Sistemas supra-anfifílicos derivados de meglumina e ácido oleico: síntese, caracterização e potencial aplicação no âmbito farmacêutico
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Data
2017-10-09
Autores
Fonseca, Mariana
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Universidade Estadual Paulista (Unesp)
Resumo
A auto-montagem é a organização dos blocos de construção que compõem um sistema, em estruturas hierarquicamente ordenadas, sem qualquer tipo de influência externa. As forças que governam esse processo de auto-montagem das moléculas são as interações não covalentes, tais como interações de van der Waals, eletrostática, hidrofóbica, ligação de hidrogênio, dentre outras. A inspiração para o surgimento de materiais com base nessas interações veio da natureza e dos sistemas biológicos, que ocorrem naturalmente, tais como o DNA. A natureza reversível das interações não covalentes assegura que os blocos de construção que constituem o sistema podem se romper e se recombinar de acordo com as características do meio externo. Essa propriedade faz desses sistemas capazes de responder aos mais variados estímulos, tais como variações de temperatura, pH, solvente, radiação, etc. A reação de um ácido orgânico com a meglumina, um aminocarboidrato, leva à formação de um par iônico denominado genericamente de carboxilato-meglumina.Os objetivos nesse estudo, além da síntese de sistemas supra-anfifílicos foi ainda avaliar esses sistemas em fase aquosa e correlacionar as propriedades com uma potencial aplicação no âmbito farmacêutico. Nesse trabalho, ácido oleico e meglumina foram utilizados como os blocos de construção de um sistema anfifílico supramolecular. Inicialmente o par iônico entre ácido oleico e meglumina se formava, gerando o par oleato-meglumina e esse anfifílico se mantinha em fase aquosa através de interações hidrofóbicas e ligação de hidrogênio. Foi sintetizado dois tipos de sistemas, sendo um em proporções equimolares e outro em excesso de meglumina. Sistemas contendo diferentes concentrações de água foram sintetizados, a partir dos adutos precursores e a caracterização desses sistemas foi realizada por microscopia de luz polarizada (MLP), espalhamento de raios-X a baixo ângulo (SAXS) e microscopia eletrônica de varredura no modo ambiental (ESEM). Os resultados mostraram que os supra-anfifílicos, sintetizados em proporções equimolares ou não, puderam se organizar em sistemas micelares ou cristais líquidos hexagonais, de acordo com a quantidade de água. O estado da água presente nesses anfifílicos foi avaliado por calorimetria exploratória diferencial (DSC) e foi observado que os supra-anfifílicos sintetizados a partir de sistemas em excesso de meglumina conseguiram reter mais a água em sua estrutura. A avaliação da citotoxicidade desses sistemas foi realizada em células SV-80, o que mostrou que eles poderiam reduzir a viabilidade celular, de um modo dose-dependente. A capacidade bioadesiva desses supra-anfifílicos foi também avaliada, in vitro, em um analisado TAXT plus no modo Hold Until Time e demonstrou que os sistemas possuíam propriedades bioadesivas superiores ao gel de Carbopol 5%, usado em formulações farmacêuticas. Por fim, um fármaco modelo foi incorporado em alguns sistemas e a organização estrutural após a incorporação foi avaliada por MLP e SAXS, o que permitiu observar que o arranjo liquido-cristalino observado inicialmente foi mantido, evidenciando assim que não houve mudança estrutural nesses sistemas com a adição do fármaco.
Self-assembly is the organization of building blocks in a system, in hierarchically-ordered structures without any external influence. The driving forces on molecular self-assembly are non-covalent interactions, such as van der Waals, electrostatics, hydrophobic, hydrogen bonding, amongst others. The inspiration for the emergent materials based on these interactions come from nature and naturally occurring biological systems such as DNA. The reversible nature of the non-covalent interactions ensures that the building blocks in a system can be broken and reunited according to the external environment. This property makes them capable of responding to different stimuli, such as variations in temperature, pH, solvent, radiation, etc. The reaction of an organic acid with meglumine, an aminocarbohydrate, leads to the formation of an ionic pair generally called carboxylate-meglumine. The aim of this work, besides the synthesis of the supra-amphiphiles, was to evaluate these systems in aqueous phase, and correlate the properties with potential application of them in the pharmaceutical field. In this work, oleic acid and meglumine were used as the building blocks for the synthesis of a supramolecular amphiphilic system. Initially, the ionic pair between oleic acid and meglumine was formed, generating oleate-meglumine. That amphiphilic was maintained in aqueous phase through hydrophobic interactions and hydrogen bonds. Two systems were synthesized, one in equimolar conditions and another in excess of meglumine. Systems with different water concentrations were synthesized from the precursor adducts, and the characterization was performed by polarized light microscopy (PLM), small angle X-ray scattering (SAXS) and scanning electron microscopy in the environmental mode (ESEM). The results showed that the supra-amphiphiles, either synthesized in equimolar conditions or not, were structured in micellar systems or hexagonal liquid crystals, according to the amount of water. The state of the water present in these amphiphiles was evaluated by differential scanning calorimetry (DSC), and it was observed that supra-amphiphiles synthesized from systems in non-equimolar conditions were able to retain a larger amount of water in their structure. The evaluation of the cytotoxicity of these systems was performed for SV-80 cells, which showed that the adducts could reduce cell viability in a dose-dependent manner. The in vitro bioadhesion of the supra-amphiphiles was also evaluated in a TAXT plus test in the Hold Until Time mode. It demonstrated that the systems presented superior bioadhesive properties compared to carbopol gel 5% used in pharmaceutical formulations. Finally, a model drug was incorporated in some systems, and the structural organization was re-evaluated by PLM and SAXS, which demonstrated that no structural change was observed in these systems with the drug incorporation
Self-assembly is the organization of building blocks in a system, in hierarchically-ordered structures without any external influence. The driving forces on molecular self-assembly are non-covalent interactions, such as van der Waals, electrostatics, hydrophobic, hydrogen bonding, amongst others. The inspiration for the emergent materials based on these interactions come from nature and naturally occurring biological systems such as DNA. The reversible nature of the non-covalent interactions ensures that the building blocks in a system can be broken and reunited according to the external environment. This property makes them capable of responding to different stimuli, such as variations in temperature, pH, solvent, radiation, etc. The reaction of an organic acid with meglumine, an aminocarbohydrate, leads to the formation of an ionic pair generally called carboxylate-meglumine. The aim of this work, besides the synthesis of the supra-amphiphiles, was to evaluate these systems in aqueous phase, and correlate the properties with potential application of them in the pharmaceutical field. In this work, oleic acid and meglumine were used as the building blocks for the synthesis of a supramolecular amphiphilic system. Initially, the ionic pair between oleic acid and meglumine was formed, generating oleate-meglumine. That amphiphilic was maintained in aqueous phase through hydrophobic interactions and hydrogen bonds. Two systems were synthesized, one in equimolar conditions and another in excess of meglumine. Systems with different water concentrations were synthesized from the precursor adducts, and the characterization was performed by polarized light microscopy (PLM), small angle X-ray scattering (SAXS) and scanning electron microscopy in the environmental mode (ESEM). The results showed that the supra-amphiphiles, either synthesized in equimolar conditions or not, were structured in micellar systems or hexagonal liquid crystals, according to the amount of water. The state of the water present in these amphiphiles was evaluated by differential scanning calorimetry (DSC), and it was observed that supra-amphiphiles synthesized from systems in non-equimolar conditions were able to retain a larger amount of water in their structure. The evaluation of the cytotoxicity of these systems was performed for SV-80 cells, which showed that the adducts could reduce cell viability in a dose-dependent manner. The in vitro bioadhesion of the supra-amphiphiles was also evaluated in a TAXT plus test in the Hold Until Time mode. It demonstrated that the systems presented superior bioadhesive properties compared to carbopol gel 5% used in pharmaceutical formulations. Finally, a model drug was incorporated in some systems, and the structural organization was re-evaluated by PLM and SAXS, which demonstrated that no structural change was observed in these systems with the drug incorporation
Descrição
Palavras-chave
Interações intermoleculares, Oleato - meglumina, Supra - anfifílicos, Cristais líquidos, Estado da água, Intermolecular interactions, Oleate - meglumine, Supra - amphiphiles, Liquid crystals, Water behavior