Avaliação do potencial de nanodispersões de cristal líquido funcionalizadas com cetuximabe na veiculação de docetaxel para o tratamento do câncer de próstata
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Data
2018-09-04
Autores
Trevizan, Lucas Noboru Fatori
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Universidade Estadual Paulista (Unesp)
Resumo
O câncer de próstata (CP) é a segunda neoplasia mais frequente entre homens no Brasil e é caracterizado por não apresentar sintomas em seus estágios iniciais, sendo diagnosticado em seu estágio avançado, o que muitas vezes dificulta o tratamento. Alguns fatores relacionados podem intensificar sua agressividade como, por exemplo, a superexpressão do receptor do fator de crescimento epidérmico (EGFR) em alguns subtipos de tumores de próstata. Neste contexto, a inibição do EGFR auxilia no combate da neoplasia, função essa que pode ser atribuída ao anticorpo monoclonal quimérico IgG1 (cetuximabe-CTX) que se liga à porção externa do EGFR, inibindo a proliferação celular, angiogênese e metástase, além de promover a apoptose. Dentre as formas de tratamento destacam-se a braquiterapia, a radioterapia e a quimioterapia utilizando o docetaxel (DTX), o qual apresenta vantagem de prolongar a sobrevivência em pacientes com CP metastático resistentes à terapia antiandrogênica. No entanto, a formulação comercial (Taxotere®) causa efeitos colaterais, como febre, anemia, retenção de líquidos, hipersensibilidades, mialgias, mucosite, neuropatias periféricas e toxidade a pele e unhas, tornando necessário o estudo de novas formas de veiculação para este fármaco Deste modo, o objetivo deste trabalho foi desenvolver uma nanodispersão de cristal líquido (NCL) de fase cúbica baseada em álcool cetílico etoxilado 20 e propoxilado 5 como tensoativo (T), ácido oleico, DSPE-PEG-MAL e fosfatidilcolina de soja (FCS) como fase oleosa (FO) e dispersão de poloxamer 1,5% em tampão PBS como fase aquosa (85% FA m/m). A formulação foi incorporada de DTX e funcionalizada com CTX para avaliação do seu potencial no tratamento do CP. A caracterização da nanodispersão foi realizada pelas análises de tamanho de partícula, polidispersividade, potencial zeta, termogravimetria, microscopia eletrônica de transmissão (MET) e espectroscopia de infravermelho. Os resultados sugeriram que o sistema obtido possui escala nanométrica e apresentou carga negativa, além de possuir capacidade termoprotetora para o fármaco e não apresentar interferência na estrutura química do mesmo, além de pertencer à fase de cristal líquido cúbica após a dispersão do cristal líquido. Os estudos de incorporação de DTX à nanodispersão indicaram taxa de incorporação de 50%. Os ensaios celulares de uptake indicaram que a NCL pode ser utilizada como mecanismo de entrega para o citoplasma celular uma vez que revelaram citotoxidade e uptake celular nas linhagens celulares DU145 e PC3. Por fim, as analises de citotoxidade indicaram maior citotoxidade das NCL com DTX não funcionalizada para ambas as linhagens DU145 e PC3; entretanto, os dados obtidos não foram conclusivos para evidenciar o efeito da funcionalização das NCL.
Prostate cancer (PC) is the second most frequent neoplasm among men in Brazil and is characterized by not presenting symptoms in its early stages, being diagnosed in its advanced stage, which often makes treatment difficult. Some related factors may intensify their aggressiveness, for example, epidermal growth factor receptor (EGFR) overexpression in some prostate tumor subtypes. In this context, inhibition of EGFR aids in the fight against neoplasia, a function that can be attributed to chimeric monoclonal antibody IgG1 (cetuximabe-CTX) that binds to the outer portion of EGFR, inhibiting cell proliferation, angiogenesis and metastasis, as well as promoting to apoptosis. Among the forms of treatment, brachytherapy, radiotherapy and chemotherapy using docetaxel (DTX), which has the advantage of prolonging survival in patients with metastatic CP resistant to antiandrogen therapy, stand out. However, the commercial formulation (Taxotere®) causes side effects such as fever, anemia, fluid retention, hypersensitivity, myalgia, mucositis, peripheral neuropathies and toxicity to the skin and nails, making it necessary to study new forms of delivery for this drug Thus, the objective of this work was to develop an ethoxylated and propoxylated cetyl alcohol-based liquid crystal (NCL) nanodispersion 20 as a surfactant (T), oleic acid, DSPE-PEG-MAL and soy phosphatidylcholine (FCS) as oily phase (FO) and 1.5% poloxamer dispersion in PBS buffer as aqueous phase (85% FA m / m). The formulation was incorporated with DTX and functionalized with CTX to assess its potential in the treatment of CP. The nanodispersion characterization was performed by the analysis of particle size, polydispersity, zeta potential, thermogravimetry, transmission electron microscopy (TEM) and infrared spectroscopy. The results suggested that the obtained system has a nanometric scale and presented negative charge, besides having thermoprotective capacity for the drug and not presenting interference in the chemical structure of the same, besides belonging to the phase of liquid crystal cubic after the dispersion of the liquid crystal. DTX incorporation studies on nanodispersion indicated a 50% incorporation rate. Uptake cell assays have indicated that NCL can be used as a delivery mechanism for cell cytoplasm since they have shown cellular cytotoxicity and uptake in DU145 and PC3 cell lines. Finally, cytotoxicity analyzes indicated higher cytotoxicity of NCL with non-functionalized DTX for both DU145 and PC3 lines; however, the data obtained were not conclusive to show the effect of NCL functionalization.
Prostate cancer (PC) is the second most frequent neoplasm among men in Brazil and is characterized by not presenting symptoms in its early stages, being diagnosed in its advanced stage, which often makes treatment difficult. Some related factors may intensify their aggressiveness, for example, epidermal growth factor receptor (EGFR) overexpression in some prostate tumor subtypes. In this context, inhibition of EGFR aids in the fight against neoplasia, a function that can be attributed to chimeric monoclonal antibody IgG1 (cetuximabe-CTX) that binds to the outer portion of EGFR, inhibiting cell proliferation, angiogenesis and metastasis, as well as promoting to apoptosis. Among the forms of treatment, brachytherapy, radiotherapy and chemotherapy using docetaxel (DTX), which has the advantage of prolonging survival in patients with metastatic CP resistant to antiandrogen therapy, stand out. However, the commercial formulation (Taxotere®) causes side effects such as fever, anemia, fluid retention, hypersensitivity, myalgia, mucositis, peripheral neuropathies and toxicity to the skin and nails, making it necessary to study new forms of delivery for this drug Thus, the objective of this work was to develop an ethoxylated and propoxylated cetyl alcohol-based liquid crystal (NCL) nanodispersion 20 as a surfactant (T), oleic acid, DSPE-PEG-MAL and soy phosphatidylcholine (FCS) as oily phase (FO) and 1.5% poloxamer dispersion in PBS buffer as aqueous phase (85% FA m / m). The formulation was incorporated with DTX and functionalized with CTX to assess its potential in the treatment of CP. The nanodispersion characterization was performed by the analysis of particle size, polydispersity, zeta potential, thermogravimetry, transmission electron microscopy (TEM) and infrared spectroscopy. The results suggested that the obtained system has a nanometric scale and presented negative charge, besides having thermoprotective capacity for the drug and not presenting interference in the chemical structure of the same, besides belonging to the phase of liquid crystal cubic after the dispersion of the liquid crystal. DTX incorporation studies on nanodispersion indicated a 50% incorporation rate. Uptake cell assays have indicated that NCL can be used as a delivery mechanism for cell cytoplasm since they have shown cellular cytotoxicity and uptake in DU145 and PC3 cell lines. Finally, cytotoxicity analyzes indicated higher cytotoxicity of NCL with non-functionalized DTX for both DU145 and PC3 lines; however, the data obtained were not conclusive to show the effect of NCL functionalization.
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Palavras-chave
nanodispersão de cristal líquido, cetuximabe, docetaxel, câncer de próstata, liquid crystalline nanodispersion, cetuximab, prostate cancer