4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN): A Phase II Clinica

DESCRIPTION (provided by applicant): In cellular and extracellular studies of individual neurons and neural networks, it is imperative to monitor both electrophysiological and neurochemical activity. Electrochemical probes have now been fabricated at a size scale appropriate for such studies, but many neurotransmitters cannot be detected electrochemically. Furthermore, chemically-sensitive electrodes often consume their target analytes; at the sub-micron size scales of interest, this can lead to significantperturbation of the system being studied. Intelligent Optical Systems (IOS), working with the University of California Los Angeles (UCLA), proposes to create a new tool for cell-level studies of neurochemistry - a probe that can measure the concentrationsof multiple analytes in sub- micron volumes. In this proposed sensor a multi-channel optical waveguide structure, tapered to a size smaller than the wavelengths of light it uses, will be functionalized with fluorescent indicators that react reversily withtarget substances. This unique probe will enable continuous monitoring of localized neurochemical concentrations on a time scale of milliseconds. During Phase I of the proposed project, IOS will construct 3- and 4-channel nanoprobes and, consulting withUCLA, will activate them with chemical- and biochemical-based recognition systems for analytes of interest. Optically-activated crosslinking will immobilize organic indicators embedded in permeable polymer dots directly in the near field of optical channels for detection of ionic species (e.g., Ca++) and small molecules. For other species of interest, photoactivated binding will be used to form a layer of patented biochemical reversible chemical recognition units in the optical field. After fabrication, these probes will be calibrated in stock solutions containing their target molecules, and then used to study extracellular analyte levels in ex vivo (cultured) neurons and brain slices to demonstrate their effectiveness in studying critically importantneurobiological phenomena. In Phase II, in vivo applications will be investigated. Ultimately, the IOS-UCLA team plans to combine these optical neuro-nanoprobes with microelectrode-based sensors of similar size to create arrays with large numbers (gt100) of multifunction probes for simultaneous electrical and chemical mapping of neurological activity at a scale out of reach, and a level of chemical detail currently out of reach with state-of-the-art technology. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: This is a project to develop and test tools for studying the way brain cells work, and how they talk to one another. We will make ultra-small probes and use them in our labs to study the chemicals that help people think, act, and remember.Large numbers of these probes, combined on a single patch, could eventually be used to monitor brain activity and help guide the treatment of epilepsy, strokes, and other diseases.