Publicação
Treatment of triple-negative breast cancer (TNBC) through externally triggered target less drug carriers
| Resumo: | Cancer still ranks as a principal public health problem worldwide, being responsible for 9.9 million related-deaths in 2020. Breast cancer is the most commonly diagnosed cancer-type and the principal cause of cancer-related mortality in women, from which the triple-negative breast cancer (TNBC) subtype is the most lethal. TNBC treatment include conventional chemotherapy (e.g., doxorubicin/DOX), radiation and surgery, but response is poor, justifying the low survival rates of these patients. Thus, there is an urgent need for more specific and targeted approaches for early diagnosis, control, and treatment. The main objective of this thesis was the preclinical validation of a biocompatible theranostic probe activated in the tumor site through a specific external stimulus, a magnetic field. The nanosystem is based on magnetic solid lipid nanoparticles (mSLNs) loaded with a chemotherapeutic drug (DOX) and magnetic nanoparticles (Fe3O4), combining the synergistic effect of thermochemotherapy with non-invasive MR imaging. The combinatory effect of a dual treatment was explored in a first screening through IC50 determination in TNBC cells, where the temperature-responsive DOX-loaded mSLNs showed powerful anticancer properties against cancer cells, associated to a higher cytotoxic outcome in comparison to free DOX. Through more specific in vitro studies in 2D monolayer, mSLNs, as drug carriers, were able to inhibit cell proliferation and migration, in a time-dependent manner, being firstly internalized into the cell cytoplasm and, with an increase of incubation time, were able to release the drug into the cell nuclei. In the 3D spheroid model and the ex vivo Chick Chorioallantoic Membrane (CAM) model, the dual-treatment enhanced the penetration of the chemotherapeutic agent into the cancer cells, with improved therapeutic properties in comparison to free DOX. Then, in vivo studies were performed using an orthotopic xenograft NSG mice model. The unloaded nanoformulations demonstrated to be safe, without any detected toxic effects on animal-wellbeing and vital organ histology and promoted a T2-MRI contrast enhancement. Additionally, the DOX-loaded mSLNs demonstrated, within two weeks post-treatment, a significant capacity to inhibit tumor growth when combined with hyperthermia, in comparison to the other treatment conditions. In conclusion, the synergistic potential brought by the combination of active targeting with thermochemotherapy, provided by temperature-sensitive DOX-loaded mSLN, against TNBC cells, revealed theranostics capabilities, constituting a promising option as contrast agents for early diagnostics, coupled with an improvement in the therapeutic index in comparison to conventional chemotherapy. |
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| Autores principais: | Cerqueira, Mónica Alexandra da Costa |
| Assunto: | Cancer Triple-negative breast cancer Theranostic Nanoparticles Hyperthermia Cancro Cancro da mama triplo-negativo Teranóstica Nanopartículas Hipertermia |
| Ano: | 2022 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | Cancer still ranks as a principal public health problem worldwide, being responsible for 9.9 million related-deaths in 2020. Breast cancer is the most commonly diagnosed cancer-type and the principal cause of cancer-related mortality in women, from which the triple-negative breast cancer (TNBC) subtype is the most lethal. TNBC treatment include conventional chemotherapy (e.g., doxorubicin/DOX), radiation and surgery, but response is poor, justifying the low survival rates of these patients. Thus, there is an urgent need for more specific and targeted approaches for early diagnosis, control, and treatment. The main objective of this thesis was the preclinical validation of a biocompatible theranostic probe activated in the tumor site through a specific external stimulus, a magnetic field. The nanosystem is based on magnetic solid lipid nanoparticles (mSLNs) loaded with a chemotherapeutic drug (DOX) and magnetic nanoparticles (Fe3O4), combining the synergistic effect of thermochemotherapy with non-invasive MR imaging. The combinatory effect of a dual treatment was explored in a first screening through IC50 determination in TNBC cells, where the temperature-responsive DOX-loaded mSLNs showed powerful anticancer properties against cancer cells, associated to a higher cytotoxic outcome in comparison to free DOX. Through more specific in vitro studies in 2D monolayer, mSLNs, as drug carriers, were able to inhibit cell proliferation and migration, in a time-dependent manner, being firstly internalized into the cell cytoplasm and, with an increase of incubation time, were able to release the drug into the cell nuclei. In the 3D spheroid model and the ex vivo Chick Chorioallantoic Membrane (CAM) model, the dual-treatment enhanced the penetration of the chemotherapeutic agent into the cancer cells, with improved therapeutic properties in comparison to free DOX. Then, in vivo studies were performed using an orthotopic xenograft NSG mice model. The unloaded nanoformulations demonstrated to be safe, without any detected toxic effects on animal-wellbeing and vital organ histology and promoted a T2-MRI contrast enhancement. Additionally, the DOX-loaded mSLNs demonstrated, within two weeks post-treatment, a significant capacity to inhibit tumor growth when combined with hyperthermia, in comparison to the other treatment conditions. In conclusion, the synergistic potential brought by the combination of active targeting with thermochemotherapy, provided by temperature-sensitive DOX-loaded mSLN, against TNBC cells, revealed theranostics capabilities, constituting a promising option as contrast agents for early diagnostics, coupled with an improvement in the therapeutic index in comparison to conventional chemotherapy. |
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