In-Vivo Monitoring of Therapeutic Drug Transport Across Biological Barriers

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Project Summary The ability of therapeutic drugs to access specific organs strongly depends on the nature of the blood-tissue barrier at said organs. The prostate and brain, for example, have tight barriers with no intercellular gaps, and most drugs cannot permeate them at sufficiently high levels to be therapeutically effective. Thus, understanding the relationships between drug chemical structure, dosing regimen, and organ penetration is crucial to the development of new and effective drug therapies. Motivated by this, the long-term goal of this program is to establish a measurement standard of molecular transport parameters affecting the passage of therapeutic agents across biological barriers in vivo. Specifically, the objective of this proposal is to demonstrate that electrochemical, aptamer-based (E-AB) sensors – an emerging sensing platform with the ability to continuously measure the levels of specific molecules in the body – can support continuous monitoring of molecular transport from blood to liver, prostate and brain. The proposed measurements will determine the transport parameters of seven therapeutic agents (three aminoglycoside, three β-lactam and one glycopeptide antibiotics) across four biological barriers (i.e., blood-liver, blood-prostate, blood-brain and blood-cerebrospinal fluid). These drugs were chosen because, although effective at treating infections across organ barriers, they cause dangerous side effects driven by their narrow therapeutic window, making their precise dosing an important medical challenge. The central hypothesis of this work is that achieving spatially and temporally resolved drug measurements in blood and target organs will produce unprecedented permeability data that will guide new therapeutic drug development toward the creation of permeability-enhanced therapeutics and more effective dosing regimens. This hypothesis will be tested by pursuing three specific aims: 1) Determine the kinetics of drug uptake in the liver via continuous, seconds-resolved E-AB measurements; 2) Determine the transport kinetics of antibiotics through the prostatic barrier; and 3) Determine the transport kinetics of prophylaxis antibiotics delivered from blood to the brain. The proposed research is significant because it will define the structural and transport characteristics necessary for therapeutic agents to penetrate targeted organs and propel the study of other therapeutics beyond the families of antibiotics considered here. Thus, this work will develop foundational knowledge and generate the necessary resources for other researchers and industries – working on drug development, in-vivo testing and clinical dose scaling – to advance the field of therapeutics. The proposed research will have an immediate positive impact as it will establish a better understanding of therapeutic drug transport within compartments in the body. Longer term, this work will have established the groundwork necessary for the in-vivo evaluation of molecular transport across tight biological barriers.