This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The long-term objective of this proposal is to develop delivery system of free-radical scavengers, RedOx enzymes, to the brain to attenuate neuroinflammation and increase neuroprotection in patients with ischemic stroke. Initial treatment for stroke involves removing the blockage and restoring blood flow. When acute phase is over, the treatment focused on restoration of brain function and cell survival. At this stage, delivery of RedOx enzymes to the brain to decrease inflammation is of great importance. However, the blood brain barrier (BBB) severely limits the delivery of therapeutic polypeptides to the brain and is a major obstacle to the successful treatment of many devastating central nervous system (CNS) diseases. To improve the therapeutic polypeptide transport to the brain, preserve enzyme activity, and reduce immunogenecity, the therapeutic RedOx enzymes will be cross-linked with a synthetic polyelectrolyte of opposite charge to form a stable polyion complex micelle, """"""""nanozyme"""""""". We hypothesize that 1) enzyme incorporated nanocontainers will be stable at physiological conditions, 2) will enhance permeability of the enzyme across the in vitro BBB, 3) will increase circulation time and/or permeability across the BBB in vivo, and 4) will improve biological activity in in vitro brain hypoxia and in vivo stroke models.
Specific Aims are 1) to assemble RedOx nanozymes (SOD, catalase) and tailor the composition for increased stability, circulation time and/or permeability across the BBB, 2) to determine permeability and transport mechanisms of the nanozymes synthesized in SA1 across the brain microvascular endothelial cells (BMVEC) in vitro and in vivo, 3) to determine whether the most promising nanozymes selected in SA2 can attenuate neuroinflammation and provide neuroprotection in an in vitro brain hypoxia and in vivo stroke models. It is anticipated that these studies will provide a novel platform for the delivery of therapeutic proteins across the BBB for regenerative therapy.
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