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. 2015 Feb 24;9(2):1692-8.
doi: 10.1021/nn5064858. Epub 2015 Jan 21.

Optical drug monitoring: photoacoustic imaging of nanosensors to monitor therapeutic lithium in vivo

Kevin J Cash  1 , Chiye Li, Jun Xia, Lihong V Wang, Heather A Clark
Affiliations

Optical drug monitoring: photoacoustic imaging of nanosensors to monitor therapeutic lithium in vivo

Kevin J Cash et al. ACS Nano. .

Abstract

Personalized medicine could revolutionize how primary care physicians treat chronic disease and how researchers study fundamental biological questions. To realize this goal, we need to develop more robust, modular tools and imaging approaches for in vivo monitoring of analytes. In this report, we demonstrate that synthetic nanosensors can measure physiologic parameters with photoacoustic contrast, and we apply that platform to continuously track lithium levels in vivo. Photoacoustic imaging achieves imaging depths that are unattainable with fluorescence or multiphoton microscopy. We validated the photoacoustic results that illustrate the superior imaging depth and quality of photoacoustic imaging with optical measurements. This powerful combination of techniques will unlock the ability to measure analyte changes in deep tissue and will open up photoacoustic imaging as a diagnostic tool for continuous physiological tracking of a wide range of analytes.

Keywords: bipolar; continuous monitoring; diagnostic; nanomedicine; nanoparticle.

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Figures

Figure 1
Figure 1
Nanosensors for detecting lithium can be monitored with both photoacoustic (a) and fluorescent (b) imaging techniques. Both approaches use multiwavelength ratiometric imaging to generate a response that changes with lithium concentration and minimizes nonspecific changes. In photoacoustic monitoring, two wavelengths are used to interrogate the chromoionophore embedded in the sensors, and the photoacoustic waves from each wavelength change as lithium concentration changes. In fluorescent imaging, a near-IR fluorophore is added to the sensors. The intensity of FRET from the chromoionophore to the near IR dye changes with lithium concentration, whereas directly exciting the near-IR dye does not change intensity—serving as a sensing reference. The fundamental mechanism of the lithium response (c) is lithium extraction by an ionophore (L) into the core of the nanosensor, which deprotonates a chromoionophore (CH+), changing the optical properties of the nanosensor. An additive (R-) balances the charge inside the sensor.
Figure 2
Figure 2
Responses of photoacoustic nanosensors to lithium within physiological ranges. The photoacoustic spectrum (a) has two peaks centered at 515 and 660 nm. The 515 peak increases with lithium concentrations, and the 660 peak decreases. In vitro measurement of this ratio (b) responds to lithium and is insensitive to common confounding factors such as concentration of nanosensors. Photoacoustic imaging of nanosensors under a 1.5 mm thick layer of chicken tissue (c) shows signal attenuation of the 515 nm peak, while retaining the ratiometric lithium response (d). PA: photoacoustics.
Figure 3
Figure 3
Photoacoustic nanosensors imaged in a small animal model. Dual wavelength images of the nanosensor injection using photoacoustic tomography (a) clearly show the boundary of the injection. A depth profile (b) taken along the line below the red asterisk in (a) shows the nanosensor injection in the tissue. The response of nanosensors to systemic lithium administration (c) for three animals yields a time to maximum lithium of 14 minutes (lithium n=3, vehicle n=1).
Figure 4
Figure 4
Fluorescent nanosensors for lithium yield similar results to photoacoustic nanosensors despite having a different readout mechanism. The images of both wavelengths (a) demonstrate the excellent signal to background obtained with near IR imaging, and the nanosensor measurement of absorption kinetics (b) yields a time to peak lithium of 18 min, similar to that measured with photoacoustics. The response is dose-dependent, with increases in lithium yielding higher signal. (n=3 for each lithium curve, n=6 for vehicle)
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