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. 2011 Jan 1;5(1):68-75.
doi: 10.1177/193229681100500110.

The design and development of fluorescent nano-optodes for in vivo glucose monitoring

Mary K Balaconis  1 , Kelvin Billingsley, Matthew J Dubach, Kevin J Cash, Heather A Clark
Affiliations

The design and development of fluorescent nano-optodes for in vivo glucose monitoring

Mary K Balaconis et al. J Diabetes Sci Technol. .

Abstract

Background: The advent of fluorescent nanosensors has enabled intracellular monitoring of several physiological analytes, which was previously not possible with molecular dyes or other invasive techniques. We have extended the capability of these sensors to include the detection of small molecules with the development of glucose-sensitive nano-optodes. Herein, we discuss the design and development of glucose-sensitive nano-optodes, which have been proven functional both in vitro and in vivo.

Methods: Throughout the design process, each of the sensor formulations was evaluated based on their response to changes in glucose levels. The percent change in signal, sensor reversibility, and the overall fluorescence intensity were the specific parameters used to assess each formulation.

Results: A hydrophobic boronic acid was selected that yielded a fully reversible fluorescence response to glucose in accordance with the sensor mechanism. The change in fluorescence signal in response to glucose was approximately 11%. The use of different additives or chromophores did not improve the response; however, modifications to the plasticized polymeric membrane extended sensor lifetime.

Conclusions: Sensors were developed that yielded a dynamic response to glucose and through further modification of the components, sensor lifetime was improved. By following specific design criteria for the macrosensors, the sensors were miniaturized into nano-optodes that track changes in glucose levels in vivo.

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Figures

Figure 1
Figure 1
Representation of the sensor mechanism. At low glucose concentrations, the boronic acid is bound to alizarin, generating a highly fluorescent species. As the concentration of glucose increases, glucose is extracted into the sensor displacing the alizarin resulting in a nonfluorescent species.
Figure 2
Figure 2
Synthesis of Compound A.
Figure 3
Figure 3
Synthesis of Compound B.
Figure 4
Figure 4
Reversibility of the glucose macrosensors composed of different boronic acids. Each cycle represents a time frame of at least 1 hour. The macrosensors contained either 4-mercaptophenylboronic acid (■, ncontrol = 7 and nglucose = 7), 2-ethoxypyridine-3-boronic acid (●, ncontrol = 6 and nglucose = 7), octylboronic acid (▲, ncontrol = 8 and nglucose = 8), or 3-aminophenylboronic acid (◄, ncontrol = 8 and nglucose = 8).
Figure 5
Figure 5
Percent change in fluorescence of the macrosensors in response to glucose after at least 1 hour. The macrosensors contained either the additive TBAC (ncontrol = 7 and nglucose = 8), TBAB (ncontrol = 8 and nglucose = 8), TBAI (ncontrol = 8 and nglucose = 8), or TDMAC (ncontrol = 8 and nglucose = 8).
Figure 6
Figure 6
Percent change in fluorescence of the macrosensors in response to glucose after at least 1 hour. The macrosensors contained either the polymer PVC-COOH (ncontrol = 7 and nglucose = 6 ), PVC (ncontrol = 7 and nglucose = 8), P(VDC/AN) (ncontrol = 9 and nglucose = 9), PCL (ncontrol = 6 and nglucose = 6), PUR (ncontrol = 7 and nglucose = 8), or PMMA(COOH)2 (ncontrol = 6 and nglucose = 6).
Figure 7
Figure 7
Percent change in fluorescence of the macrosensors in response to 1 M glucose in PBS after at least 1 hour. The macrosensors contained either the plasticizer DOS (ncontrol = 7 and nglucose = 6), NPOE (ncontrol = 8 and nglucose = 8), DPP (ncontrol = 8 and nglucose = 8), 3-octanone (ncontrol = 8 and nglucose = 8), or TEP (ncontrol = 8 and nglucose = 8).
Figure 8
Figure 8
Percent change in fluorescence of the macrosensors in response to glucose after at least 1 hour. The macrosensors contained either the chromophore alizarin (ncontrol = 4 and nglucose = 3), ARS (ncontrol = 8 and nglucose = 8), 7,8-DHMC (ncontrol = 3 and nglucose = 3), Compound A (ncontrol = 8 and nglucose = 8), or Compound B (ncontrol = 8 and nglucose = 8).
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