Pharmacokinetics of Therapeutic Nanoparticles in the CNS

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DESCRIPTION (provided by applicant): Progressive degeneration of neurons within the central nervous system (CNS) has a profound negative effect on the normal functions controlled by those cells and especially on the overall functioning of the individual. There are numerous neurodegenerative diseases which affect the brain including Alzheimer's disease, Parkinson's disease, Huntington's disease, etc. Degeneration of neurons in the retina, another part of the CNS, also occurs in many diseases including Age Related Macular Degeneration, Retinitis Pigmentosa, Diabetic Retinopathy, etc. Each of these neurodegenerative diseases appears to arise from unique primary defects which result in a chronic or an acute exposure of the neurons to Reactive Oxygen Intermediates (ROI). These toxic products of oxidative metabolism activate a cell suicide pathway - apoptosis. A universal goal in this area of research has been to find molecules which destroy or scavenge ROI in anticipation that the progression of these diseases can be slowed or halted. We hypothesized that specific inorganic nanoparticles, because of their activity, size (~5nm), nanoparticle status, insolubility and inorganic nature, would be able to enter cells and scavenge ROI and thereby prevent the activation of apoptosis and the death of the cells. Our preliminary data demonstrate that these specific nanoparticles can destroy ROI in test tubes, in retinal neurons in culture and can prevent ROI-mediated retinal degeneration in vivo. The overall objective of this project is to determine the pharmacokinetics (distribution and turnover) of these nanoparticles in order to test our hypothesis that they are acting by entering cells and preventing increases in ROI for as long as they are present. Specific Aim One will ask the question: How long after injection do the nanoceria particles remain within the cells of the eye? A corollary is whether the nanoparticles are toxic at any concentration and over prolonged periods of time. Modified preparations of the nanoparticles will also be tested. Transmission electron microscopy will be used to directly detect the nanoparticles whereas the albino rat light-damage model will be used to detect the retention of their ability to protect retinal function. Specific Aim Two will test the hypothesis that the mechanism by which the nanoceria particles function is by preventing the activation of apoptotic pathways rather than inducing other rescue pathways. Our data suggest that the nanoparticles will also be effective in inhibiting the progression of ROI-induced cell death that occurs in a variety of neurodegenerative diseases. The characterization of their pharmacokinetics in the retina is very important for validating their potential therapeutic applications in humans. The use of these inorganic nanoparticles as direct therapy for multiple diseases represents a novel strategy and suggests they may represent a unique technology. There are millions of people in the USA who have some form of neurodegenerative disease such as, Alzheimer's disease, Parkinson's disease, Dementia, Age Related Macular Degeneration, Diabetic Retinopathy, etc. Our preliminary data demonstrate that our rare earth element inorganic nanoparticles prevent Reactive Oxygen Species induced retinal degeneration in rats. Achievement of our specific aims, the characterization of the pharmacokinetics (uptake, distribution, and elimination) of these nanoparticles, is necessary for the eventual inhibition of neuronal degeneration and the preservation of mental abilities, vision, and overall physical activities in humans which are dependent on the central nervous system.