Preparo, caracterização e avaliação da atividade antitumoral de lipossomas folatados pH-sensíveis contendo irinotecano e/ou 5-fluorouracil em modelo murino de câncer colorretal.
Ano de defesa: | 2022 |
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Autor(a) principal: | |
Orientador(a): | |
Banca de defesa: | |
Tipo de documento: | Tese |
Tipo de acesso: | Acesso aberto |
Idioma: | por |
Instituição de defesa: |
Universidade Federal de Minas Gerais
Brasil FARMACIA - FACULDADE DE FARMACIA Programa de Pós-Graduação em Ciências Farmacêuticas UFMG |
Programa de Pós-Graduação: |
Não Informado pela instituição
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Departamento: |
Não Informado pela instituição
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País: |
Não Informado pela instituição
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Palavras-chave em Português: | |
Link de acesso: | http://hdl.handle.net/1843/76417 |
Resumo: | Worldwide estimates point out colorectal cancer as the third most common type of malignant tumor, representing about 1.9 million new cases and one in 10 deaths. Systemic chemotherapy has evolved from the use of basic cytotoxic agents to the combination of different chemotherapeutics. The most commonly used drugs for this type of tumor are 5-fluorouracil (5-FU), oxaliplatin, and irinotecan (IRN). However, high toxicity has been observed in the different therapy regimens used, which makes conventional treatments inefficient. In this sense, the use of new therapeutic agents, such as nanosystems, mainly liposomes, to carry these drugs constitutes a promising strategy to improve the treatment of colorectal cancer. Liposomes are lipid vesicles that passively accumulate in the tumor region. In addition, structural changes in these systems can increase specificity, and selective release of the drug in the tumor region, in addition to reducing toxic effects. In this study, a new pH-sensitive liposomal system functionalized with folate encapsulating IRN and/or 5-FU was developed for the evaluation of antitumor activity in a murine colorectal tumor model (CT-26). In the first chapter, liposomal formulations containing IRN were evaluated, which showed reduced size (less than 200nm) and homogeneous distribution, with zeta potential close to neutrality. The release and pH-sensitivity study showed a slower release of the encapsulated drug in comparison to the free IRN, and faster in acidic than in physiological pH. The multifunctionalized formulation of SpHL-IRN-FOL demonstrated significantly better antitumor activity than free IRN. Treatment with SpHL-IRN-Fol resulted in even more extensive tumor growth inhibition when compared to the non-folated formulation (57.8 and 41.5%, respectively), and no evidence of toxicity was found. These data support additional preclinical studies of SpHL-IRN-FOL as a drug delivery system for the treatment of colorectal cancer. In chapter 2, the co-encapsulation of IRN and 5-FU was evaluated. Homogeneous, monodisperse vesicles with zeta potential close to neutrality were prepared, but further studies for better characterization of 5-FU liposomes need to be conducted to improve encapsulation stability. However, preliminary results with SpHL-IRN-FOL combined with 5-FU liposomes showed promise to promote an even more significant increase in the antitumor activity of these drugs in the colorectal cancer model used. |