Ligand-functionalized nanoparticles for targeted therapy of melanoma in situ
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2016
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El melanoma cutáneo es un tipo de cáncer con origen en los melanocitos que se vuelven malignos. El tratamiento del melanoma cutáneo ha evolucionado mucho en los últimos treinta años, sin embargo, no ha conseguido incrementar significativamente la supervivencia de los pacientes con cáncer avanzado. Además, el tratamiento presenta muchas limitaciones, como una reducida especificidad, efectos secundarios graves y multi-resistencia a los fármacos.
De hecho, un paso importante para el éxito del tratamiento del melanoma es su detección precoz. En el caso de que no haya metástasis, el cáncer puede ser extirpado por cirugía, pero hay casos en que el riesgo de la intervención, así como el elevado riesgo de recurrencia, obligan a un tratamiento adyuvante. Actualmente, sólo está aprobado un tratamiento adyuvante, con interferón alfa, para estos casos.
De este modo, el principal objetivo de esta tesis es el estudio de alternativas para tratamientos adyuvantes, más eficientes y menos agresivos, del melanoma cutáneo. En este contexto, se han estudiado dos estrategias para aplicación de sistemas de nanopartículas. La primera estrategia consiste en el desarrollo de nanopartículas de oro, cubiertas con polímeros naturales y péptidos, con absorción en la región del infrarojo próximo, para terapia fototérmica. La segunda estrategia incluye el desarrollo de nanopartículas hibridas, para encapsulación de compuestos antitumorales, cubiertas con polímeros naturales y péptidos, capaces de una acción química local en el tumor. Conjuntamente, hemos investigado el comportamiento físico-químico y la estabilidad de las nanopartículas para cada aplicación. Reconociendo la importancia de un tratamiento eficaz y específico, ambas las estrategias se basan en un direccionamiento específico hacia las células de melanoma, que sobre-expresan múltiples receptores en su superficie. Por fin, se utilizaron modelos animales de melanoma humano para evaluación de la eficacia de las dos formulaciones propuestas.
En conclusión, es posible desarrollar nanosistemas que comprenden diferentes estrategias terapéuticas, basadas en núcleos con estructuras distintas y funcionalización de superficies con múltiples ligandos, para una aplicación amplia y exitosa en los cánceres heterogéneos, tales como el melanoma cutáneo.
Cutaneous melanoma occurs on the skin and is the most common type of melanoma. Treatment of cutaneous melanoma has improved over the last thirty years; however, without demonstrating a significant increase on survival of patients with advanced disease. Indeed, conventional treatment generally shows several limitations, such as reduced target specificity, severe adverse effects and multiple drug resistance. In fact, an important step for the success of melanoma treatment is its early detection. In cases where there are no metastases, this cancer can be removed by surgery, but in some cases the risk of intervention has to be measured, as well as the high risk of recurrence, which impose the use of an adjuvant treatment. Currently, there is only one adjuvant treatment approved, with interferon alpha, in these cases. Therefore, the main objective of this thesis was the study of alternatives as adjuvant treatments, more efficient and less aggressive, for cutaneous melanoma. In this context, two strategies have been studied for application of nanoparticles systems. The first strategy is focused on the development of gold nanoparticles, coated with natural polymers and peptides, with absorption at the near infrared range, for photothermal therapy. The second strategy includes the development of hybrid nanoparticles, for encapsulation of anti-tumor compounds, coated with natural polymers and peptides, capable of a local chemotherapy at the tumor site. Overall, the physico-chemical behavior and stability of both nanoparticles for each application were investigated. Recognizing the importance of an efficient and specific treatment, both strategies were based on a specific targeting to melanoma cells, which overexpressed multiple receptors at their surface. At last, animal models for human melanoma were used for evaluation of the efficiency of both proposed strategies. In conclusion, it is possible to develop nanosystems comprising different therapeutic strategies, based on distinct core structures and surface functionalization with multiple targeting ligands, for a broad and potential application in heterogeneous cancers, such as cutaneous melanoma.
Cutaneous melanoma occurs on the skin and is the most common type of melanoma. Treatment of cutaneous melanoma has improved over the last thirty years; however, without demonstrating a significant increase on survival of patients with advanced disease. Indeed, conventional treatment generally shows several limitations, such as reduced target specificity, severe adverse effects and multiple drug resistance. In fact, an important step for the success of melanoma treatment is its early detection. In cases where there are no metastases, this cancer can be removed by surgery, but in some cases the risk of intervention has to be measured, as well as the high risk of recurrence, which impose the use of an adjuvant treatment. Currently, there is only one adjuvant treatment approved, with interferon alpha, in these cases. Therefore, the main objective of this thesis was the study of alternatives as adjuvant treatments, more efficient and less aggressive, for cutaneous melanoma. In this context, two strategies have been studied for application of nanoparticles systems. The first strategy is focused on the development of gold nanoparticles, coated with natural polymers and peptides, with absorption at the near infrared range, for photothermal therapy. The second strategy includes the development of hybrid nanoparticles, for encapsulation of anti-tumor compounds, coated with natural polymers and peptides, capable of a local chemotherapy at the tumor site. Overall, the physico-chemical behavior and stability of both nanoparticles for each application were investigated. Recognizing the importance of an efficient and specific treatment, both strategies were based on a specific targeting to melanoma cells, which overexpressed multiple receptors at their surface. At last, animal models for human melanoma were used for evaluation of the efficiency of both proposed strategies. In conclusion, it is possible to develop nanosystems comprising different therapeutic strategies, based on distinct core structures and surface functionalization with multiple targeting ligands, for a broad and potential application in heterogeneous cancers, such as cutaneous melanoma.
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Diretores de Tese : Dra. Patrícia Rijo ; Dra. Catarina Reis ; Dr. Jesús Molpeceres
Palavras-chave
DOUTORAMENTO EM CIÊNCIAS DA SAÚDE, CIÊNCIAS DA SAÚDE, FARMACOLOGIA, CANCRO CUTÂNEO, NANOTECNOLOGIA, TERAPÊUTICAS, HEALTH SCIENCES, PHARMACOLOGY, SKIN CANCER, NANOTECHNOLOGY, THERAPEUTICS, NANOPARTÍCULAS, NANOPARTICLES