Click hidrogéis de gelatina e nanopartícula polimérica como plataforma de liberação simultânea de fármacos hidrofílico e hidrofóbico
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Data
2018-04-20
Autores
Piazza, Rodolfo Debone [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
Nas últimas décadas as plataformas para liberação controlada de fármacos têm sido estudadas pela comunidade científica para o desenvolvimento materiais aplicados à biomedicina, principalmente para o tratamento de câncer. Estruturas como nanopartículas poliméricas, micelas, lipossomas, hidrogéis, dendrímeros, entre outras, foram modificadas para que suas propriedades físico-químicas apresentassem compatibilidade com o meio biológico de interesse para liberação de moléculas bioativas. Recentemente a combinação de terapias utilizando fármacos com diferente ação terapêutica tem se tornando uma alternativa efetiva para o tratamento de doenças e regeneração de tecidos, sendo necessário que as propriedades das plataformas de liberação sejam ajustadas para controlar a liberação de dois ou mais fármacos. O presente trabalho consiste no desenvolvimento de uma plataforma de liberação simultânea de diclofenaco de potássio e metotrexato, fármacos que apresentam hidrofilicidade distinta. Assim, hidrogéis a base de gelatina e dextrana foram obtidos como plataforma de liberação de diclofenaco e metrotrexato incorporado à nanopartículas de mPEG-co-PCL. O hidrogel foi reticulado a partir de reações click, nos quais as estruturas poliméricas da gelatina e dextrana foram modificadas com anidrido maleico e ácido furóico, respectivamente. Estes reagentes contêm grupos dieno e dienófilo que permitem a formação de ligações covalentes através das reações click de Diels – Alder. O intumescimento do hidrogel e a liberação de diclofenaco de potássio foram estudados em diversos meios de dissolução. Foi possível observar que o aumento da capacidade de intumescimento resultou em liberações mais rápidas de diclofenaco. Foi possível obter copolímero de mPEG-co-PCL a partir da polimerização por abertura de anel do monômero de e-caprolactona, cujo método permitiu controlar o tamanho do segmento hidrofóbico da cadeia polimérica. Com os copolímeros sintetizados, nanopartículas poliméricas contendo metotrexato foram obtidas pelo método da emulsão/evaporação por solvente. A eficiência de incorporação do metotrexato foi superior a 80%, enquanto a liberação se mostrou dependente do tamanho de cadeia do copolímero: o aumento do segmento hidrofóbico da cadeia reduz a fração de metotrexato liberado, sendo dependente da lenta biodegradação da cadeia de PCL pelo organismo. Quando as nanopartículas de mPEG-co-PCL foram incorporadas ao hidrogel de gelatina para avaliação da liberação simultânea do diclofenaco de potássio e metotrexato foi observado que o fármaco hidrofílico apresentou rápida liberação da matriz de hidrogel, enquanto o fármaco hidrofóbico teve um comportamento de liberação sustentado devido a degradação do segmento hidrofóbico.
In recent decades, platforms for drugs delivery have been studied by the scientific community for the development of materials applied to biomedicine, mainly for the cancer treatment. Structures such as polymeric nanoparticles, micelles, liposomes, hydrogels, dendrimers, among others, were modified to adjust their physicochemical properties to show co mpatibility with the biological milieu of interest for the release of bioactive molecules. Recently, the combination of drugs with different therapeutic actions has become an effective alternative for the treatment of diseases and tissue regeneration, howe ver further adjustment of properties is required to control the release of two or more drugs. The present work consists in the development of a dual drug delivery platform to release potassium diclofenac and methotrexate, drugs that presented different hyd rophilicity. Thus, gelatin and dextran - based hydrogels w ere obtained as a platform for the release of diclofenac and methotrexate incorporated into nanoparticles of mPEG - co - PCL. The hydrogel was cross - linked from click reactions, wich polymer backbone was modified with maleic anhydride and furoic acid, respectively. These reagents contain diene and dienophile groups that allow bond formation through Diels - Alder clic k reactions. Hydrogel swelling and release of diclofenac potassium have been studied in var ious dissolution media, showing the increase in swelling capacity resulted in slower drug release. It was possible to obtain mPEG - co - PCL copolymer from the ring - opening polymerization of the e - caprolactone monomer, technique which allowed controlling the l ength of the hydrophobic segment of the polymer chain. From the synthesized copolymers, polymeric nanoparticles containing methotrexate were obtained for emulsion / solvent evap oration method. The encapsulation efficiency of methotrexate was greater than 8 0%, while release was shown to be dependent of the copolymer chain size: increasing the hydrophobic segment of the chain reduces the fraction of methotrexate is released, being dependent of slow biodegradation of the PCL chain by the human body. When the m PEG - co - PCL nanoparticles were incorporated into the gelatin hydrogel to evaluate the simultaneous release of diclofenac potassium and methotrexate, it was observed that the hydrophilic drug showed a rapid release from the hydrogel matrix, whereas the hydro phobic drug had a release behavior sustained by degradation of the hydrophobic segment.
In recent decades, platforms for drugs delivery have been studied by the scientific community for the development of materials applied to biomedicine, mainly for the cancer treatment. Structures such as polymeric nanoparticles, micelles, liposomes, hydrogels, dendrimers, among others, were modified to adjust their physicochemical properties to show co mpatibility with the biological milieu of interest for the release of bioactive molecules. Recently, the combination of drugs with different therapeutic actions has become an effective alternative for the treatment of diseases and tissue regeneration, howe ver further adjustment of properties is required to control the release of two or more drugs. The present work consists in the development of a dual drug delivery platform to release potassium diclofenac and methotrexate, drugs that presented different hyd rophilicity. Thus, gelatin and dextran - based hydrogels w ere obtained as a platform for the release of diclofenac and methotrexate incorporated into nanoparticles of mPEG - co - PCL. The hydrogel was cross - linked from click reactions, wich polymer backbone was modified with maleic anhydride and furoic acid, respectively. These reagents contain diene and dienophile groups that allow bond formation through Diels - Alder clic k reactions. Hydrogel swelling and release of diclofenac potassium have been studied in var ious dissolution media, showing the increase in swelling capacity resulted in slower drug release. It was possible to obtain mPEG - co - PCL copolymer from the ring - opening polymerization of the e - caprolactone monomer, technique which allowed controlling the l ength of the hydrophobic segment of the polymer chain. From the synthesized copolymers, polymeric nanoparticles containing methotrexate were obtained for emulsion / solvent evap oration method. The encapsulation efficiency of methotrexate was greater than 8 0%, while release was shown to be dependent of the copolymer chain size: increasing the hydrophobic segment of the chain reduces the fraction of methotrexate is released, being dependent of slow biodegradation of the PCL chain by the human body. When the m PEG - co - PCL nanoparticles were incorporated into the gelatin hydrogel to evaluate the simultaneous release of diclofenac potassium and methotrexate, it was observed that the hydrophilic drug showed a rapid release from the hydrogel matrix, whereas the hydro phobic drug had a release behavior sustained by degradation of the hydrophobic segment.
Descrição
Palavras-chave
Click hidrogel, Nanopartícula polimérica, Sistemas de liberação simultâneo de fármaco, Diclofenaco de potássio, Metotrexato