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Anticancer prodrugs for targeted therapy
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Nos tempos que correm, o cancro é a segunda maior causa de morte globalmente, sendo uma doença com uma grande expressão e fisiopatologia complexa. Existem diversos tipos de tratamentos anti cancro como, por exemplo, cirurgia e radioterapia porém, quando o tumor se encontra distribuído e com desenvolvimento de metástases, surge a quimioterapia. Apesar da sua ação ser focada no decréscimo da proliferação de células cancerígenas, a maioria dos fármacos citotóxicos não está apta a localizar, seletivamente, o local do tumor, o que leva a variados efeitos adversos indesejados. Por este motivo, tornou-se urgente a procura de novas soluções que possam otimizar o tratamento anti cancro e a terapia localizada, com a utilização de pró fármacos, é uma das potenciais estratégias. Em comparação com os tecidos ditos normais, as células cancerígenas são caracterizadas por únicos e anormais marcadores e, por isso, a estratégia baseada no uso de pró fármacos irá explorar essas diferenças, de modo a afetar somente o tumor, sem causar dano aos tecidos saudáveis. As células cancerígenas são, então, caracterizadas pelo seu microambiente específico com baixos valores de pH, elevada concentração de espécies reativas de oxigénio e glutationa e, ainda, por uma elevada expressão de certas enzimas e antigénios específicos. Esta última característica está relacionada com abordagens mais experimentais focando-se em anticorpos monoclonais ou terapia genómica. Deste modo, estão a ser desenvolvidas estratégias centradas nos mecanismos e singularidades do cancro e alguns exemplos já se encontram disponíveis, incluindo não só pró fármacos que já se encontram no mercado, mas também aqueles que ainda se encontram em estados mais primordiais do seu desenvolvimento. Consequentemente, esta monografia irá focar-se não só no design de pro fármacos mas na tentativa de ter uma maior perceção de todos estes métodos através de vários exemplos detalhados de alguns dos pro fármacos já comercializados ou ainda em desenvolvimento.
In the current times, cancer is the second leading cause of death globally, being a wide spread disease with a complex physiopathology. There are various types of cancer treatment, such as surgery and radiotherapy but, when the tumor is well spread with the development of metastases, chemotherapy comes to picture. Although its action is focused on decreasing the proliferation of cancer cells, the majority of antitumor drugs cannot selectively localize the cancer site, leading to several undesired side effects. So, it has become urgent to find new solutions that can optimize the anticancer treatment and targeted therapy, using prodrugs, is one potential strategy. In comparison with normal tissues, cancer cells are characterized by unique abnormal markers, thus the prodrug strategy will exploit these differences, in order to kill solely the cancer tissues without damaging the healthy ones. Cancer cells are, then, characterized of its specific microenvironment with low pH levels, elevated ROS or high levels of GSH, unique overexpressed enzymes and also specific antigens. This last characteristic is related to more experimental approaches focusing on mAb or gene therapy. Therefore, strategies are being developed focusing on the cancer mechanisms and singularities and some proven examples are already coming to light, regarding non only prodrugs that are already in the market, but also the ones that are still in earlier stages of development. Hence, this review will be focused not only on the prodrug design but also in trying to have a better understanding of all these methods with given detailed examples of some prodrugs already on the market or still in development.
In the current times, cancer is the second leading cause of death globally, being a wide spread disease with a complex physiopathology. There are various types of cancer treatment, such as surgery and radiotherapy but, when the tumor is well spread with the development of metastases, chemotherapy comes to picture. Although its action is focused on decreasing the proliferation of cancer cells, the majority of antitumor drugs cannot selectively localize the cancer site, leading to several undesired side effects. So, it has become urgent to find new solutions that can optimize the anticancer treatment and targeted therapy, using prodrugs, is one potential strategy. In comparison with normal tissues, cancer cells are characterized by unique abnormal markers, thus the prodrug strategy will exploit these differences, in order to kill solely the cancer tissues without damaging the healthy ones. Cancer cells are, then, characterized of its specific microenvironment with low pH levels, elevated ROS or high levels of GSH, unique overexpressed enzymes and also specific antigens. This last characteristic is related to more experimental approaches focusing on mAb or gene therapy. Therefore, strategies are being developed focusing on the cancer mechanisms and singularities and some proven examples are already coming to light, regarding non only prodrugs that are already in the market, but also the ones that are still in earlier stages of development. Hence, this review will be focused not only on the prodrug design but also in trying to have a better understanding of all these methods with given detailed examples of some prodrugs already on the market or still in development.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2019
Palavras-chave
Pró fármacos Cancro Terapia localizada pH Microambiente cancerígeno Enzimas específicas do cancro ADC ADEPT GDEPT Mestrado Integrado - 2019