Indwelling biosensor for real-time chemotherapeutic blood level monitoring

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 DESCRIPTION (provided by applicant): The Specific Aim of this proposal is to test the feasibility of developing a catheter-based, indwelling biosensor for the real-time, continuous monitoring of chemotherapeutic blood levels of lung cancer patients. A tool that continuously monitors blood drug levels in real-time will enable an unprecedented understanding of an individual patient's distinctive metabolism and clearance of drugs. This information is critically needed for three reasons: 1) to reduce drug dosing related toxicities, such as heart tissue damage, 2) to potentially improve efficacy of chemotherapeutics by ensuring patients maintain therapeutic drug blood levels, and 3) to facilitate development and approval of new drugs with narrow therapeutic ranges and high interindividual variability. The proposed tool will measure blood levels of chemotherapeutic drug doxorubicin every 5 seconds in flowing venous whole blood for real-time determination of blood levels and accurate calculation of cumulative drug exposure. Current methods require multiple, timely blood draws that are error prone and require manual labor for both sample collection and laboratory analysis. No point-of-care method is available to detect doxorubicin. The proposed work is based upon an existing doxorubicin microfluidic biosensor that works in whole blood for over 4 hours (Ferguson et al., 2013; see Plaxco letter of support). We propose to design and fabricate a biosensor that utilizes the advantageous fluidic dynamics of the existing system, but that is small enough to fit in an I.V. catheter in a patient's arm. Diagnostic Biochips has already developed a proprietary MEMS process for fabricating implantable multi-electrode arrays. We will accomplish our Specific Aim by: 1) using finite element analysis to model fluid flow in venous, flowing, whole blood to demonstrate a laminar boundary buffer layer at the sensor interface to prevent biofouling, 2) fabricate the optimized catheter design and functionalize the biosensor, and 3) develop electronics for point-of-care use. The test of feasibility will be the successful detection of doxorubicin in flowing whole blood for at least 8 hours at physiologically relevant concentrations (10 nM - 10 uM; Eksborg et al., 1985) in a device that with clinically implementable design (defined by similarity in size and geometry to existing I.V. catheters and acceptable levels of I.V fluid delivered). In Phase II, we will test our sensors in live animals and, using principles of robust design, turn our prototype into a commercial product.