Measure for Measure – Continuous Glucose Monitoring (CGM) using Fluorescent ortho-aminomethylphenylboronic acids - An ongoing Shakespearian Drama

Measure for Measure – Continuous Glucose Monitoring (CGM) using Fluorescent ortho-aminomethylphenylboronic acids - An ongoing Shakespearian Drama

The Holy Grail for a glucose sensor is that it should be non-invasive and continuous. Continuous glucose monitoring (CGM) in the case of diabetes mellitus patients provides information on the trajectory of glucose concentrations, thus avoiding both hyper- and hypo- glycemia. Such systems could potentially lead to closed loop monitoring where a sensor and insulin pump are coupled. In addition, it has been shown that tight glycemic control in hospital intensive care units (ICU) can reduce morbidity and mortality. 

In a seminal review by Anthony P. F. Turner in 1985 it was highlighted that for a successful sensor … the principal hurdle to success being seen as the lack of long-term stability of the biological component. (Biosensors, 1985, 1, 85-115. doi:10.1016/0265-928X(85)85006-9

Therefore, while the scientific debates were raging between Anslyn, James and Wang on the mechanisms of action of fluorescent ortho-aminomethylphenylboronic acids, several shrewd commercial ventures recognised the importance of an ortho-aminomethylphenylboronic acid system for the development of practical CGM systems. Since, an ortho-aminomethylphenylboronic acid is a chemosensor (a term introduced by Anthony W. Czarnik to describe chemical receptors), it would be stable unlike the glucose oxidase enzyme component of traditional electrochemical based glucose sensors. 

Two particular ventures worthy of notice are the Eversense system by Senseonics (Biosens. Bioelectron. 2014, 61, 227–231. doi:10.1016/j.bios.2014.05.022) and the Glysure Ltd system (J. Diabetes Sci. Technol. 2015, 9, 751-761. doi:10.1177/1932296815587937), both commercial systems use fluorescent ortho-aminomethylphenylboronic acids. The Eversense system is based on the first glucose selective fluorescent sensor developed by James, Sandanayake and Shinkai in 1994 (Angew. Chem. Int. Ed. Engl., 1994, 33, 2207-2209. doi:10.1002/anie.199422071 and J. Am. Chem. Soc. 1995, 117, 8982-8987. doi:10.1021/ja00140a013), and the Glysure system (Figure 1) is derived from the modular fluorescent system developed at the University of Bath by Arimori, Frimat and James in 2001 as part of a collaboration with Beckman Coulter (Chem. Commun., 2001, 1836-1837. doi:10.1039/B105994G and J. Chem. Soc., Perkin Trans. 1, 2002, 803-808. doi:10.1039/B108998F).   

Figure 1. Glucose selective fluorescent ortho-aminomethylphenylboronic acids. 

The Eversense system, which received FDA approval in 2019 (CE Mark approval 2017), is currently available in both the United States and Europe (Via Roche). While the Glysure system obtained a CE Mark approval 2015. Both the Eversense and Glysure Ltd systems have demonstrated that glucose selective fluorescent ortho-aminomethylphenylboronic acids are suitable for use in CGM systems.  

Great progress has been made since the first glucose selective fluorescent ortho-aminomethylphenylboronic acid was introduced 25 years ago. However, the story continues. The next step will be to develop sensor systems that are non-invasive and able to work in a closed loop with an insulin pump. In addition, while measuring glucose is important for diabetes mellitus - in order to fully understand the disease it is clear that many other biomarkers will need to be monitored. 

As well as this being the 25th Birthday of the first glucose selective fluorescent ortho-aminomethylphenylboronic acid, this year marks the 75th Birthday of Seiji Shinkai. Consequently, in June 2020 we will celebrate his career at the 7th International Conference on Molecular Sensors & Molecular Logic Gates (MSMLG 2020) in Reno Nevada (