Development of graphene oxide-based hydrogels for cancer therapy

Detalhes bibliográficos
Autor(a) principal: Costa, Francisco José Palácio
Data de Publicação: 2022
Tipo de documento: Dissertação
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10400.6/13193
Resumo: Breast cancer is a major cause of death of women worldwide. This high mortality rate is a consequence of the limitations of the currently used therapies, such as surgery, chemotherapy and radiotherapy. Such therapies exhibit a poor efficacy and induce several side effects. Therefore, the development of new therapies is imperative. Along the years, researchers have developed several types of nanomaterials (e.g. dendrimers, liposomes, micelles) for application in different anticancer modalities. Recently, the focus has turned towards the photothermal capacity of some nanomaterials. When irradiated with Near Infrared (NIR; 750 – 1000 nm) light, these nanomaterials can absorb its energy, releasing it as heat that induces damage in cancer cells. These light-responsive nanomaterials can also accommodate drugs in their structure, enabling their use in combinatorial therapeutic approaches. However, the nanomaterials are commonly administered by intravenous injection, which is not ideal considering the weak tumor-homing capacity of systemically administered nanomaterials, leading to a subpar outcome. Due to that, new technologies capable of delivering nanoparticles directly into the tumor tissue are under investigation. In particular, hydrogels formed through Thiol-Maleimide Michael type additions display potential to this application owing to their ability to incorporate high doses of nanoparticles into their compact 3D structure, as well as good chemical selectivity, biocompatibility, and simple production. However, such hydrogels have been mostly prepared using synthetic polymers, which are not ideal considering their non-biodegradability. Herein, a novel Thiol-Maleimide crosslinked hydrogel, engineered using natural polymers, was produced for application in the chemo-photothermal therapy of breast cancer cells. To obtain natural polymers compatible with this crosslinking chemistry, Hyaluronic Acid was decorated with Thiol groups and deacetylated Chitosan was grafted with Maleimide groups. Simultaneously, Dopamine-reduced Graphene Oxide was produced and loaded with Doxorubicin (DOX/DOPA-rGO) to create NIR light responsive nanomaterial with chemo-photothermal capabilities. In order to formulate the Thiol-Maleimide crosslinked hydrogels incorporating this therapeutic nano-agent (DOX/DOPA-rGO@TMgel), a simple mixture of Hyaluronic acid-Thiol, deacetylated Chitosan-Maleimide and DOX/DOPA-rGO was performed. In in vitro studies, when breast cancer cells were incubated with DOPA-rGO@TMgel and exposed to NIR ligh (photothermal therapy), their viability was reduced to about 59 %. On the other hand, DOX/DOPA-rGO@TMgel (chemotherapy) reduced cancer cells’ viability to 50 %. In stark contrast, the combined action of DOX/DOPA-rGO@TMgel and NIR light decreased breast cancer cells’ viability to just 21 %, highlighting its chemo-phototherapeutic potential.
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spelling Development of graphene oxide-based hydrogels for cancer therapyCancroHidrogéis Tiol-MaleimidaNanomateriais da Família do GrafenoSistemas de Entrega à Macro-EscalaTerapia Quimio-FototérmicaDomínio/Área Científica::Engenharia e Tecnologia::BiotecnologiaBreast cancer is a major cause of death of women worldwide. This high mortality rate is a consequence of the limitations of the currently used therapies, such as surgery, chemotherapy and radiotherapy. Such therapies exhibit a poor efficacy and induce several side effects. Therefore, the development of new therapies is imperative. Along the years, researchers have developed several types of nanomaterials (e.g. dendrimers, liposomes, micelles) for application in different anticancer modalities. Recently, the focus has turned towards the photothermal capacity of some nanomaterials. When irradiated with Near Infrared (NIR; 750 – 1000 nm) light, these nanomaterials can absorb its energy, releasing it as heat that induces damage in cancer cells. These light-responsive nanomaterials can also accommodate drugs in their structure, enabling their use in combinatorial therapeutic approaches. However, the nanomaterials are commonly administered by intravenous injection, which is not ideal considering the weak tumor-homing capacity of systemically administered nanomaterials, leading to a subpar outcome. Due to that, new technologies capable of delivering nanoparticles directly into the tumor tissue are under investigation. In particular, hydrogels formed through Thiol-Maleimide Michael type additions display potential to this application owing to their ability to incorporate high doses of nanoparticles into their compact 3D structure, as well as good chemical selectivity, biocompatibility, and simple production. However, such hydrogels have been mostly prepared using synthetic polymers, which are not ideal considering their non-biodegradability. Herein, a novel Thiol-Maleimide crosslinked hydrogel, engineered using natural polymers, was produced for application in the chemo-photothermal therapy of breast cancer cells. To obtain natural polymers compatible with this crosslinking chemistry, Hyaluronic Acid was decorated with Thiol groups and deacetylated Chitosan was grafted with Maleimide groups. Simultaneously, Dopamine-reduced Graphene Oxide was produced and loaded with Doxorubicin (DOX/DOPA-rGO) to create NIR light responsive nanomaterial with chemo-photothermal capabilities. In order to formulate the Thiol-Maleimide crosslinked hydrogels incorporating this therapeutic nano-agent (DOX/DOPA-rGO@TMgel), a simple mixture of Hyaluronic acid-Thiol, deacetylated Chitosan-Maleimide and DOX/DOPA-rGO was performed. In in vitro studies, when breast cancer cells were incubated with DOPA-rGO@TMgel and exposed to NIR ligh (photothermal therapy), their viability was reduced to about 59 %. On the other hand, DOX/DOPA-rGO@TMgel (chemotherapy) reduced cancer cells’ viability to 50 %. In stark contrast, the combined action of DOX/DOPA-rGO@TMgel and NIR light decreased breast cancer cells’ viability to just 21 %, highlighting its chemo-phototherapeutic potential.especialmente nas mulheres. A alta mortalidade desta doença está fortemente associada às limitações das terapias atualmente usadas em meio clínico, como a cirurgia, quimioterapia e radioterapia. Estas modalidades terapêuticas apresentam uma baixa eficácia e induzem diversos efeitos secundários no ser humano. Tais fatores revelam a necessidade de desenvolver novas terapias que sejam mais eficazes no tratamento desta doença. Neste contexto, ao longo dos anos, os investigadores têm desenvolvido diversos tipos de nanomateriais (p. ex. dendrímeros, lipossomas, micelas) para aplicação em diferentes modalidades terapêuticas anticancerígenas. Recentemente, as atenções voltaram-se para os nanomateriais com capacidade fototérmica. Estes, quando interagem com a luz com um comprimento de onda no infravermelho próximo (em inglês: Near Infrared (NIR); 750 – 1000 nm), conseguem absorver a sua energia, libertando-a sob a forma de calor, que pode induzir dano nas células cancerígenas. Os nanomateriais responsivos à luz NIR conseguem ainda encapsular fármacos, possibilitando o seu uso em terapia combinatória. Estes são geralmente administrados por injeção intravenosa. Contudo, os nanomateriais administrados por via sistémica são incapazes de atingir o tumor em quantidades elevadas, não tendo assim o efeito o terapêutico desejado. Desta forma, estão a ser desenvolvidas novas tecnologias capazes de entregar as nanopartículas diretamente no tecido tumoral. Em particular, os hidrogéis formados através de reações de adição tipo Michael entre os grupos Tiol e Maleimida adequam-se a esta aplicação devido à sua capacidade para incorporar altas doses de nanopartículas na sua estrutura 3D compacta. Para além disto, estes apresentam uma boa seletividade química, biocompatibilidade, e preparação simples. No entanto, os referidos hidrogéis têm sido, na sua maioria, preparados recorrendo a polímeros sintéticos, sendo que este fator não é ideal considerando a fraca biodegradabilidade destas moléculas. No trabalho de investigação desenvolvido no 2º ano deste ciclo de estudos, foi produzido um novo hidrogel, tendo por base polímeros naturais e posterior reticulação através da ligação Tiol-Maleimida, para aplicação na terapia quimio-fototérmica de células do cancro da mama. De modo que fossem obtidos polímeros naturais compatíveis com esta química de reticulação, o Ácido Hialurónico foi funcionalizado com grupos Tiol e o Quitosano desacetilado foi imobilizado com grupos Maleimida. Simultaneamente, o Óxido de Grafeno reduzido com Dopamina foi produzido e encapsulado com Doxorrubicina (DOX/DOPA-rGO), de forma a criar-se um nanomaterial responsivo à luz NIR com propriedades quimio-fototérmicas. Posteriormente, os hidrogéis reticulados pela ligação Tiol-Maleimida contendo este nano-agente terapêutico (DOX/DOPA-rGO@TMgel) foram preparados através de uma mistura simples dos seus precursores (Ácido Hialurónico-Tiol, Quitosano desacetilado-Maleimida e DOX/DOPA-rGO). Nos estudos in vitro, os resultados obtidos demonstraram que as células do cancro da mama expostas ao DOPA-rGO@TMgel juntamente com luz NIR tiveram uma redução na sua viabilidade para cerca de 59 %. Por outro lado, o DOX/DOPA-rGO@TMgel provocou uma redução na viabilidade das células cancerígenas para 50 %. Em contraste, a ação combinada do DOX/DOPA-rGO@TMgel com a luz NIR conseguiu reduzir a viabilidade das células cancerígenas da mama para apenas 21 %, salientando o seu potencial para a terapia quimio-fototérmica.Correia, Ilídio Joaquim SobreiraDiogo, Duarte Miguel de MeloSousa, Ana Rita LimauBibliorumCosta, Francisco José Palácio2022-11-302022-10-062025-10-06T00:00:00Z2022-11-30T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10400.6/13193TID:203219813enginfo:eu-repo/semantics/embargoedAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-11-27T12:41:58Zoai:ubibliorum.ubi.pt:10400.6/13193Portal AgregadorONGhttps://www.rcaap.pt/oai/openairemluisa.alvim@gmail.comopendoar:71602024-11-27T12:41:58Repositório 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 Development of graphene oxide-based hydrogels for cancer therapy
title Development of graphene oxide-based hydrogels for cancer therapy
spellingShingle Development of graphene oxide-based hydrogels for cancer therapy
Costa, Francisco José Palácio
Cancro
Hidrogéis Tiol-Maleimida
Nanomateriais da Família do Grafeno
Sistemas de Entrega à Macro-Escala
Terapia Quimio-Fototérmica
Domínio/Área Científica::Engenharia e Tecnologia::Biotecnologia
title_short Development of graphene oxide-based hydrogels for cancer therapy
title_full Development of graphene oxide-based hydrogels for cancer therapy
title_fullStr Development of graphene oxide-based hydrogels for cancer therapy
title_full_unstemmed Development of graphene oxide-based hydrogels for cancer therapy
title_sort Development of graphene oxide-based hydrogels for cancer therapy
author Costa, Francisco José Palácio
author_facet Costa, Francisco José Palácio
author_role author
dc.contributor.none.fl_str_mv Correia, Ilídio Joaquim Sobreira
Diogo, Duarte Miguel de Melo
Sousa, Ana Rita Lima
uBibliorum
dc.contributor.author.fl_str_mv Costa, Francisco José Palácio
dc.subject.por.fl_str_mv Cancro
Hidrogéis Tiol-Maleimida
Nanomateriais da Família do Grafeno
Sistemas de Entrega à Macro-Escala
Terapia Quimio-Fototérmica
Domínio/Área Científica::Engenharia e Tecnologia::Biotecnologia
topic Cancro
Hidrogéis Tiol-Maleimida
Nanomateriais da Família do Grafeno
Sistemas de Entrega à Macro-Escala
Terapia Quimio-Fototérmica
Domínio/Área Científica::Engenharia e Tecnologia::Biotecnologia
description Breast cancer is a major cause of death of women worldwide. This high mortality rate is a consequence of the limitations of the currently used therapies, such as surgery, chemotherapy and radiotherapy. Such therapies exhibit a poor efficacy and induce several side effects. Therefore, the development of new therapies is imperative. Along the years, researchers have developed several types of nanomaterials (e.g. dendrimers, liposomes, micelles) for application in different anticancer modalities. Recently, the focus has turned towards the photothermal capacity of some nanomaterials. When irradiated with Near Infrared (NIR; 750 – 1000 nm) light, these nanomaterials can absorb its energy, releasing it as heat that induces damage in cancer cells. These light-responsive nanomaterials can also accommodate drugs in their structure, enabling their use in combinatorial therapeutic approaches. However, the nanomaterials are commonly administered by intravenous injection, which is not ideal considering the weak tumor-homing capacity of systemically administered nanomaterials, leading to a subpar outcome. Due to that, new technologies capable of delivering nanoparticles directly into the tumor tissue are under investigation. In particular, hydrogels formed through Thiol-Maleimide Michael type additions display potential to this application owing to their ability to incorporate high doses of nanoparticles into their compact 3D structure, as well as good chemical selectivity, biocompatibility, and simple production. However, such hydrogels have been mostly prepared using synthetic polymers, which are not ideal considering their non-biodegradability. Herein, a novel Thiol-Maleimide crosslinked hydrogel, engineered using natural polymers, was produced for application in the chemo-photothermal therapy of breast cancer cells. To obtain natural polymers compatible with this crosslinking chemistry, Hyaluronic Acid was decorated with Thiol groups and deacetylated Chitosan was grafted with Maleimide groups. Simultaneously, Dopamine-reduced Graphene Oxide was produced and loaded with Doxorubicin (DOX/DOPA-rGO) to create NIR light responsive nanomaterial with chemo-photothermal capabilities. In order to formulate the Thiol-Maleimide crosslinked hydrogels incorporating this therapeutic nano-agent (DOX/DOPA-rGO@TMgel), a simple mixture of Hyaluronic acid-Thiol, deacetylated Chitosan-Maleimide and DOX/DOPA-rGO was performed. In in vitro studies, when breast cancer cells were incubated with DOPA-rGO@TMgel and exposed to NIR ligh (photothermal therapy), their viability was reduced to about 59 %. On the other hand, DOX/DOPA-rGO@TMgel (chemotherapy) reduced cancer cells’ viability to 50 %. In stark contrast, the combined action of DOX/DOPA-rGO@TMgel and NIR light decreased breast cancer cells’ viability to just 21 %, highlighting its chemo-phototherapeutic potential.
publishDate 2022
dc.date.none.fl_str_mv 2022-11-30
2022-10-06
2022-11-30T00:00:00Z
2025-10-06T00:00:00Z
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