University of Central Florida Proposal Number: CBET - 0708172
Retinal diseases lead to partial or complete loss of vision to millions of people throughout the world and causing economic stress on healthcare systems. In the United States alone, there are approximately 14 million cases per year and is likely to increase further as the average lifespan increases. Although the causes of these disorders are multiple and complex, reactive oxygen species (ROS) are considered to play a central role. Rare earth metal oxide nanoparticles (NPs) have shown promise as a therapeutic agent to scavenge these ROS responsible for retinal degeneration. However the current understanding of the biological interaction of these NPs with cells and tissue is limited and the correlation of this with thematerial chemistry, size and surface properties is necessary to ensure safe clinical usage. The proposed collaborative research between University of Central Florida (UCF) and University of Oklahoma (OU) will address the basic scientific aspects involved in engineering active NPs for SOD mimetics and therapeutic applications and evaluate its effectiveness as novel antioxidants in preventing the death of photoreceptor cells in a living animal model. The results should lead to therapies which will prolong the functional life of neurons and tissues in multiple diseases which currently afflict many people.
From the intensive research, we have concluded that microenvironment plays an important role in regulating the reactivity of our surface engineered nanoceria (CNPs). It was found that CNPs crystallized in water has higher activity (energetically easier to extract oxygen from the surface of the nanoparticles) to compared to CNPs crystallized in vacuum. Simulation result reveal that degree of reduction (Ce3+/Ce4+ =0.6) are more active towards oxygen release compared to nanoparticle with Ce3+/Ce4+ = 0.02). The surface chemistry alteration on CNPs enable us to design unique antioxidant properties, that could be harnessed in its proapoptotic properties important in cancer therapy, where the cancer cells needs to be destroyed. Further, we have continued to focus on the study of the interaction of CPNs with reactive nitrogen species, such as, peroxynitrite and the results are published in journal papers. The specific molecules scavenged in vivo and the oxidation state of the CNPs still needs to be deciphered however the results from this study suggest that in the presence of CNPs, peroxynitrite, or one of its breakdown products may react with the surface of CNPs. It is likely that the protection seen in many of these studies may be attributed to CNPs interaction with ONOO- and the nature of this reaction and its products are still actively under investigation by our group. Some of the unique features are now being applied to some select retina degeneration models. Our findings demonstrate that CNPs slow degeneration and improve retinal function and structure for up to 120 days. CNPs also increase the expression of photoreceptor-specific genes catalytic antioxidants in vivo and may be broad spectrum therapeutic agents for multiple types of ocular diseases. We also did not observe any acute or long term negative effects of CNPs on retinal function or cytoarchitecture even after a long term exposure. Because CNPs are effective at low dosages, nontoxic and are retained in the retina for extended periods, we conclude that CNPs (a new type of inorganic catalytic antioxidants developed from this research) are promising ophthalmic therapeutics for treating retinal diseases known to involve oxidative stress in their pathogeneses.
