RESUMEN
Polymeric microparticles with covalently attached biotin are proposed as versatile targeting vehicles for drug delivery. The proposed microparticles made of 85/15 poly (lactic-co-glycolic acid) (PLGA) will have biotin available on the outside of the particle for the further attachment with an avidin group. Taking advantage of biotin's high affinity for avidin, and avidin's well-known chemistry, the particle has the potential to be easily coated with a variety of targeting moieties. This paper focuses on the design and resulting effect of adding biotin to PLGA microparticles using an integrated experimental and modeling approach. A fluorescent-tagged avidin (488-streptavidin) was used to confirm the presence and bioavailability of biotin on the outside of the particles. For the purpose of this study, bovine serum albumin (BSA) was used as a model therapeutic drug. Microparticles were created using two different types of polyvinyl alcohol 88 and 98 mol% hydrolyzed, which were then analyzed for their size, morphology, and encapsulation capacity of BSA. Release studies performed in vitro confirmed the slow release of the BSA over a 28-day period. Based on these release profiles, a release kinetics model was used to further quantify the effect of biotinylation of PLGA microparticles on their release characteristics by quantitatively extracting the effective drug diffusivity and drug desorption rate from the release profiles. It was found that the biotinylation of the PLGA microparticles slowed down both the drug desorption and drug diffusion process, which confirmed that biotinylated PLGA microparticles can be used for controlled drug release. The presented technology, as well as the proposed integrated experimental and modeling approach, forms a solid foundation for future studies using a cell-specific ligand that can be attached to avidin and incorporated onto the microparticles for targeted delivery.
RESUMEN
Spinal cord injury (SCI) triggers a large inflammatory response that results in exacerbated tissue damage. Locally delivering anti-inflammatory drugs could mitigate this secondary wave of degeneration. The mitogen-activated protein kinase family members p38 and c-Jun N-terminal kinase (JNK) play important roles in the inflammatory response and cell death. We propose that the use of polymer thin films, made of polyvinyl alcohol and polyvinyl pyrrolidone blends (PVA-PVP), can be used to provide local release of inhibitors to p38 and JNK post-SCI. Release studies performed in vitro confirmed the inhibitors could be released from the film for up to 7 days. The thin film was also tested for its surgical feasibility using a cervical contusion model of SCI in adult female rats. Films with or without the inhibitors were placed subdurally over the injury site immediately following SCI. Animals were sacrificed 5 days post-SCI and spinal cord tissue above and below the injury site was harvested. Additionally, films were removed for analysis. Scanning electron microscopy confirmed the anti-fouling properties of the PVA-PVP film. Tissue histology confirmed that the films themselves did not generate a large immune response, but they did compress the tissue slightly at its placement above the injury site. Finally, quantitative Western blot analysis determined the films loaded with p38 and JNK inhibitors delivered bioactive agents to the injury site and resulted in a significantly decreased amount of pro-cell death proteins. These data indicate that PVA-PVP films can be used to effectively deliver drugs to a SCI site.