Molecular Design of a New Diboronic Acid for the Electrohydrodynamic Monitoring of Glucose

Article abstract of DOI:10.1002/anie.201904595

A new dicationic diboronic acid structure, DBA2+, was designed to exhibit good affinity (K_d≈1 mm) and selectivity toward glucose. Binding of DBA2+ to glucose changes the pK_a of DBA2+ from 9.4 to 6.3, enabling opportunities for detect

Full text of DOI:10.1002/anie.201904595

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Accepted Article
Title: Molecular Design of a New Diboronic Acid for Electrohydro-
dynamic Monitoring of Glucose
Authors: Guillermo Carlos Bazan, Bing Wang, Kuang-Hua Chou,
Bridget Queenan, and Sumita Pennathur
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201904595
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Molecular Design of a New Diboronic Acid for Electrohydro-
dynamic Monitoring of Glucose
Bing Wang,[a] Kuang-Hua Chou,[b] Bridget N. Queenan, [b,c] Sumita Pennathur *[b] and Guillermo C.
Bazan* [a]
Abstract: A new dicationic diboronic acid structure, DBA2+, was
designed to exhibit good affinity (Kd ≈ 1 mM) and selectivity toward
acidity can induce changes in solution pH, electrostatic
interactions and surface charge. These properties may
glucose. Glucose binding changes the pKa of DBA2+ from 9.4 to 6.3, ultimately be useful for optical, conductimetric, and field-effect
enabling opportunities for detection at physiological pH. Proton
release from DBA2+ is firmly relative to glucose concentrations
within the physiologically relevant range (0-30 mM), as verified by
conductimetric monitoring. Neglectable interference from other
sugars (e.g. maltose, fructose, sucrose, lactose, and galactose) was
observed. These results demonstrate the potential of DBA2+ for
selective, quantitative glucose sensing. The overall nonenzymatic
strategy based on electrohydrohynamic effects may enable the
development of stable, accurate and continuous glucose monitoring
platforms.
transistor-based glucose sensing.[4a,4c,5] Mono boronic acids bind
glucose, but also other sugars, especially fructose, galactose
and ribose, which are considered interferents in practical
glucose-detection platforms. Two strategies have evolved to
confront this challenge: i) using glucose as a linker to change
the
aggregation
of
BA-functionalized
hydrogels
or
fluorophores;[6] ii) the development of diboronic acids (DBAs)
with molecular architectures that are more selective toward
glucose.[7] Indeed, DBAs have now contributed to the first non-
enzymatic commercial CGM.[7b,7c,8] However, DBAs have been
primarily studied within the context of optical sensing of glucose,
while the changes in pKa that take place upon glucose binding
remain to be fully harnessed. It is therefore an opportune time to
examine the design of DBA structures that open up different
alternate detection strategies, while meeting requirements at
physiological conditions. [7f,9]
Dysfunction of feedback regulations responsible for controlling
glucose levels generally cause diabetes, leading to serious
complications such as heart disease, kidney failure, and
blindness.[1] Continuous glucose monitors (CGMs) are a class of
on-body devices which track glucose levels. If the CGM provides
stable, quantitative, real-time glucose measurements, it can be
integrated with insulin-delivery systems to automate closed-loop
control of glucose. Most commercially available CGMs employ
enzymatic electrochemical glucose-sensing strategies. Due to
enzyme instability and drift, these devices therefore suffer from
delayed startup times (> two hours), short lifetimes (< two
weeks) and the need for frequent calibration.[2] Non-enzymatic
catalytic electrochemical sensors are a promising alternative, but
traditionally have been challenged by selectivity and changes in
electrode performance.[3] To develop a non-enzymatic and non-
electrochemical glucose-sensing platform, we explored the
molecular design of synthetic glucose-recognition moieties
based on boronic acid (BA).[4]
BAs can form reversible covalent linkages to 1,2- and 1,3-
diols, and in particular those present in sugars. In the process of
binding diols, BAs become considerably more acidic, with pKa
decreases of 2-4 units. The binding-induced change in BA
Scheme 1. Schematic illustration of the binding of DBA2+ to glucose in PBS
buffer solution and the anticipated changes to solution conductivity due to the
difference in the composition of ions.
In this contribution, we report on a new DBA structure
(DBA2+, see Scheme 1) that combines appropriate affinity
toward and changes in pKa upon glucose binding. This
combination of properties enables integration into a simple
glucose-sensing assay based on solution conductivity, see
Scheme 1. That DBA2+ contains two BAs at a relatively
restricted distance was anticipated to provide the basis for
glucose selectivity. Glucose binding causes DBA2+ to lower its
pKa from 9.4 to 6.3, thus causing deprotonation at physiological
pH. In phosphate buffer, released protons are neutralized by
[a]
[b]
[c]
Dr. B. Wang, Prof. G. C. Bazan
Center for Polymers and Organic Solids, Department of Chemistry
and Biochemistry, University of California, Santa Barbara
California 93106, United States
E-mail: bazan@chem.ucsb.edu
K. H. Chou, Dr. B. N. Queenan, Prof. S. Pennathur
Department of Mechanical Engineering,
University of California, Santa Barbara
California 93106, United States
E-mail: sumita@engineering.ucsb.edu
Dr. B. N. Queenan
Quantitative Biology, Harvard University, Cambridge,
Massachusetts 02138, United States
HPO42-. Therefore, glucose mediates the conversion of DBA2+
2-
and HPO4
(higher ionic conductivity, left, red) to
Supporting information for this article is given via a link at the end of
the document.
-
DBA2+/glucose complex (DBA-G) and H2PO4 (lower ionic
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10.1002/anie.201904595
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conductivity, right, blue). The glucose sensing strategy is thus
built around the reduction of pKa provided by the molecular
structure DBA2+.
We next determined the affinity and selectivity of DBA2+ to
glucose compared to other sugars (fructose, galactose, maltose,
sucrose and lactose) by measuring changes in UV-vis
absorption at 280 nm with increasing sugar concentration
Absorbance values of 1 mM DBA2+Br were measured in
phosphate buffer (50 mM, pH = 7.4) containing various sugar
species ([sugar] = 0 to 512 mM). The disassociation constant (Kd)
of DBA2+ was calculated through non-linear curve fitting
according to previous work (see Supporting Information for
details).[12] The Kd value for glucose was found to be 0.9±0.1 mM
(Figure 2B, red). Kd values for fructose and galactose were
determined to be 1.7 mM and 16 mM, respectively (Figure 2B,
brown and blue). The Kd values for maltose, sucrose and lactose
could not be determined due to their low affinity towards DBA2+.
DBA2+ therefore shows selectivity to glucose and fructose
relative to other saccharides. Importantly, the maximum
physiological or therapeutic plasma concentrations of fructose
(0.13 mM) and galactose (0.28 mM) are well below those for
glucose (normal range: 4-8 mM, diabetic range 0-30 mM). Due
to the marked difference in absolute concentrations, any
influence by the presence of fructose and/or galactose on the
DBA2+ based system is predicted to be negligible.[8b]
Successful operation of the assay in Scheme 1 requires
DBA2+ to exhibit good solubility, high selectivity to glucose and
a change of pKa upon glucose binding in an aqueous medium at
pH = 7.4. Examination of the literature revealed the summary of
typical DBA structures and properties summarized in Figure S1
and Table S1, respectively.[7b,7e-g] Our rationale for designing
DBA2+ based on this previous body of work is provided in the
Supporting Information.[10] Figure 1 shows the remarkably simple
synthesis of DBA2+. Briefly, 1,4-dibromomethyl benzene was
reacted with dimethyl amine in tetrahydrofuran; a subsequent
reaction with 2-bromomethylphenyl boronic acid yields the target
DBA2+ with bromide counter anions (DBA2+Br).
OH
OH
HO
HO
B
B
HO
OH
B
Br
Br
Br
Br
N
Br
CH3NHCH3
N
30%
95%
DBA2+Br
Figure 1. Synthesis route to DBA2+Br.
We first determined the pKa of DBA2+ before and after
glucose binding. To do so, we took advantage of differences in
absorption spectra upon formation of tetrahedral borate anion in
high pH media.[11] Specifically, 1 mM DBA2+Br was dissolved
with or without 200 mM glucose in a series of 50 mM buffers of
pH 4 to 11.5. Absorbance at 280 nm was measured and pKa
values were determined by curve fitting the changes in
absorbance as a function of pH (Figure 2A). DBA2+ exhibits a
pKa value of 9.4. In the presence of 200 mM glucose, conditions
that provide DBA-G, one observes a shift in the plot, from which
one derives a pKa value of 6.3. Importantly, the ~3 unit change
in pKa for DBA2+ and DBA-G centers around pH = 7.4. These
conditions were anticipated to provide the basis for the response
toward glucose under physiologically relevant conditions.
Figure 3. Measuring glucose concentration via monitoring solution resistance.
(A) Structure of DBA2+P through anion exchange. (B) Schematic device
architecture for impedance spectra and time resolution monitoring at high
frequency. (C-D) Solution resistance (R) of 1mL of test solution changes with
continues addition of 0.5 M or 2 M glucose concentration (C) or the same
volume of water for control (D). After adding glucose to 30 mM, the testing
solution was diluted to 12 mM (brown in C) to confirm repeatability.
Based on its properties, we concluded that DBA2+ could
potentially support
a
conductivity-based glucose-sensing
platform using low voltage AC impedance spectroscopy, which
offers the promise of long-term stability and the potential for
miniaturization.[13] Impedance spectra in the 1 kHz to 1 MHz
range are dominated by the sum of the mobilities of individual
ionic species. The conductivity of the ion species is determined
by their solution concentration and molar conductivity under the
assay conditions. Based on these considerations and the
glucose-dependent changes in the nature and charge of ions in
the medium (Scheme 1), a conductimetric assay based on
Figure 2. Chemical properties of DBA2+. (A) Glucose-dependent pKa of
DBA2+ by measuring absorbance at 280 nm and fitting the curve as a function
of pH. Absorbance of 100 µL of 1 mM DBA2+Br as a function of pH in buffer in
the absence (black) or presence (red) of 200 mM glucose with calculated pKa
indicated. (B) Absorbance of 200 µL of 1 mM DBA2+Br at 280 nm in 50 mM
phosphate buffer at pH 7.4 in the presence of various concentrations of
glucose and other sugars as indicated. Dissociation constants were
determined by fitting curves as a function of [sugar].
solution resistance (R) was envisioned. From
a practical
perspective, we note that the accuracy of this approach is
dependent on the influence of CO2. CO2 in solution may form
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10.1002/anie.201904595
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carbonic acid, which would decrease the pH and the background
conductance.[13] It is critical to select a buffer that maintains pH
and does not generate a large background conductance. For
this purpose, we chose mM levels of H2PO4 /HPO4 (see
Experimental Section for additional considerations).
To assess reproducibility of the approach, quadruplicate
measurements of R and conductance (σ) were carried out at
room temperature. Examination of the plots of percentage
change (R or σ) vs. [glucose] (Figure 4A) reveals good
agreement between measurements, suggesting the accuracy
and stability of the glucose sensing platform. It is highly likely
that some of the statistical variations arise from changes in
either solution volume or solution temperature (1-2% total
conductance change per °C). These errors can be minimalized
with membranes for glucose diffusion and temperature
monitoring, among other strategies.
Lastly, we examined possible interference effects from other
sugars, see Table 1. Tests were performed at two different
glucose concentrations, 5 mM and 20 mM, in 1 mL of testing
solution. In these tests, interferent concentrations were higher or
equal to three times the maximum plasma concentration (MPC).
To the testing solution containing glucose, 2 µL or 5 µL of
interference solutions were added and the R was monitored.
The interference by 1 mM fructose or galactose was tested due
-
2-
To decrease background conductivity from spectator ions,
-
the Br- anions in DBA2+Br were replaced with H2PO4 through
anion exchange, yielding DBA2+P (Figure 3A). A schematic of
the device architecture for monitoring R is provided in Figure 3B.
Changes in R of the initial solution (2 mM DBA2+P and 2.5 mM
Na3PO4, pH = 7.6) as a function of glucose levels were tested.
Typically, 1 mL of testing solution was included in the reservoir.
The impedance vs. frequency response was monitored at 20 mV
at frequency of 1×105 Hz. These conditions minimize
contributions from capacitance and reactance, relative to the
resistance (R) (Figure S2).
Using this strategy, changes in R of the solution over time
as a function of glucose were measured (Figure 3C). Glucose
solutions were added every 30 minutes with concentrations
spanning the diabetes-relevant range, (i.e. [glucose] = 0-30 mM). to the considerable high affinity compared to the other three
An increase in solution resistance after each glucose addition
over the full range of glucose concentrations was observed. In
contrast, a control study that used water instead of glucose
disaccharides. As shown in Figure 4B, the addition of galactose
had a negligible effect on solution resistance. The addition of
fructose caused a 3% increase in resistance under low glucose
solution showed a much narrower range of R values (Figure 3D). (5 mM) conditions and only a transient increase under high
Any non-specific effect by glucose on solutions R was evaluated
in a DBA2+ free buffer.[14] These experiments show R changes
on the order of 1-2% for up to [glucose] = 30 mM (Figure S3).
After the addition of the maximum glucose concentration 1.5 mL
of fresh testing solution was added to dilute the glucose
concentration from 30 mM to 12 mM, and 1 mL of the mixture
was left in the reservoir for continued test. After equilibration, the
R value reaches almost the same value (R = 2115 Ω) as the
previous test for 12 mM (R = 2109 Ω), which is shown in Figure
3C. This result demonstrates a reversible and repeatable
response to glucose.
glucose (20 mM) conditions. Maltose and lactose, which have
been shown to influence other DBA-based assays, were also
tested.[8b] Under our conditions, 10 mM maltose and 1 mM
lactose show no significant change to R.
Table 1. Effect of Interfering Sugars on Performance of Conductimetric
Sensor. Each interfering sugar at > 2.5x its MPC in the presence of
physiological concentrations of glucose (5 mM) or pathophysiological
concentrations of glucose (20 mM) experienced in diabetes.
Figure 4. Robustness of glucose-sensing strategy. (A) Changes in solution
resistance (R, left, black) or conductance (δ, right, blue) as a function of
glucose concentration (n = 4 independent experiments at RT). Values are
expressed as a percentage, normalized to the initial resistance (R0) and
conductance (δ0) of the testing solution. (B) Changes in R upon addition of low
(5 mM) or high (20 mM) glucose solutions (Glu), followed by addition of 1 mM
fructose (Fru, solid lines) or galactose (Gal, dotted lines)
Interfering
Sugar
Max plasma
[sugar] (mM)
Interference
[sugar] (mM)
[Glucose]
(mM)
Resistance
increase (%)a
5
20
5
2.9
-0.3
1.4
0.6
0.4
1.6
0.2
1.6
Fructose
Galactose
Maltose
0.133
0.28
3.5
1
1
In conclusion, we report the design of DBA2+ for
nonenzymatic and non-optical conductimetric determination of
glucose concentrations. Despite a simple molecular structure,
DBA2+ achieved relevant target properties, namely: 1) good
affinity and selectivity to glucose; 2) ability to change pKa upon
glucose binding at physiological pH; 3) sufficient water solubility;
4) ease of synthesis. Therefore, glucose binding to DBA2+
changes solution resistance, and monitoring of solution
conductivity can be used to determine the concentration of
glucose at physiological pH. Other sugars tested in this study
show no substantial interference at relevant physiological
concentrations. These findings suggest that DBA2+ and related
20
5
10
1
20
5
Lactose
0.015
20
[a] Resistance increase is based on the resistance value of testing solution
with 5 mM Glucose or 20 mM glucose.
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Acknowledgements
This work was supported by grant 1-17-VSN-18 from the
American Diabetes Association. The authors acknowledge the
use of the Biological Nanostructures Laboratory within the
California Nano Systems Institute, supported by UCSB and UC
Office of the President.
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Keywords: • biosensors• diboronic acid • glucose monitoring •
non-enzymatic •synthesis design
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Entry for the Table of Contents
COMMUNICATION
Bing Wang, Kuang-Hua Chou, Bridget
N. Queenan, Sumita Pennathur* and
Guillermo C. Bazan*
Page No. – Page No.
Molecular Design of a New Diboronic
Acid for Electrohydrodynamic
Monitoring of Glucose
New diboronic acid, DBA2+, was prepared, which shows good affinity, selectivity
toward glucose and changeable pKa centered physiological pH upon binding.
DBA2+ realized non-enzymatic, conductimetric monitoring of glucose within
diabetic range. With neglectable interference from other sugars, DBA2+ was
demonstrated with the potential for selective, quantitative continuous glucose
sensing.
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