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Avaliação de novas combinações de fármacos em cancro do pulmão de não pequenas células
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| Documento em Acesso Embargado até dia 12-10-2028. Tente solicitar cópia ao autor carregando no ficheiro | 2.4 MB | Adobe PDF |
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O cancro do pulmão de não pequenas células (CPNPC) continua a ser uma das principais causas de mortalidade oncológica, sendo a resistência adquirida aos inibidores da tirosina-quinase (TKIs) um dos maiores obstáculos à eficácia terapêutica. O osimertinib, TKI de terceira geração dirigido a mutações ativadoras do EGFR, é um exemplo de fármaco que apresenta eficácia clínica significativa, mas enfrenta limitações devido ao desenvolvimento de resistência. Paralelamente, a sinvastatina tem demonstrado, em investigação pré-clínica, propriedades antitumorais relevantes, incluindo indução de apoptose e modulação de vias de sinalização associadas à progressão tumoral. Neste contexto, a coentrega destes fármacos em lipossomas surge como uma estratégia inovadora a ser desenvolvida para aumentar a eficácia terapêutica e reduzir a toxicidade sistémica da sinvastatina. Neste estudo, foram desenvolvidas e caracterizadas formulações lipossomais contendo sinvastatina ou osimertinib. Ambas as formulações apresentaram diâmetro hidrodinâmico nanométrico (=90 nm), baixo índice de polidispersidade (PDI <0,2) e estabilidade físico-química adequada, garantindo consistência entre diferentes lotes. O método de encapsulamento revelou-se eficiente, com recuperações superiores a 80% para ambos os fármacos e eficácias de encapsulamento de aproximadamente de 100%. A avaliação da viabilidade celular revelou que a sinvastatina apresentou uma redução significativa do IC50 quando encapsulada em lipossomas (1,160 µM) comparativamente à forma livre (1,770 µM). O osimertinib mostrou uma diminuição ligeira do IC50 em lipossomas em relação à forma livre (0,02076 µM vs. 0,02569 µM). Notavelmente, a combinação dos dois fármacos induziu uma redução mais pronunciada do IC50 quando encapsulada em lipossomas (0,01562 µM) comparativamente à forma livre (0,1566 µM), evidenciando um efeito sinérgico significativo que supera a contribuição de cada fármaco isoladamente. Estes resultados sugerem que a encapsulação lipossomal potencia a eficácia antiproliferativa das combinações de sinvastatina e osimertinib na linha celular H1975. Estes resultados fornecem uma prova de conceito sólida para a utilização de lipossomas como veículos de coentrega de sinvastatina e osimertinib, evidenciando a sua aplicabilidade enquanto estratégia combinada no CPNPC. A abordagem demonstra potencial para maximizar a eficácia terapêutica, reduzir efeitos adversos e constituir uma base para futuros estudos pré-clínicos e clínicos.
Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer mortality, with acquired resistance to tyrosine kinase inhibitors (TKIs) being one of the major obstacles to therapeutic efficacy. Osimertinib, a third-generation TKI targeting EGFR activating mutations, is an example of a drug that has significant clinical efficacy but faces limitations due to the development of resistance. At the same time, simvastatin has demonstrated relevant antitumor properties in preclinical research, including induction of apoptosis and modulation of signaling pathways associated with tumor progression. In this context, the co-delivery of these drugs in liposomes emerges as an innovative strategy to be developed to increase therapeutic efficacy and reduce the systemic toxicity of simvastatin. In this study, liposomal formulations containing simvastatin or osimertinib were developed and characterized. Both formulations had a nanometric hydrodynamic diameter (=90 nm), low polydispersity index (PDI <0.2), and adequate physicochemical stability, ensuring consistency between different batches. The encapsulation method proved to be efficient, with recoveries greater than 80% for both drugs and encapsulation efficiencies of approximately 100%. The assessment of cell viability revealed that simvastatin showed a significant reduction in IC50 when encapsulated in liposomes (1.160 µM) compared to the free form (1.770 µM). Osimertinib showed a slight decrease in IC50 in liposomes compared to the free form (0.02076 µM vs. 0.02569 µM). Notably, the combination of the two drugs induced a more pronounced reduction in IC50 when encapsulated in liposomes (0.01562 µM) compared to the free form (01566 µM), evidencing a significant synergistic effect that exceeds the contribution of each drug alone. These results suggest that liposomal encapsulation enhances the antiproliferative efficacy of simvastatin and osimertinib combinations in the H1975 cell line. These results provide solid proof of concept for the use of liposomes as co-delivery vehicles for simvastatin and osimertinib, demonstrating their applicability as a combined strategy in NSCLC. The approach demonstrates potential to maximize therapeutic efficacy, reduce adverse effects, and provide a basis for future preclinical and clinical studies.
Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer mortality, with acquired resistance to tyrosine kinase inhibitors (TKIs) being one of the major obstacles to therapeutic efficacy. Osimertinib, a third-generation TKI targeting EGFR activating mutations, is an example of a drug that has significant clinical efficacy but faces limitations due to the development of resistance. At the same time, simvastatin has demonstrated relevant antitumor properties in preclinical research, including induction of apoptosis and modulation of signaling pathways associated with tumor progression. In this context, the co-delivery of these drugs in liposomes emerges as an innovative strategy to be developed to increase therapeutic efficacy and reduce the systemic toxicity of simvastatin. In this study, liposomal formulations containing simvastatin or osimertinib were developed and characterized. Both formulations had a nanometric hydrodynamic diameter (=90 nm), low polydispersity index (PDI <0.2), and adequate physicochemical stability, ensuring consistency between different batches. The encapsulation method proved to be efficient, with recoveries greater than 80% for both drugs and encapsulation efficiencies of approximately 100%. The assessment of cell viability revealed that simvastatin showed a significant reduction in IC50 when encapsulated in liposomes (1.160 µM) compared to the free form (1.770 µM). Osimertinib showed a slight decrease in IC50 in liposomes compared to the free form (0.02076 µM vs. 0.02569 µM). Notably, the combination of the two drugs induced a more pronounced reduction in IC50 when encapsulated in liposomes (0.01562 µM) compared to the free form (01566 µM), evidencing a significant synergistic effect that exceeds the contribution of each drug alone. These results suggest that liposomal encapsulation enhances the antiproliferative efficacy of simvastatin and osimertinib combinations in the H1975 cell line. These results provide solid proof of concept for the use of liposomes as co-delivery vehicles for simvastatin and osimertinib, demonstrating their applicability as a combined strategy in NSCLC. The approach demonstrates potential to maximize therapeutic efficacy, reduce adverse effects, and provide a basis for future preclinical and clinical studies.
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Palavras-chave
Cancro do pulmão de não pequenas células Osimertinib Sinvastatina Lipossomas Terapia combinada Efeito sinérgico Non-small cell lung cancer Simvastatin Liposomes Combination therapy Synergistic effect