Diboronate crosslinking: Introducing glucose specificity in glucose-responsive dynamic-covalent networks

Xiang, Yuanhui; Xian, Sijie; Ollier, Rachel C.; Yu, Sihan; Su, Bo; Pramudya, Irawan; Webber, Matthew J.

doi:10.1016/j.jconrel.2022.06.016

Cited by 33 publications

(102 citation statements)

References 52 publications

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“…Although these networks use PyPBA chemistry with K eq of glucose binding measured at 166.7 M −1 , this motif also binds the GdL-derived diol structure used on the PEG 4a −diol macromer with a K eq of 5280 M −1 . 35 In a 5 wt % hydrogel, the effective concentration of macromer-presented diols is 10.7 mM, increasing to 21.4 mM at 10 wt %. Meanwhile, 400 mg/ dL of ambient glucose corresponds to a concentration of 22 mM.…”

Section: Glucose-responsive Polymer Hydrogel Networkmentioning

confidence: 97%

“…A previously reported PyPBA group was shown to afford glucose binding (K eq = 166.7 M −1 ) that was almost 20-fold higher than was achieved using traditional PBA chemistry (K eq = 8.6 M −1 ); the improved glucose-binding affinity of PyPBA was also accompanied by a ∼2-fold reduction in binding to common competing analytes such as fructose and lactate compared to this same traditional PBA. 35 Critical to this observation is the low pKa of PyPBA (pKa ∼ 4.4) arising from the adjacent pyridinium salt, making this a stronger acid than traditional PBAs. 35,36 Accordingly, PyPBA was selected here as the glucose-binding motif for use in preparing glucose-responsive microneedles from PBA−diol crosslinking.…”

Section: Polymer Designmentioning

confidence: 99%

“…35 Critical to this observation is the low pKa of PyPBA (pKa ∼ 4.4) arising from the adjacent pyridinium salt, making this a stronger acid than traditional PBAs. 35,36 Accordingly, PyPBA was selected here as the glucose-binding motif for use in preparing glucose-responsive microneedles from PBA−diol crosslinking.…”

Section: Polymer Designmentioning

confidence: 99%

“…The rate of crosslink exchange in dynamic-covalent networks, and the influence of ambient glucose level on PBA−diol bond formation and dynamics, is especially useful to understand the function of these materials. 35 Oscillatory frequency sweeps were thus collected at a constant strain value of 1%, determined to be within the linear viscoelastic regime, in order to investigate the dynamic viscoelastic behavior of networks prepared from PyPBA−diol dynamic-covalent crosslinks (Figure 2).…”

Section: Glucose-responsive Polymer Hydrogel Networkmentioning

confidence: 99%

“…The observed loss of glucose responsiveness as the polymer concentration is increased is also expected based on observations of this behavior in other PBA−diol crosslinked networks. 35 This effect is hypothesized to arise from glucose being a less efficient competitor as the local concentration of PBA-binding diol groups on the polymer is increased. Although these networks use PyPBA chemistry with K eq of glucose binding measured at 166.7 M −1 , this motif also binds the GdL-derived diol structure used on the PEG 4a −diol macromer with a K eq of 5280 M −1 .…”

Section: Glucose-responsive Polymer Hydrogel Networkmentioning

confidence: 99%

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Polymeric Microneedle Arrays with Glucose-Sensing Dynamic-Covalent Bonding for Insulin Delivery

Xiang

Monroe

et al. 2022

Biomacromolecules

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The ongoing rise in diabetes incidence necessitates improved therapeutic strategies to enable precise blood glucose control with convenient device form factors. Microneedle patches are one such device platform capable of achieving therapeutic delivery through the skin. In recent years, polymeric microneedle arrays have been reported using methods of in situ polymerization and covalent crosslinking in microneedle molds. In spite of promising results, in situ polymerization carries a risk of exposure to toxic unreacted precursors remaining in the device. Here, a polymeric microneedle patch is demonstrated that uses dynamic-covalent phenylboronic acid (PBA)−diol bonds in a dual role affording both network crosslinking and glucose sensing. By this approach, a pre-synthesized and purified polymer bearing pendant PBA motifs is combined with a multivalent diol crosslinker to prepare dynamic-covalent hydrogel networks. The ability of these dynamic hydrogels to shear-thin and self-heal enables their loading to a microneedle mold by centrifugation. Subsequent drying then yields a patch of uniformly shaped microneedles with the requisite mechanical properties to penetrate skin. Insulin release from these materials is accelerated in the presence of glucose. Moreover, short-term blood glucose control in a diabetic rat model following application of the device to the skin confirms insulin activity and bioavailability. Accordingly, dynamic-covalent crosslinking facilitates a route for fabricating microneedle arrays circumventing the toxicity concerns of in situ polymerization, offering a convenient device form factor for therapeutic insulin delivery.

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Section: Glucose-responsive Polymer Hydrogel Networkmentioning

confidence: 97%

Section: Polymer Designmentioning

confidence: 99%

Section: Polymer Designmentioning

confidence: 99%

Section: Glucose-responsive Polymer Hydrogel Networkmentioning

confidence: 99%

Section: Glucose-responsive Polymer Hydrogel Networkmentioning

confidence: 99%

See 3 more Smart Citations

Polymeric Microneedle Arrays with Glucose-Sensing Dynamic-Covalent Bonding for Insulin Delivery

Xiang

Monroe

et al. 2022

Biomacromolecules

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Insulin–Dendrimer Nanocomplex for Multi‐Day Glucose‐Responsive Therapy in Mice and Swine

Xian,

Xiang,

Liu

et al. 2023

Advanced Materials

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The management of diabetes in a manner offering autonomous insulin therapy responsive to glucose‐directed need, and moreover with a dosing schedule amenable to facile administration, remains an ongoing goal to improve the standard of care. While basal insulins with reduced dosing frequency, even once‐weekly administration, are on the horizon, there is still no approved therapy that offers glucose‐responsive insulin function. Herein, a nanoscale complex combining both electrostatic‐ and dynamic‐covalent interactions between a synthetic dendrimer carrier and an insulin analogue modified with a high‐affinity glucose‐binding motif yields an injectable insulin depot affording both glucose‐directed and long‐lasting insulin availability. Following a single injection, it is even possible to control blood glucose for at least one week in diabetic swine subjected to daily oral glucose challenges. Measurements of serum insulin concentration in response to challenge show increases in insulin corresponding to elevated blood glucose levels, an uncommon finding even in preclinical work on glucose‐responsive insulin. Accordingly, the subcutaneous nanocomplex that results from combining electrostatic‐ and dynamic‐covalent interactions between a modified insulin and a synthetic dendrimer carrier affords a glucose‐responsive insulin depot for week‐long control following a single routine injection.

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Glucose‐Triggered Gelation of Supramolecular Peptide Nanocoils with Glucose‐Binding Motifs

Yu,

Ye,

Roy

et al. 2023

Advanced Materials

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Peptide self‐assembly is a powerful tool to prepare functional materials at the nanoscale. Often, the resulting materials have high aspect‐ratio, with intermolecular β‐sheet formation underlying 1D fibrillar structures. Inspired by dynamic structures in nature, peptide self‐assembly is increasingly moving toward stimuli‐responsive designs wherein assembled structures are formed, altered, or dissipated in response to a specific cue. Here, a peptide bearing a prosthetic glucose‐binding phenylboronic acid (PBA) is demonstrated to self‐assemble into an uncommon nanocoil morphology. These nanocoils arise from antiparallel β‐sheets, with molecules aligned parallel to the long axis of the coil. The binding of glucose to the PBA motif stabilizes and elongates the nanocoil, driving entanglement and gelation at physiological glucose levels. The glucose‐dependent gelation of these materials is then explored for the encapsulation and release of a therapeutic agent, glucagon, that corrects low blood glucose levels. Accordingly, the release of glucagon from the nanocoil hydrogels is inversely related to glucose level. When evaluated in a mouse model of severe acute hypoglycemia, glucagon delivered from glucose‐stabilized nanocoil hydrogels demonstrates increased protection compared to delivery of the agent alone or within a control nanocoil hydrogel that is not stabilized by glucose.

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Diboronate crosslinking: Introducing glucose specificity in glucose-responsive dynamic-covalent networks

Cited by 33 publications

References 52 publications

Polymeric Microneedle Arrays with Glucose-Sensing Dynamic-Covalent Bonding for Insulin Delivery

Polymeric Microneedle Arrays with Glucose-Sensing Dynamic-Covalent Bonding for Insulin Delivery

Insulin–Dendrimer Nanocomplex for Multi‐Day Glucose‐Responsive Therapy in Mice and Swine

Glucose‐Triggered Gelation of Supramolecular Peptide Nanocoils with Glucose‐Binding Motifs

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