Almodóvar-Arbelo, Noelia E.

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    Design of composite protein microcrystals for the sustained oral delivery of antigens
    (2015) Almodóvar-Arbelo, Noelia E.; Torres-Lugo, Madeline; College of Engineering; Domenech Garcia, Maribella; Latorre Esteves, Magda; Department of Chemical Engineering; Cancelos, Silvina
    Oral immunization is a promising method to decrease access of allergens and pathogens to the body. Oral delivery of antigens is challenged by the anatomical conditions of the gastrointestinal tract, such as degradation by the acidic environment of the stomach and protein breakdown by proteases. The use of protein composite microcrystals to deliver antigens to the gastrointestinal tract was proposed to challenge these difficulties. Composite microcrystals were composed of an antigen in the form of crystalline protein and a biodegradable polymeric carrier, alginate. This work focused on testing the application of this mechanism with the model protein lysozyme, insulin and ovalbumin, as well as testing the protein release behavior in simulated gastrointestinal conditions of lysozyme microcrystals from the alginate matrix. It was hypothesized that by using a protein in crystalline form, the release in simulated gastrointestinal conditions of the protein in alginate beads would be controlled and sustained. Alginate beads and microbeads were created via ionic crosslinking with calcium. Successful crystallization of lysozyme was performed in these systems demonstrating that calcium-alginate served as an adequate matrix for lysozyme protein crystallization. Protein release behavior of solvated and crystallized protein from alginate beads when exposed to simulated gastric and intestinal fluid was compared. Composite microcrystals released the majority of its content in simulated intestinal fluid and a smaller quantity in simulated gastric fluid. Protein transport of the liquid protein from the alginate matrix was characterized by the power law as pseudo Fickian, while the composite system was found to be anomalous, where the release is characterized by a combination of polymer relaxation and diffusion. Release kinetics studies showed that crystalline protein was released slower and in a sustained way than its liquid counterpart, independently from the alginate content being used as indicated by a smaller diffusion coefficient. The proposed crystallization method was furthermore applied to insulin and ovalbumin. Insulin was found to crystallize in covalent crosslinked alginate beads. Ovalbumin, on the other hand, preferably crystallizes on the surface of calcium alginate beads. These results showed a potential new approach for the oral delivery of proteins.