Publicação
Desenvolvimento de nanomateriais para a terapia fototermal do cancro
| Resumo: | Breast cancer is one of the most prevalent and one of the leading causes of cancer-related deaths among women worldwide. In the specific case of the Portuguese population, breast cancer incidence and mortality rates increased in the past years. This scenario is mostly owed to the ineffectiveness of the currently available treatments (surgery, radiotherapy and small molecule-based therapies), whose therapeutic success is hindered by safety issues, non-specific toxicity and resistance mechanisms displayed by cancer cells to drugs. Such emphasizes the demand for a plethora of novel therapeutic approaches. In the past decades, light-induced therapies have started to be investigated as alternative strategies to combat cancer. These treatment modalities comprise photodynamic therapy (PDT) and photothermal therapy (PTT). Both therapeutic approaches depend on the external irradiation of the tumor region with near-infrared (NIR) light for activating photosensitizers or photothermal agents, that lead to the generation of reactive oxygen species (ROS; in PDT) or to a temperature increase (in PTT), which have a cytotoxic effect on cancer cells. Yet, such treatments still need to be further improved in what concerns their efficacy and selectivity towards the tumor region. Recently, the entrapment of NIR photoabsorbers in nanoparticles surpassed problems like the poor solubility of these molecules in biological fluids. Moreover, nanoparticles due to their physicochemical properties can display a preferential tumor accumulation, which is crucial for increasing the loaded NIR photoabsorbers bioavailability and ultimately the efficacy and selectivity of this therapeutic approach. Herein, a novel nanovehicle loaded with a NIR dye aimed for breast cancer phototherapy was developed. To accomplish that, two vitamin E derivatives, D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and D-α-tocopheryl succinate (TOS), were used to assemble amphiphilic micelles with a core-shell structure. TPGS and TOS were selected due to their intrinsic anticancer activity (e.g. through the generation of ROS) and ability to encapsulate poorly water-soluble molecules. 2-[2-[2-Chloro-3-[(1,3-dihydro-3,3-dimethyl-1-propyl-2H-indol-2-ylidene)ethylidene]-1-cyclohexen-1-yl]ethenyl]-3,3-dimethyl-1-propylindolium iodide (IR780) was chosen due to its versatile nature as a NIR light-responsive compound (photothermal agent, photosensitizer and NIR imaging dye). IR780-loaded TPGS-TOS micelles (IR780-TTM) with suitable sizes were obtained by using specific TPGS and TOS weight feed ratios during micelles formulation and these were able to encapsulate IR780 with high efficiency. In in vitro assays, the IR780-TTM induced a cytotoxic effect in cancer cells upon exposure to NIR irradiation through the generation of reactive oxygen species (PDT). This effective ablation of cancer cells was achieved using an ultra-low IR780 concentration. Moreover, IR780-TTM also demonstrated the ability to act as photothermal and imaging agents. Overall, the novel micellar nanoplatforms developed in this study possess a huge potential for breast cancer PDT. Moreover, IR780-TTM also demonstrate promising results to act as photothermal and imaging agents, which widens their applicability for the treatment and diagnosis of cancer. |
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| Autores principais: | Silva, Cleide Isabel Pais |
| Assunto: | Cancro da mama IR780 Micelas de TPGS-TOS Terapia fotodinâmica Terapia fototérmica |
| Ano: | 2016 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade da Beira Interior |
| Idioma: | inglês |
| Origem: | uBibliorum |
| Resumo: | Breast cancer is one of the most prevalent and one of the leading causes of cancer-related deaths among women worldwide. In the specific case of the Portuguese population, breast cancer incidence and mortality rates increased in the past years. This scenario is mostly owed to the ineffectiveness of the currently available treatments (surgery, radiotherapy and small molecule-based therapies), whose therapeutic success is hindered by safety issues, non-specific toxicity and resistance mechanisms displayed by cancer cells to drugs. Such emphasizes the demand for a plethora of novel therapeutic approaches. In the past decades, light-induced therapies have started to be investigated as alternative strategies to combat cancer. These treatment modalities comprise photodynamic therapy (PDT) and photothermal therapy (PTT). Both therapeutic approaches depend on the external irradiation of the tumor region with near-infrared (NIR) light for activating photosensitizers or photothermal agents, that lead to the generation of reactive oxygen species (ROS; in PDT) or to a temperature increase (in PTT), which have a cytotoxic effect on cancer cells. Yet, such treatments still need to be further improved in what concerns their efficacy and selectivity towards the tumor region. Recently, the entrapment of NIR photoabsorbers in nanoparticles surpassed problems like the poor solubility of these molecules in biological fluids. Moreover, nanoparticles due to their physicochemical properties can display a preferential tumor accumulation, which is crucial for increasing the loaded NIR photoabsorbers bioavailability and ultimately the efficacy and selectivity of this therapeutic approach. Herein, a novel nanovehicle loaded with a NIR dye aimed for breast cancer phototherapy was developed. To accomplish that, two vitamin E derivatives, D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and D-α-tocopheryl succinate (TOS), were used to assemble amphiphilic micelles with a core-shell structure. TPGS and TOS were selected due to their intrinsic anticancer activity (e.g. through the generation of ROS) and ability to encapsulate poorly water-soluble molecules. 2-[2-[2-Chloro-3-[(1,3-dihydro-3,3-dimethyl-1-propyl-2H-indol-2-ylidene)ethylidene]-1-cyclohexen-1-yl]ethenyl]-3,3-dimethyl-1-propylindolium iodide (IR780) was chosen due to its versatile nature as a NIR light-responsive compound (photothermal agent, photosensitizer and NIR imaging dye). IR780-loaded TPGS-TOS micelles (IR780-TTM) with suitable sizes were obtained by using specific TPGS and TOS weight feed ratios during micelles formulation and these were able to encapsulate IR780 with high efficiency. In in vitro assays, the IR780-TTM induced a cytotoxic effect in cancer cells upon exposure to NIR irradiation through the generation of reactive oxygen species (PDT). This effective ablation of cancer cells was achieved using an ultra-low IR780 concentration. Moreover, IR780-TTM also demonstrated the ability to act as photothermal and imaging agents. Overall, the novel micellar nanoplatforms developed in this study possess a huge potential for breast cancer PDT. Moreover, IR780-TTM also demonstrate promising results to act as photothermal and imaging agents, which widens their applicability for the treatment and diagnosis of cancer. |
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