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Optimization of microfluidic based nanoprecipitation for block polymer nanoparticles production and release studies for therapy to gliomas
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Resumo(s)
Numerosas investigações prorrogam a elevada morbilidade e mortalidade associadas ao glioma, devido à sua fraca diferenciação celular, elevada capacidade invasiva e inacessibilidade cirúrgica. Apesar dos avanços terapêuticos e soluções disponíveis como cirurgia, radioterapia e quimioterapia, o tempo médio de sobrevivência dos doentes permanece baixo. A nanotecnologia é um campo emergente com potencial aplicação na investigação e terapia do cancro, devido ao seu tamanho, carga electroestática e modificações superficiais, que permitem atingir o tecido cerebral. As nanopartículas poliméricas têm sido, extensivamente, estudadas nos campos farmacêutico e médico devido às suas propriedades de libertação controlada e sustentada de fármacos, tamanho subcelular e biocompatibilidade com tecidos e células. Os copolímeros anfifílicos são normalmente utilizados na produção destas nanopartículas devido à sua capacidade de solubilização/estabilização, alteração do perfil farmacocinético e inibição da resistência associados aos fármacos. Não obstante, em solventes apropriados associam-se em micelas com estruturas esféricas, vesiculares vermiformes e tubulares. O presente estudo centra-se na preparação de nanopartículas poliméricas pela técnicas de nanoprecipitação, recorrendo a tecnologias com microfluídos, utilizando poli(ε-caprolactona-b-etilenoglicol)- metilado e carboxilado, para a administração de sorafenib-livre. Adicionalmente, debruça-se sobre os estudos de libertação e dissolução deste fármaco, extremamente hidrofóbico. Neste estudo, foi possível, com recurso à microfluídica, encapsular um fármaco pouco solúvel em nanosferas poliméricas com diâmetro nanométrico, monodispersas, carga negativa, e estáveis em água, para o possível tratamento do glioma. Tal como era previsível, a fração de água, a concentração de polímero e de fármaco na solução orgânica, a quantidade relativa de polímero funcionalizado com ácido carboxílico, o pH da fase aquosa, a temperatura de precipitação e o número de Reynolds demonstraram um impacto significativo nas características do nanosistema. Neste estudo as variáveis analisadas foram a morfologia, diâmetro hidrodinâmico médio, índice de polidispersão, potencial zeta, fração de fármaco e eficiência de encapsulamento. Quanto à dissolução e libertação do fármaco o método de ultracentrifugação não mostrou ser eficaz enquanto a diálise afigura-se uma alternativa viável. As conclusões do presente estudo sugerem a possibilidade de utilizar a microfluídica aplicada à nanoprecipitação por forma a produzir nanopartículas pequenas (<100 nm), monodispersas (PDI<0.2), negativas (-8.9mV) e estáveis em água para o tratamento do glioma.
Numerous investigations have shown that gliomas are associated with high morbidity and mortality owing to their poor cellular differentiation, high grade of invasiveness, and surgical inaccessibility. Furthermore, the median overall patient survival time remains low despite advanced treatment with surgery, radiotherapy, and chemotherapy. Nanotechnology is an emerging field with potential application in cancer research and therapy due to its nanometric size, electrostatic charge, and surface characteristics, allowing them to penetrate the brain tissue freely. Polymeric nanoparticles have been extensively studied in the pharmaceutical and medical fields on account of their controlled and sustained release properties, subcellular size, biocompatibility with tissue and cells. Amphiphilic block copolymers are commonly used in producing polymeric nanoparticles due to their capacity of enabling drug solubilization/stabilization, changing the pharmacokinetic profile of encapsulated molecules, and suppressing multidrug resistance. Furthermore, they self-assemble in appropriate solvents to form micelles or spherical, vesicular, worm-like, and tubular structures. The present study focuses on preparing polymeric nanoparticles with a microfluidic-based solvent evaporation method, using poly(ε-caprolactone-block-ethylene glycol)-methyl ether and carboxylic acid, for delivery of a very hydrophobic drug, sorafenib free-base. Additionally, it dwells on the drug release studies using dialysis and sample and separation methods, particularly ultracentrifugation and ultrafiltration. It was possible to encapsulate a poorly water-soluble drug into a di-block polymer nanosphere by a microfluidic-based technology. It was noticeable that water fraction, polymer concentration in organic solution, drug fraction, relative amount of carboxylic acid functionalized polymer, aqueous phase pH, precipitation temperature, and Reynolds number have crucial importance to the nanosystem’s characteristics. Morphology, average hydrodynamic diameter, polydispersity index, zeta potential, loading degree, and encapsulation efficiency were analyzed. In terms of release study, although the ultracentrifugation method did not show ability, the dialysis bag method is viable. These findings suggest the possibility of using microfluidic-based nanoprecipitation to produce polymeric nanoparticles with small size (<100 nm), low polydispersity index (<0.2), negative charge (-8.9mV), and water stability for glioma treatment.
Numerous investigations have shown that gliomas are associated with high morbidity and mortality owing to their poor cellular differentiation, high grade of invasiveness, and surgical inaccessibility. Furthermore, the median overall patient survival time remains low despite advanced treatment with surgery, radiotherapy, and chemotherapy. Nanotechnology is an emerging field with potential application in cancer research and therapy due to its nanometric size, electrostatic charge, and surface characteristics, allowing them to penetrate the brain tissue freely. Polymeric nanoparticles have been extensively studied in the pharmaceutical and medical fields on account of their controlled and sustained release properties, subcellular size, biocompatibility with tissue and cells. Amphiphilic block copolymers are commonly used in producing polymeric nanoparticles due to their capacity of enabling drug solubilization/stabilization, changing the pharmacokinetic profile of encapsulated molecules, and suppressing multidrug resistance. Furthermore, they self-assemble in appropriate solvents to form micelles or spherical, vesicular, worm-like, and tubular structures. The present study focuses on preparing polymeric nanoparticles with a microfluidic-based solvent evaporation method, using poly(ε-caprolactone-block-ethylene glycol)-methyl ether and carboxylic acid, for delivery of a very hydrophobic drug, sorafenib free-base. Additionally, it dwells on the drug release studies using dialysis and sample and separation methods, particularly ultracentrifugation and ultrafiltration. It was possible to encapsulate a poorly water-soluble drug into a di-block polymer nanosphere by a microfluidic-based technology. It was noticeable that water fraction, polymer concentration in organic solution, drug fraction, relative amount of carboxylic acid functionalized polymer, aqueous phase pH, precipitation temperature, and Reynolds number have crucial importance to the nanosystem’s characteristics. Morphology, average hydrodynamic diameter, polydispersity index, zeta potential, loading degree, and encapsulation efficiency were analyzed. In terms of release study, although the ultracentrifugation method did not show ability, the dialysis bag method is viable. These findings suggest the possibility of using microfluidic-based nanoprecipitation to produce polymeric nanoparticles with small size (<100 nm), low polydispersity index (<0.2), negative charge (-8.9mV), and water stability for glioma treatment.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2021, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Glioma Microfluidics Nanoprecipitation Polymeric nanoparticles Mestrado integrado - 2021