The specific aim of this proposal is to test the feasibility of developing a tool for the simultaneous and continuous measurement of pharmaceutical drug concentrations and electrophysiology recording in the brain for preclinical testing of central nervous system (CNS) drug candidates. The benefits of the proposed tool are three-fold: 1) improved method of performing in vivo pharmacokinetics (PK) studies with orders of magnitude improvements in spatial and temporal resolutions over microdialysis, 2) the ability to monitor physiological changes at the cellular level for improved understanding of pharmacodynamics (PD) and 3) the combination of these capabilities in a single tool reduces the number of animals needed for evaluation of a drug candidate. The proposed probe will detect lurasidone (Latuda) and measurements with the proposed probe will be directly compared with traditional PK techniques microdialysis, plasma draw, and cerebral spinal fluid (CSF) draw to demonstrate utility in drug development. Through our use of aptamers as a detecting mechanism, this platform is extensible to monitor most any drug (MW~300 Da) in the brain. Currently, microdialysis is used to determine PK of drugs in the brain, but it is labor-intensive, error-prone, unsuitable for a significant number of drug candidates, and has low temporal resolution at 10-20 minutes per data point (Griffin et al., 2009; Loryan et al., 2014). Additionally, the proposed tool can monitor changes in neuronal firing, which is currently used to study the effect of marketed drugs and has been suggested as an effective way to improve the evaluation of drug candidates (Tan et al., 2010; Depoortere et al., 2005). The proposed tool combines PK and PD studies for improved scientific information and a reduction in required animals and labor. We will accomplish our specific aim by: 1) Fabricating silicon probes and functionalize with aptamers, 2) Selecting an aptamer against psychiatric drug lurasidone (Latuda), 3) Developing electronics for point-of-use neural recording and chemical sensing, and then 4) Performing in vivo studies with both the proposed sensor and traditional PK methods. Success in this Phase I feasibility study will be determined by will be determined by the accurate detection of physiologically relevant lurasidone concentrations and concomitant neural firing recording for 24 hours (typical during of a PK study, depending on drug half-life).
Public Health Relevance Statement: Public Health Relevance: Psychiatric diseases are the leading cause of healthcare costs at approximately $57.5 billion annually in the US alone. Despite the significant need for improved psychiatric drugs, many large pharmaceutical companies are reducing or eliminating R&D in this area due to the multitude of failures experienced over the last 20 years. The goal of this proposal is to develop a tool for the simultaneous recording of neuron electrical activity and measurement of brain drug levels to facilitate psychiatric drug discovery through improved data on the brain response to drugs.
Project Terms: Animal Testing; Animals; aptamer; Area; Base Pairing; Behavioral; Binding (Molecular Function); biochip; Brain; Central Nervous System Agents; Cerebrospinal Fluid; Chemicals; Clinical; Clinical Trials; Collection; cost; Custom; Data; depressive symptoms; Detection; Diagnostic; DNA Sequence; drug candidate; drug development; drug discovery; drug efficacy; Drug Kinetics; drug market; Electronics; Electrophysiology (science); Evaluation; experience; Failure (biologic function); Feasibility Studies; gamma-Aminobutyric Acid; Goals; Half-Life; Health Care Costs; Hour; improved; in vivo; Institutes; Legal patent; Letters; Licensing; Measurement; Measures; Mental disorders; Methods; Microdialysis; Monitor; Mus; Neurons; Noise; novel; novel strategies; Performance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Physiologic Monitoring; Plasma; pre-clinical; preclinical evaluation; Preclinical Testing; Process; Production; public health relevance; Rattus; Reaction Time; relating to nervous system; research and development; response; Running; Science; sensor; Signal Transduction; Silicon; Site; success; Techniques; Technology; Testing; Tissues; tool
