon nanomaterials for cancer therapies |
| title_sort | Porphyrinoid functionalized carbon nanomaterials for cancer therapies |
| topic | Cancer therapies Carbon nanomaterials DNA G-quadruplex Gold nanoparticles Graphene oxide Graphene quantum dot Photodynamic therapy Phthalocyanine Porphyrin |
| topic_facet | Cancer therapies Carbon nanomaterials DNA G-quadruplex Gold nanoparticles Graphene oxide Graphene quantum dot Photodynamic therapy Phthalocyanine Porphyrin |
| url | http://hdl.handle.net/10773/39109 |
| visible | 1 |
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