Publicação
Fucoidan-based strategies envisioning antitumor therapies
| Resumo: | Current cancer treatments present some drawbacks, namely unwanted side effects of chemotherapeutics, due to their toxicity over healthy tissues. Trying to overcome this impactful limitation, the use of natural compounds that may present diminished effects over non-cancer cells is of great interest. Among them, fucoidan, a sulfated polysaccharide extracted from brown algae, has been highlighted over the last years due to its interesting biological features. Since different fucoidans may present distinct antitumor behaviors, one of the main goals of this PhD work was to optimize fucoidan usage by developing more effective antitumor therapies. Accordingly, in Chapter III, different fucoidan extracts from Fucus vesiculosus were tested over human breast cancer and normal cells. Three types of biological outcomes were observed: i) toxicity to cancer and normal cells; ii) toxicity to cancer cells at lower concentrations than normal cells (an effective antitumor behavior) and iii) toxicity to normal cells at lower dosages than cancer cells (for high concentrations). These discrepant activities were attributed to differences in the sulfates position and branching of fucoidan. The anti angiogenic potential of the effective fucoidan extract (type ii) was also validated by an endothelial cell tube formation assay (in vitro) and a Chick Chorioallantoic Membrane assay (in vivo) (Chapter IV). The cytotoxic effect of the same fucoidan extract was also demonstrated to human melanoma cells (Chapter V). In a complementary approach, a skin patch to treat melanoma was developed by the immobilization of fucoidan at the surface of an electrospun nanofibrous mesh. Empowering the use of this marine-origin polymer, the fucoidan extract type iii was chosen to develop a drug delivery system for breast cancer. Gemcitabine, a chemotherapeutic drug, was successfully encapsulated into fucoidan/chitosan nanoparticles showing higher toxicity to cancer cells than to normal endothelial cells (Chapter VI). Aiming to reduce gemcitabine side-effects and to develop more precise therapies, an ErbB-2 antibody was immobilized at the surface of the previously described nanoparticles (Chapter VII). The targeting to cancer cells was confirmed in a co-culture system (increased toxicity to cancer cells) and in vivo, observing the impaired tumor growth and reduced lungs metastasis. These studies proposed fucoidan-based strategies (either extracts or systems) that should be further explored in the development of more effective antitumor therapies based in natural compounds. |
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| Autores principais: | Oliveira, Ana Catarina Freitas Salazar |
| Assunto: | Antitumor Breast Cancer Drug Delivery System Fucoidan Nanofibrous Mesh Nanoparticles Melanoma Targeting System Antitumoral Cancro da mama Fucoidana Malhas de nanofibras Melanoma Sistemas de libertação de fármacos Sistemas direcionados |
| Ano: | 2020 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | Current cancer treatments present some drawbacks, namely unwanted side effects of chemotherapeutics, due to their toxicity over healthy tissues. Trying to overcome this impactful limitation, the use of natural compounds that may present diminished effects over non-cancer cells is of great interest. Among them, fucoidan, a sulfated polysaccharide extracted from brown algae, has been highlighted over the last years due to its interesting biological features. Since different fucoidans may present distinct antitumor behaviors, one of the main goals of this PhD work was to optimize fucoidan usage by developing more effective antitumor therapies. Accordingly, in Chapter III, different fucoidan extracts from Fucus vesiculosus were tested over human breast cancer and normal cells. Three types of biological outcomes were observed: i) toxicity to cancer and normal cells; ii) toxicity to cancer cells at lower concentrations than normal cells (an effective antitumor behavior) and iii) toxicity to normal cells at lower dosages than cancer cells (for high concentrations). These discrepant activities were attributed to differences in the sulfates position and branching of fucoidan. The anti angiogenic potential of the effective fucoidan extract (type ii) was also validated by an endothelial cell tube formation assay (in vitro) and a Chick Chorioallantoic Membrane assay (in vivo) (Chapter IV). The cytotoxic effect of the same fucoidan extract was also demonstrated to human melanoma cells (Chapter V). In a complementary approach, a skin patch to treat melanoma was developed by the immobilization of fucoidan at the surface of an electrospun nanofibrous mesh. Empowering the use of this marine-origin polymer, the fucoidan extract type iii was chosen to develop a drug delivery system for breast cancer. Gemcitabine, a chemotherapeutic drug, was successfully encapsulated into fucoidan/chitosan nanoparticles showing higher toxicity to cancer cells than to normal endothelial cells (Chapter VI). Aiming to reduce gemcitabine side-effects and to develop more precise therapies, an ErbB-2 antibody was immobilized at the surface of the previously described nanoparticles (Chapter VII). The targeting to cancer cells was confirmed in a co-culture system (increased toxicity to cancer cells) and in vivo, observing the impaired tumor growth and reduced lungs metastasis. These studies proposed fucoidan-based strategies (either extracts or systems) that should be further explored in the development of more effective antitumor therapies based in natural compounds. |
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