Development of multifunctional phototherapeutic nanoagents

• Autor(a) principal: Mó, Inês Martins Dias da
• Data de Publicação: 2020
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.6/10549
• topic: Cancro; Esferóides; Nanopartículas; Quimioterapia; Terapia Combinatória; Terapia Fototérmica; Domínio/Área Científica::Ciências Médicas::Ciências Biomédicas

Breast cancer remains as one of the world's deadliest diseases, a fact that can be explained by the low efficacy and systemic toxicity of the therapies currently in use in the clinic. Recently, researchers have been developing new therapeutic approaches, among which the chemo-photothermal therapy mediated by nanomaterials has been showing promising results, due to its capacity to produce a spatio-temporal controlled anti-cancer effect. During the development of nanomaterials aimed for cancer chemo-photothermal therapy, their efficacy is initially assessed using monolayers of cancer cells (2D in vitro models). The best formulations screened in 2D are then evaluated in tumor bearing mice (in vivo models). However, the 2D in vitro models present some drawbacks, since they are unable to mimic the key features of the in vivo solid tumors. Due to this reason, several nanoformulations that displayed therapeutic efficacy when tested in the 2D in vitro models induce a subpar effect in vivo. To overcome this limitation, spheroids (3D in vitro models) have recently emerged for the screening of nanomedicines. In fact, spheroids are able to reproduce the main properties of the in vivo solid tumors, namely: i) their 3D architecture, ii) microenvironment (gradients of nutrients, pH and gases), iii) cellular and acellular composition, and iv) biochemical and physical resistance patterns to the therapeutics. In this Master thesis, the efficacy of the chemo-photothermal therapy mediated by nanoparticles based on bovine serum albumin functionalized with sulfobetaine methacrylate, co-encapsulating IR780 and Doxorubicin (IR+DOX/SBMA-BSA NPs) was evaluated in 2D in vitro models and spheroids. In 2D in vitro models, it was found that photothermal therapy mediated by nanoparticles loading IR780 (IR/SBMA-BSA NPs and NIR irradiation) reduced cells’ viability to about 58 %, while chemotherapy induced by nanomaterials (IR+DOX/SBMA-BSA NPs) led to a decrease in their viability to 29 %. In addition, the nanoparticles’ mediated chemo-photothermal therapy (IR+DOX/SBMA-BSA NPs and NIR irradiation) achieved a better therapeutic effect by reducing cells’ viability to 1 %. On the other hand, when the therapies were screened on 3D breast cancer models (spheroids), the photothermal therapy mediated by the nanoparticles (IR/SBMA-BSA NPs and NIR irradiation) did not induce an appreciable cytotoxic effect, while the chemotherapy mediated by the nanostructures (IR+DOX/SBMA-BSA NPs) decreased the viability of the spheroids to 42 %. In turn, the chemo-photothermal therapy mediated by the nanomaterials (IR+DOX/SBMA-BSA NPs and NIR irradiation) was able to further reduce the viability of spheroids to 16 %, revealing that this is the most promising therapeutic modality.