Design and Development of In Vivo Sensor Systems: The Long and Tortured Road to a Self-Contained, Implantable Glucose Sensor for Diabetes Management - Designing Receptors for the Next Generation of Biosensors - page 216

bind diols in aqueous environments, through boronate ester formation [ 72 - 74 ].
This favorable interaction occurs with high affinity and selectivity [ 62 - 64 , 69 , 70 ].
As a result, boronic acid-based detection systems find application where quantita-
tive detection of saccharides is critically linked to disease therapies, such as
diabetes management [ 75 - 77 ]. The use of appropriately designed boronic acids
as molecular recognition units provides the ability to both selectively recognize and
signal analytes, such as glucose, at low concentrations and in real time [ 78 - 80 ].
Numerous advances have been made in understanding how the electronic,
geometric, and polar properties of functional groups on boronic acid analogues
affect the mechanism and process of reversible diol complexation [ 73 , 74 , 76 ,
81 - 84 ]. Several groups have demonstrated that saccharide selectivity and binding
properties are affected by the location and type of substituents about the aromatic
boronic acid substructure [ 81 , 85 ]. It has also been reported that, in general, aryl
boronic acids with lower p K a s tend to have higher binding affinities for diols near
neutral pH, although optimal binding depends not only on the p K a of the boronic
acid but also on the structure and properties of the diol in question, as well as the pH
and ionic strength of the binding environment [ 73 , 74 , 76 , 81 , 82 , 86 ]. Boronic acid
p K a s are tunable by altering the substituents [ 75 ]. For example, Badugu et al. [ 75 ]
have shown that the p K a of phenylboronic acid can be decreased by adding electron
withdrawing groups, while adding electron donating groups increases the p K a .
Alternatively, there is evidence that a neighboring nitrogen can enhance the forma-
tion of boronate esters under neutral pH conditions by coordinating intramolecu-
larly with boron to create a more electron deficient atomic center, resulting in a
reduction in the apparent p K a of the boronic acid [ 66 , 87 - 89 ]. In our efforts to
design a boronic acid-based receptor and signaling component, we exploited the
physical and chemical influence of substituent type and location to improve the
binding affinity and selectivity of DBAs for glucose and iDIOLs.
The ability of boronic acid-based sensors to function efficiently in a physiologi-
cal system is reflected by their selective interaction with saccharides. For saccha-
ride recognition to proceed, cyclic boronate ester formation must occur upon
binding of a boronic acid to, preferably, a 1,2- or 1,3- diol to form a five- or six-
membered cyclic ester [ 72 , 90 ]. It is possible for boronate esters to form under
aqueous conditions, but at neutral pH binding affinity is low [ 84 ]. Greater binding
affinity can be obtained under elevated pH conditions (pH 10), where the more
favorable tetrahedral boronate form dominates [ 66 , 73 , 87 , 88 ]. Designing a boronic
acid-based sensor component that has greater binding affinity in a neutral physio-
logical system can be achieved by (1) strategically outfitting the phenylboronic acid
substructure with electron withdrawing groups in the meta -or para - position in
order to stabilize the boronate form of the acid and lower the p K a value [ 73 - 76 , 81 ,
82 , 86 ] and/or (2) introduce an ortho -amino methyl substituent to facilitate boronate
ester formation at neutral pH through donation of the nitrogen lone pairs into the
empty boron p-orbital [ 66 , 87 - 89 ]. Strategic selection of boronic acid receptor