Dr. Alexey Vertegel
Associate Professor of Bioengineering
Free radical-induced damage makes an important contribution to secondary neuronal injury in central nervous system (CNS). No therapy exists at present to prevent or alleviate these effects. The use of enzymatic degradation of free radicals is a promising therapeutic approach to address the secondary neuronal damage in CNS. Superoxide dismutase (SOD) has recently been proposed as potentially powerful therapeutic agent for reducing free radical-induced injury, and has been shown to be efficient in a number of conditions, such as arthritis and asthma. It can thus be expected that the sustained presence of SOD in CNS will improve the outcome of secondary injury. However, therapeutic use of SOD for treatment of CNS injury is limited due to its inability to penetrate the blood-brain barrier.
Recently, ability of biodegradable poly(butylcyanoacryalte) (PBCA) nanoparticles (NPs) to penetrate through blood-brain barrier has been demonstrated. Here, we propose to achieve targeted delivery of SOD to the site of CNS injury using enzyme-coated PBCA nanoparticles. Targeting will be achieved through specific delivery of PBCA to CNS and/or through simultaneous conjugation of anti-NR1 receptor antibody to the NPs. Our working hypothesis is that enhanced delivery of targeted NPs with SOD to the site of injury can reduce free radical damage and reduce the degree of secondary damage to CNS. The strategic goal of this study is to develop a medication for intravenous administration, which could be used as neuroptotective treatment to reduce free radical mediated secondary neuronal damage.
To accomplish this goal, we will first determine optimal conditions for the preparation of protein-nanoparticle conjugates. Possibility to control system's bioactivity and targeting ability by varying the ratio of SOD and targeting anti-NR1 antibody attached to PBCA nanoparticles will be studied. Experiments with rat cortical neuronal cultures will then be used to evaluate safety and efficacy in vitro, and estimate dosage ranges for animal experiments. Finally, mouse stroke model will be used for the in vivo evaluation of the efficacy of the proposed therapeutic approach.
The short-term goal of this project is to collect preliminary data necessary for submission of a competitive RO1 application. In the long term, this research will lead to the development of a novel therapy for treatment/prophylactics of secondary neuronal injury in CNS. Results of this research will have implications in development new approaches for treatment of broad range of CNS conditions including stroke and spinal cord injury.
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