Non-invasive and continuous therapeutic drug monitoring (TDM) in humans is vital to assess drug efficacy and safety. It is known that patients exhibit significant differences in absorption, distribution and elimination of drugs. Especially for drugs with a narrow therapeutic window, continuous TDM is critical to develop personalized medicine. Conventional drug monitoring requires a patient blood draw and subsequent clinical tests. Thus, new technology for routine TDM without drawing blood samples would be of extremely high value. Here, we develop fluorescent sensors where signals are collected by an In Vivo Flow Cytometer. The sensors can continuously monitor changes in analyte concentration during circulation in the body. The sensor particles are coated with natural erythrocyte membranes to extend the circulation time. This camouflage strategy allows sensors to bypass macrophage uptake and/or systemic clearance. Here, we use cloaked sodium sensors to validate our TDM scheme for the first time. Sodium ions are extracted from surrounding environment into the sensor core by the sodium ionophore and protons are expelled from the sensor to maintain the electro neutrality, reporting changes in sodium concentration via the fluorescence intensity change of the pH-responsive chromoionophore. The sensitivity of the sodium sensor is 43% change per log unit of sodium concentration in the physiology range. The sensors also exhibit full reversibility and retain in vitro stability over 7 days. The circulation time of the sensor reaches over 72 hours with a half-life over 6 hours in nude mice. In the future, we will advance our sensing platform including ratiometric measurements and apply it to therapeutic lithium level monitoring for the treatment of bipolar disorder.

Erythrocyte membrane-camouflaged sensor for continuous therapeutic drug monitoring

256th National Meeting (2018)

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