RESUMO
PURPOSE: Brain-derived neurotrophic factor (BDNF) plays an important role in neuroprotection and repair, but long-term delivery from polymer systems has been challenging. We investigated the role the chemistry of the polymer played in loading and delivery of BDNF via microspheres, which are suitable for minimally invasive administration. METHODS: We synthesized polymers based on PLGA and PEG to determine what components augmented loading and delivery. We characterized microspheres fabricated from these polymers using a battery of tests, including sizing, in vitro release, and bioactivity of the BDNF using PC12 cells engineered to express the trkB receptor. RESULTS: We found that a triblock polymer of PLGA, PLL, and PEG led to the delivery of BDNF for periods of time greater than 60 days and that the BDNF delivered was bioactive. The microsphere size was amendable to injection via a 30 gauge needle, allowing minimally invasive delivery. CONCLUSIONS: PLGA-PLL-PEG leads to greater loading and longer-term delivery of BDNF than PLGA or a blend of the polymers. We hypothesize that the introduction of an amphiphilic PLGA-based polymer increases the interaction of the BDNF with the polymer and leads to release that more closely correlates with the degradation of the polymer.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Química Farmacêutica/métodos , Portadores de Fármacos/síntese química , Microesferas , Polímeros/química , Animais , Fator Neurotrófico Derivado do Encéfalo/química , Fator Neurotrófico Derivado do Encéfalo/farmacocinética , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Diferenciação Celular/efeitos dos fármacos , Portadores de Fármacos/química , Ácido Láctico/química , Modelos Químicos , Células PC12 , Tamanho da Partícula , Polietilenoglicóis/química , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Polilisina/química , Polímeros/síntese química , Ratos , Receptor trkB/agonistas , SolubilidadeRESUMO
Neural stem cells (NSCs) have the potential to replace the major cell types of the central nervous system (CNS) and may be important in therapies for injuries to and diseases of the CNS. However, for such treatments to be safe and successful, NSCs must survive and differentiate appropriately following transplantation. A number of polymer scaffolds have shown promise in improving the survival and promoting the differentiation of NSCs. To capitalize on the interaction between scaffolds and NSCs, we need to determine the fundamental material properties that influence NSC behavior. To investigate the role of material properties on NSCs, we synthesized a library of 52 hydrogels composed of poly(ethylene glycol) and poly(L-lysine) (PLL). This library of hydrogels allows independent variation of chemical and mechanical properties across a wide range of values. By culturing NSCs on this library, we have identified a subset of gels that promotes NSC migration and a further subset that promotes NSC differentiation. By combining the material properties of these subsets with the cell behavior, we determined that mechanical properties play a critical role in NSC behavior with elastic moduli promoting NSC migration and neuronal differentiation. Amine concentration is less critical, but PLL molecular weight also plays a role in NSC differentiation.
