SBIR-STTR Award

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.

Public Health Relevance Statement:


Public Health Relevance:
The proposed work will result in a tool that can be used to monitor patient blood levels of chemotherapeutic drugs. Through continuous, real-time data collection, the proposed device will reduce toxicity from overdoses and inefficacy from under-dosing. Diagnostic Biochips already makes implantable biosensors for electrical detection and has the expertise required producing robust, commercially viable implantable biosensors for neuroscience and clinical applications. (End of Abstract)

Project Terms:
abstracting; Acute; Address; Adverse effects; Affect; Animals; aptamer; Area Under Curve; arm; base; Binding (Molecular Function); biochip; Biosensing Techniques; Biosensor; Blood; Blood drug level result; Blood Tests; Buffers; Cancer Patient; Cardiotoxicity; Catheters; Cells; Chemicals; Chronic; Cisplatin; Clinical; clinical application; Clinical Research; cost; Cytotoxic agent; Data; Data Collection; Dependence; design; Detection; Development; Devices; Diagnostic; DNA; docetaxel; Dose; Dose-Limiting; Doxorubicin; drug clearance; Drug Exposure; Drug Kinetics; Electronics; Ensure; Evolution; Finite Element Analysis; fluid flow; Geometry; Gold; Heart; Hour; improved; In Vitro; Indium; Individual; Infusion procedures; IV Fluid; Laboratories; Legal patent; Letters; Licensing; Life; Ligands; Malignant neoplasm of lung; Malignant Neoplasms; Manuals; Measurement; Measures; Metabolism; Methods; Microfluidics; minimally invasive; Modeling; Monitor; Neurosciences; New Drug Approvals; Non-Small-Cell Lung Carcinoma; novel strategies; Overdose; Patient Monitoring; Patients; personalized medicine; Pharmaceutical Preparations; Phase; point of care; preclinical study; prevent; Process; Production; Proteins; prototype; public health relevance; Risk; RNA; sample collection; sensor; small molecule; System; Techniques; Technology; Testing; Therapeutic; Therapeutic Uses; Time; Tissues; tool; Topotecan; Toxic effect; trend; Variant; Venous; Whole Blood; Work

The Specific Aim of this Phase II SBIR proposal is to develop a catheter-based biosensor for monitoring chemotherapeutic blood levels during drug infusion. This Phase II includes an IDE submission for clinical testing of our device. The ability to monitor blood levels in real-time will facilitate drug dosing within a narrow therapeutic range o minimize toxic side effects (commonly cardiotoxicity) and potentially maximize efficacy. Our initial target therapeutic agent is doxorubicin. Doxorubicin is a commonly used chemotherapeutic whose use is limited by dose-related cardiotoxicity (Swain et al., 2002; Legha et al., 1982). The proposed device allows for monitoring of doxorubicin peak blood levels and cumulative exposure, which are correlated to heart tissue damage (Desoize and Robert, 1994). In part, avoidance of cardiotoxicity is difficult due to inter-individual pharmacokinetic variabiliy - individuals receiving the same dose may have a five-fold variation in area-under- curve (AUC) and peak blood concentrations (Eksborg et al., 1985). Additionally, we will develop a similar imatinib sensor as part of this Phase II proposal as imatinib exposure is highly time dependent and plasma levels are correlated to toxicities (Eechoute et al., 2012; Widmer et al., 2008). In Phase I (1R43HL126473), we demonstrated a catheter-based biosensor for doxorubicin with a physiologically relevant dynamic range of 10nM - 10uM with a stable readout in blood for >8 hours. This device will be inserted into a patient's vein a few minutes prior to a chemo infusion, and will continuously measure drug levels prior to, during, and post infusion. The burdensome existing method of blood draws and lab analysis to monitor patient drug blood levels generally precludes pharmacokinetically guided treatment in a non-research setting. Our device will make individual PK monitoring possible and affordable on a routine basis during drug treatment in most any setting. Studies on pharmacokinetically guided treatment with fluorouracil have demonstrated improved objective response, produced a trend towards higher survival rate, and resulted in fewer grade 3/4 toxicities in metastatic colorectal patients (Gamelin et al., 2008). Th proposed device will allow such monitoring to be routine. In Phase I we showed that we could detect physiologically relevant doxorubicin concentrations for >8 hrs in blood using a prototype of a clinically implementable catheter design for IV fluid delivery. In order to commercialize this product for clinical use, we need to translate our device to a scalable, FDA-compliant manufacturing process and validate sensor functionality in vivo. Success will be determined by demonstrating in vivo sensing for 24 hours in devices manufactured by a process capable of producing 2,600 units/month at $15 per device. The proposed work will culminate in an FDA IDE submission.

Public Health Relevance Statement:
PUBLIC HEALTH RELEVANCE The proposed work will result in a tool that can be used to monitor patient blood levels of chemotherapeutic drugs. Through continuous, real-time data collection, the proposed device will reduce toxicity from overdoses and inefficacy from under-dosing. Diagnostic Biochips already makes implantable biosensors for electrical detection and has the expertise required to produce robust, commercially viable implantable biosensors for neuroscience and clinical applications.

Project Terms:
Adverse effects; Affinity; Animals; aptamer; Area Under Curve; base; Binding (Molecular Function); biochip; Biosensing Techniques; Biosensor; Blood; Blood drug level result; Blood Tests; Cardiotoxicity; Catheters; chemotherapeutic agent; Clinical; clinical application; cost; Data Collection; design; Detection; Devices; Diagnostic; DNA; Dose; Dose-Limiting; Doxorubicin; Drug Kinetics; Evolution; Exposure to; Fluorouracil; Gold; Heart; Hour; Human Resources; Imatinib; improved; in vivo; Indium; Individual; Infusion procedures; IV Fluid; Laboratories; Legal patent; Letters; Licensing; Ligands; Longevity; Malignant Neoplasms; manufacturing process; Measurement; Measures; metastatic colorectal; Methods; Methotrexate; minimally invasive; Monitor; Neurosciences; novel strategies; Overdose; Patient Monitoring; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Plasma; Process; Production; Proteins; prototype; public health relevance; Research; research clinical testing; response; sensor; Small Business Innovation Research Grant; small molecule; success; Survival Rate; targeted treatment; Technology; Testing; Therapeutic; Time; Tissues; tool; Toxic effect; Translating; trend; Variant; Veins; Work