Repurposing pinacol esters of boronic acids for tuning viscoelastic properties of glucose-responsive polymer hydrogels: effects on insulin release kinetics

Ali, Akbar; Nouseen, Shaista; Saroj, Saroj; Shegane, Meenakshi; Majumder, Priyankar; Puri, Aarti; Rakshit, Tatini; Manna, Debasish; Pal, Soumik

doi:10.1039/d2tb00603k

Cited by 13 publications

(15 citation statements)

References 49 publications

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“…For the insulin release assay, human recombinant insulin was covalently attached to ATTO 495 via well-known NHS ester chemistry . Labeled insulin was purified with a G25 spin filtration column (GE healthcare) two times.…”

Section: Methodsmentioning

confidence: 99%

“…For the insulin release assay, human recombinant insulin was covalently attached to ATTO 495 via wellknown NHS ester chemistry. 35 Labeled insulin was purified with a G25 spin filtration column (GE healthcare) two times. The desired amount of insulin (10 μL, 10 mg/mL in 1 mL HG) was incorporated during the preparation of PPHGs.…”

Section: Insulin Release Assaymentioning

confidence: 99%

“…They are often considered for smart drug delivery applications. − For instance, dynamic covalent phenylboronic acid (PBA)–diol ester bond-based HGs have demonstrated glucose-responsive behavior and promise to be smart insulin delivery systems for maintaining blood glucose levels in insulin-dependent diabetes patients. − PBA–diol ester bonds are susceptible to break in the presence of d -glucose, the most abundant carbohydrate in the human body. The advantages of using PBA-based glucose-responsive HGs are their chemical stability and minimum toxicity, which enables long-term use in preclinical studies. , In current practice, PBA-containing synthetic polymers are derived from radical polymerization reactions. − Therefore, these materials are exclusively used for external use as catheters and microneedle patches due to their nonbiodegradability. ,− Recently, diol-containing synthetic polymers, such as polyvinyl alcohol (PVA), are crosslinked with bis-PBA-based molecules to produce injectable glucose-responsive insulin-releasing HGs. − Noticeably, for most glucose-responsive HGs, the correlation between bulk rheological properties and glucose-responsive insulin release profile remains elusive. Further, the use of biomacromolecules in the HG composition is desired to improve biocompatibility, biodegradability, and, most importantly, sustainability for future biomedical applications .…”

Section: Introductionmentioning

confidence: 99%

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In Situ-Forming Protein-Polymer Hydrogel for Glucose-Responsive Insulin Release

Ali

Saroj

Saha

et al. 2023

ACS Appl. Bio Mater.

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Phenylboronic acid (PBA)-containing hydrogels (HGs), capable of glucose-responsive insulin release, have shown promise in diabetes management in preclinical studies. However, sustainable material usage and attaining an optimum insulin release profile pose a significant challenge in such HG design. Herein, we present the development of a straightforward fabrication strategy for glucose-responsive protein-polymer hybrid HGs (PPHGs). We prepare PPHGs by crosslinking polyvinyl alcohol (PVA) with various nature-abundant proteins, such as bovine serum albumin (BSA), egg albumin, casein, whey protein, and so forth, using formylphenylboronic acid (FPBA)-based crosslinkers. We showcase PPHGs with diverse bulk rheological properties that are appropriately modulated by the positions of aldehyde, boronic acid, and fluorine substitutions in the FPBA-crosslinker. The orthogonal imine and boronate ester bonds formed by FPBAs are susceptible to the acidic pH environment and glucose concentrations, leading to the glucose-responsive dissolution of the PPHGs. We further demonstrate that by an appropriate selection of FPBAs, glucose-responsive insulin release profiles of the PPHGs can be precisely engineered at the molecular level. Importantly, PPHGs are injectable, incur no cytotoxicity, and, therefore, hold great potential as smart insulin for in vivo applications in the near future.

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Section: Methodsmentioning

confidence: 99%

Section: Insulin Release Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In Situ-Forming Protein-Polymer Hydrogel for Glucose-Responsive Insulin Release

Ali

Saroj

Saha

et al. 2023

ACS Appl. Bio Mater.

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“…Therefore, PBA and its derivatives are regularly employed in glucose sensors. − Bulk and nanosized HGs cross-linked with boronate ester bonds have been developed for glucose-responsive drug delivery applications. PBA-functionalized synthetic polymers have been predominately used to realize glucose-responsive insulin delivery in vitro and in vivo . − There are few reports of using biocompatible poly(vinyl alcohol) (PVA) cross-linked with benzene diboronic acids. − However, the fabrication of such materials requires rigorous synthesis, and the materials suffer from non-biodegradability issues. Therefore, these materials are amenable to external use, such as catheters and microneedles.…”

Section: Introductionmentioning

confidence: 99%

Glucose-Responsive Chitosan Nanoparticle/Poly(vinyl alcohol) Hydrogels for Sustained Insulin Release In Vivo

Ali

Saroj

Saha

et al. 2023

ACS Appl. Mater. Interfaces

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Stimuli-responsive hydrogels (HGs) with a controlled drug release profile are the current challenge for advanced therapeutic applications. Specifically, antidiabetic drug-loaded glucose-responsive HGs are being investigated for closed-loop insulin delivery in insulindependent diabetes patients. In this direction, new design principles must be exploited to create inexpensive, naturally occurring, biocompatible glucose-responsive HG materials for the future. In this work, we developed chitosan nanoparticle/poly(vinyl alcohol) (PVA) hybrid HGs (CPHGs) for controlled insulin delivery for diabetes management. In this design, PVA and chitosan nanoparticles (CNPs) are cross-linked with a glucose-responsive formylphenylboronic acid (FPBA)-based cross-linker in situ. Leveraging the structural diversity of FPBA and its pinacol ester-based cross-linkers, we fabricate six CPHGs (CPHG1−6) with more than 80% water content. Using dynamic rheological measurements, we demonstrate elastic solid-like properties of CPHG1−6, which are dramatically reduced under low-pH and high-glucose environments. An in vitro drug release assay reveals size-dependent glucose-responsive drug release from the CPHGs under physiological conditions. It is important to note that the CPHGs show appreciable self-healing and noncytotoxic properties. Promisingly, we observe a significantly slower insulin release profile from the CPHG matrix in the type-1 diabetes (T1D) rat model. We are actively pursuing scaling up of CPHGs and the in vivo safety studies for clinical trial in the near future.

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“…So far, the synthesis of glucose-responsive materials was performed via solution-based deposition methods. − An example is based on the boronate esterification reaction of the diol groups of poly(vinyl alcohol) with the boronic acid groups of 2-acrylamidophenylboronic acid in aqueous conditions . Other examples of interesting boronic acid-based hydrogels obtained in solution are the biosynthetic hybrid ones, formed by mixing aqueous solutions of biohydrogels (e.g., mucin or alginate) with synthetic polymers carrying boronic acid groups.…”

Section: Introductionmentioning

confidence: 99%

Glucose-Responsive Boronic Acid Hydrogel Thin Films Obtained via Initiated Chemical Vapor Deposition

Unger

Coclite

2022

Biomacromolecules

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Glucose-responsive materials are of great importance in the field of monitoring the physiological glucose level or smart insulin management. This study presents the first vacuum-based deposition of a glucose-responsive hydrogel thin film. The successful vacuum-based synthesis of a glucose-responsive hydrogel may open the door to a vast variety of new applications, where, for example, the hydrogel thin film is applied on new possible substrates. In addition, vacuumdeposited films are free of leachables (e.g., plasticizers and residual solvents). Therefore, they are, in principle, safe for in-body applications. A hydrogel made of but-3-enylboronic acid units, a boronic acid compound, was synthesized via initiated chemical vapor deposition. The thin film was characterized in terms of chemical composition, surface morphology, and swelling response toward pH and sucrose, a glucose−fructose compound. The film was stable in aqueous solutions, consisting of polymerized boronic acid and the initiator unit, and had an undulating texture appearance (rms 2.1 nm). The hydrogel was in its shrunken state at pH 4−7 and swelled by increasing the pH to 9. The pK a was 8.2 ± 0.2. The response to glucose was observed at pH 10 and resulted in thickness shrinking.

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Repurposing pinacol esters of boronic acids for tuning viscoelastic properties of glucose-responsive polymer hydrogels: effects on insulin release kinetics

Abstract: In the era of the diabetes pandemic, Injectable hydrogels (HGs) capable of releasing the desired amount of insulin under hyperglycemic conditions will significantly advance smart insulin development. Several smart boronic...

Cited by 13 publications

References 49 publications

In Situ-Forming Protein-Polymer Hydrogel for Glucose-Responsive Insulin Release

In Situ-Forming Protein-Polymer Hydrogel for Glucose-Responsive Insulin Release

Glucose-Responsive Chitosan Nanoparticle/Poly(vinyl alcohol) Hydrogels for Sustained Insulin Release In Vivo

Glucose-Responsive Boronic Acid Hydrogel Thin Films Obtained via Initiated Chemical Vapor Deposition

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