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Meta-Isobutoxy Phenylboronic Acid for Nanoscale Multi-Stimuli-Responsive Low-Molecular-Weight Hydrogelator

Cite this: ACS Appl. Nano Mater. 2023, 6, 17, 16055–16064
Publication Date (Web):August 18, 2023
https://doi.org/10.1021/acsanm.3c03259

Copyright © 2023 The Authors. Published by American Chemical Society. This publication is licensed under

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Abstract

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Hydrogelators generate hydrogels when dissolved in water, forming a network of interlocking chains on the nanoscale level. For their unique viscoelastic, mechanical, and swelling properties, these hydrogels have found various applications, such as water absorbent, biocompatible, and biodegradable scaffolds in tissue engineering and nanocarriers in drug delivery. When measuring the solubility of p-, m-, and o-isobutoxy derivatives of phenylboronic acid, we identified m-isobutoxyphenylboronic acid (PBA) as a low-molecular-weight hydrogelator, the first of which solely based on phenylboronic acid. At low concentrations, PBA gelated water into a network of cross-linked nanofibers combining amorphous and crystalline phases, as shown by electron and optical microscopy, rheometry, and differential scanning calorimetry and confirmed by small- and wide-angle X-ray scattering. By increasing the PBA concentration, we were able to tailor the elastic modulus (G′) of PBA hydrogels across 2 orders of magnitude, from 2.5 to 103 kPa. In turn, at a specific PBA concentration, we tuned their viscoelastic properties by adding urea, thereby adjusting the gelation temperature between 62 and 56 °C and G′ at body temperature between 63.4 and 30.4 kPa. Moreover, PBA hydrogels dissolved in response to various triggers (pH increase, H2O2 and cyclodextrin addition) and selectively absorbed dyes for liquid mixture separation. These findings demonstrate that PBA has a high potential as a biodegradable, multistimuli-responsive, low-molecular-weight hydrogelator for bioapplications.

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Introduction

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Hydrogels consist of major liquid (water) and minor solid (gelator) components with intermediate viscoelastic properties between solid and liquid and with a wide range of applications, particularly in biomedicine, thanks to their biocompatibility. (1) Among these applications, their potential uses as scaffolds in tissue engineering and as nanocarriers in drug delivery (2) stand out given the ability of hydrogels to provide structural support for cell division while mimicking tissues (3) and responding to external stimuli when releasing a drug, (4) respectively. Accordingly, these applications depend on the physical and chemical properties of the gelator and its biocompatibility.
Low-molecular-weight (LMW) gelators, in particular, can easily trigger reversible gelation because they consist of small organic molecules bound by noncovalent interactions. (5) In addition, LMW gelators are more easily biodegradable and often more biocompatible (6) than most classical polymer gelators. Many LMW gelators have a similar design (7) with small structural alterations specifically introduced to tune mechanical properties or to generate molecularly responsive properties (especially in small peptide gelators), (8) including responsiveness to light, (9) temperature, magnetic fields, (10) and chemical stimuli. (11,12) However, this approach is limited by the sensitivity of LMW gelators to structural changes, whereby extremely small changes, such as introducing a single functional group, can preclude their ability to gelate. Although the formation of nanofibers can be described as 1D aggregation, 1D intermolecular interactions have not been correlated with the ability to gelate. (13)
Hydrogels can also be utilized as chemical sensors with mechanical sol–gel responses. Modifying a gelator with a functional group reactive to specific stimuli can produce a gel sensitive to those stimuli with a sol–gel phase transition response. In particular, phenylboronic acids are sensitive to pH changes (acting as acid–base indicators) and to 1,2- or 1,3-diols (sensitivity toward sugars, including glucose and fructose) (14–16) or the fluoride anion. (17) Furthermore, the acid–base properties of phenylboronic acids can be easily tuned by substitutions on the benzene ring, resulting in pKa values ranging from 9.24 for p-methoxy- to 7.23 for p-nitro-substituted phenylboronic acid. (18) When a substituent stabilizes a tetrahedral boronate anion structure, such as B–N Wulff-type phenylboronic acid (Figure 1B), where nitrogen coordinates boron, pKa can reach values as low as 5.3. (19) Nitrogen may also be swapped for oxygen, leading to benzoxaborole (Figure 1C) with pKa = 7.3. (20) The pKa value close to physiological pH is highly desired for drug delivery purposes. Combining the functionality of phenylboronic acids and amphiphilic copolymers extends their use as nanoscale drug delivery systems. (14,21,22) However, studies on the toxicity and biocompatibility of PBA-based compounds have reported varying results. Therefore, the cytotoxicity and cell viability of these nanomaterials must be thoroughly evaluated before considering their practical applications in biomedical contexts. (23–26)

Figure 1

Figure 1. Arylboronic acids of interest: (A) 3-isobutoxyphenylboronic acid (PBA); (B) Wulff type acid; and (C) benzoxaborole.

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In this context, we aimed to measure the solubility and dehydration and acid–base properties of a series of substituted phenylboronic acids. (27,28) As a result, we identified a new and simple LMW gelator, PBA pKa = 8.5, with a unique structure capable of gelating water at low concentrations. To analyze its mechanical properties and their variation as a function of the temperature, we used rheometry and differential scanning calorimetry (DSC). Furthermore, we studied the microscopic structure of PBA hydrogels by light microscopy and scanning and transmission electron microscopy (TEM). We also assessed the effect of urea on the viscoelastic properties of PBA hydrogels to test their tunability. Lastly, we examined the ability of PBA hydrogels to selectively absorb dyes for liquid mixture separation and the potential of PBA hydrogels as stimuli-responsive materials by testing various triggers (pH, H2O2, and CD) for the sol–gel transition.

Materials and Methods

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Materials

PBA (molecular weight: 194.04 g/mol, purchased from Sigma-Aldrich and used as received), distilled water (used also for dilutions), ethanol (Penta, Czech Republic, 96%, for UV) hydrogen peroxide 30% hydrogen peroxide (Lach-Ner, Czech Republic, 30% p.a. nonstabilized), (2-hydroxypropyl)-β-cyclodextrin (Sigma-Aldrich, powder, estimated mol weight 1396 Da), sodium hydroxide (Penta, p.a.), hydrochloric acid (Lach-Ner, 35% p.a.), Congo red (Sigma-Aldrich, BioXtra, certified by the BSC), Fluorescein (Honeywell Fluka, Reag. Ph. Eur.), Methylene blue (Sigma-Aldrich, certified by the BSC), Nile red (Sigma-Aldrich, for microscopy grade), and urea (Sigma-Aldrich, ACS reagent >99–100%).

Methods

Gel Preparation

The PBA gelator was placed in sealed glass vials and heated to form a solution. The solution was cooled to room temperature to obtain a gel. The xerogels for TEM and scanning electron microscopy (SEM) measurements were dried at room temperature in vacuum. The critical gelation concentration (CGC) was determined by measuring the minimum amount of gelator to form a stable gel at 25 °C. CGC under these conditions was 1.5 mg/mL.

Gels Preparation Doped with Urea for Rheometry

Three gel samples were prepared by dissolving 27 mg of PBA in 10 mL of boiling water, pipetting them to preweighted amounts of urea, and letting them cool freely to room temperature, leading to gels with a gelator concentration of 2.7 mg/mL and urea concentrations of 0, 3.5, and 10.4 mg/mL. A sample with 100 mg of urea per 3 mL of gel was prepared as well but did not solidify, even after cooling to 6 °C in a fridge overnight.

Capillary Microcalorimetry

Microcalorimetry measurements were performed on a Nano DSC microcalorimeter (TA Instruments-Waters LLC, New Castle, USA). The microcalorimeter consists of a 0.3 mL sample and reference platinum capillary cells. Three gel samples were prepared by dissolving 2.04, 2.70, and 3.54 mg of PBA per 1 mL of boiling water and letting them freely cool to room temperature. Before analysis, the samples were preheated to liquify the gel. The sample cell was filled by overfilling with ca. 0.6 mL of sample solution, and the reference cell was filled with deionized water. The measurements were performed under a constant pressure of 3 atm with the temperature span from 5 to 80 °C. For each sample, a series of two consecutive heating and cooling scans were performed to confirm reproducibility. After each sample, the cell was cleaned by flushing with 2 L of deionized water. All data were subtracted from the measurement of deionized water, which was performed on the same day.

Small-Angle X-ray Scattering and Wide-Angle X-ray Scattering

Small-angle X-ray scattering (SAXS) experiments were performed using a pinhole camera (Molecular Metrology SAXS System) attached to a microfocused X-ray beam generator (Osmic Micro-Max 002) operating at 45 kV and 0.66 mA (30 W). The X-ray beam wavelength used was 0.154 nm. The camera was equipped with a multiwire gas-filled detector with an active area diameter of 20 cm (Gabriel design). Two experimental setups were used to cover the q range of 0.04–11 nm–1. Scattering vector q = (4πn/λ)sin(θ), where λ = 0.154 nm is the wavelength and θ is the angle between the incident X-ray beam and the detector measuring the scattered intensity. Glassy carbon samples, purchased from Rigaku Company (Japan), were used for calibration.
Wide-angle X-ray scattering (WAXS) experiments were performed using a pinhole camera (Older Rigaku SMAX2000 upgraded by SAXSLAB/Xenocs) attached to a microfocused X-ray beam generator (Rigaku MicroMax 003) operating at 50 kV and 0.6 mA (30 W). The camera was equipped with a vacuum version of a Pilatus 300 K detector. The experimental setup covered a q range of 0.004–3 Å–1. The primary beam position and sample-to-detector distances were calibrated using a Si powder sample.

Scanning Electron Microscopy

The morphology of the nanofibrous hydrogel structure was also confirmed under a scanning electron microscope (FEGSEM MAIA3, Tescan, Czech Republic) operating at an acceleration voltage of 10 kV. A drop of liquid sample was placed on a freshly cleaved-off mica surface and left to completely dry at room temperature. Prior to SEM, a conductive thin Pt film was deposited on the sample surface using a Leica EM SCD 050 vacuum sputter coater. The sample was examined in high vacuum mode at a typical operating voltage of 10 keV. ImageJ software was used for image analysis.

Transmission Electron Microscopy

TEM micrographs were acquired using a JEOL NEOARM transmission electron microscope (JEOL, Japan) operating at an acceleration voltage of 200 kV and equipped with a TemCamXF416R 4k × 4k CMOS camera (TVIPS, Germany). The homogenized solid sample of xerogel was deposited on a copper TEM grid coated with a lacey amorphous carbon film. ImageJ software was used for image analysis.

Rheometry

Rheological experiments were performed on a strain-controlled ARES-G2 rheometer (from TA Instruments, USA), using a parallel plate fixture with a diameter of 25 mm and a gap of 1.0 mm.
Strain sweep tests were performed to find a range of deformation values where the deformations did not damage the physical network of the gels s follows: the monomer solutions were heated to 80 °C and stirred at this temperature for 10 min. Subsequently, they were loaded between the parallel plates of the rheometer, which were preheated to 80 °C. To prevent the gel samples from drying, the border layer of the rheology samples (placed between the parallel plates), which was exposed to the environment, was protected by applying a layer of silicon oil to the edge of the platelets. Thereafter, the sample was left to cool (by heat radiation only) to room temperature and to gelate (15 min of waiting time). Lastly, at T = const. = 30 °C, the oscillatory strain sweep experiment was started at a constant frequency of 1 Hz, whereas the deformation amplitude ranged from 2 × 10–3 to 500% (ascending values). The rheological results were evaluated, and the “safe” value of the deformation amplitude was chosen as 1/10 of the deformation amplitude, below which the dynamic modulus G′ started to be deformation-independent. This “safe” deformation amplitude (0.01%) was then used in the gelation tests.
The gelation process of the different PBA solutions was investigated as follows: the samples were loaded into the preheated rheometer plates as described above, but each measurement was performed immediately after sample installation. After the experiment started, the studied system was cooled exclusively via heat radiation (without blowing air). The rheological properties were recorded simultaneously with the directly measured temperature of the plates (embedded contact thermometer). The time-dependent dynamic shear storage modulus G′(t) and loss modulus G″(t) were assessed in oscillatory measurements at a frequency of 1 Hz and at a strain amplitude of 0.01% (which was previously determined as “safe” in the strain-sweep test, that is, found not to damage the physical cross-links in the gel─“linear deformation region”). Based on the values of the time-dependent sample temperature T(t), the rheology results were expressed as temperature-dependent moduli G′(T) and G″(T). The temperature of gelation was defined as the temperature of G′/G″ crossover (G′ is higher in the gel phase). Frequency sweep tests of the gels were performed at 30 °C, with the oscillatory deformation frequency ranging from 0.01 to 100 Hz. The deformation amplitude was kept constant at 0.01%.

Confocal Laser Scanning Microscopy

The gels (concentration of PBA 2.25 mg/mL) stained with Nile red were analyzed under an IX83 confocal laser scanning microscope (Olympus, Tokyo, Japan) equipped with an Ultra-Plan Apochromat objective (lens magnification 60×, NA 1.20, water immersion). The excitation light at 488 nm was delivered into a diffraction-limited spot, and the emitted fluorescence was collected by a dichroic mirror DM405/488/543/635; all measurements were performed at 23 ± 1 °C. The Olympus FV10-ASW software, version 4.2.3.6, was used for image acquisition, reconstruction, and z- and time-scanning.

Polarized Light Microscopy

The vial with a homogeneous PBA hydrogel was placed in a hot water bath for a few minutes to receive a clear solution. A drop of the solution was placed between two cover glasses and observed under a Nikon80i polarized light microscope (Nikon) equipped with a Linkam THMS 600/TMS 9. The sample was heated from room temperature to 88 °C at a rate of 2 °C/min. The nanofiber gel structure started to undergo sol transition at 85 °C.

Chemically Triggered Sol–Gel Transition Experiments

Gel samples were prepared by dissolving 22.5 mg of PBA in 10 mL of boiling water and pipetting 0.7 mL of solution with a micropipette with a plastic tip to every glass vial while still hot and letting them cool to room temperature, leading to a gel with 10 μmol of PBA gelator per vial (vials used in experiments were 2 mL). The following experiments were performed: (1) upon addition of 50 μL (1 equiv) of 0.2 M sodium hydroxide solution, the gel dissolved in 15 min. To this solution, 50 μL (1 equiv) of 0.2 M aqueous hydrochloric acid was added, which caused the immediate formation of a gel. (2) 20 μL (6 equiv) of 10% hydrogen peroxide solution was added, which caused the complete dissolution of the gel in approximately 1 h. (3) 20 mg (approximately 1.3 equiv) of solid (2-hydroxypropyl)-β-cyclodextrin was added, which caused the complete dissolution of the gel in approximately 1 h.

Dye Absorption by the Hydrogel

Gel samples were prepared by pipetting 0.3 mL of PBA solution in boiling water (2.5 mg/mL) and letting the solution cool to room temperature. After cooling, 0.5 mL of 0.1 mM solutions of Congo red and methylene blue were added to each of the two vials; the first photo was taken immediately after dye addition, and the second photo was taken after 2 h. Subsequently, 0.5 mL of hot PBA solution (2.5 mg/mL) was pipetted into each vial, which already contained 4.5 mg (1 equiv) of Congo red and 2 mg (1 equiv) of methylene blue. Additionally, 0.4 mg (0.2 equiv) and 0.2 mg (0.1 equiv) of methylene blue were added to different vials. Each vial was shaken while hot to ensure the complete dissolution of the dye, and the samples were then cooled to room temperature. To analyze the maximum dye absorption capacity, 0.3 mL of a methylene blue solution (0.4 mg/mL, 0.1 equiv) was added to a vial containing 0.3 mL of a PBA gel (2.5 mg/mL) sample. The vial was sealed, and after 24 h, the absorbance at 663 nm was measured after a 100-fold dilution of the starting solution (0.780) and the gel-absorbed solution (0.266). Considering the dilution volume, the binding capacity of the PBA gel under these conditions was 0.03 mol equiv of dye per PBA gelator. Gelation was observed in the solution with 1 mol equivalent of Congo red, in line with the absence of absorption of anionic dye by PBA due to the lack of interactions. In contrast, no gelation occurred in samples containing 0.2 mol equiv of cationic dye, methylene blue, or higher, but samples containing 0.1 mol equiv of methylene blue resulted in stable gels at room temperature.

Results and Discussion

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In this study, we found that PBA easily self-assembles into multiresponsive hydrogels in aqueous solutions. As such, PBA is a paradigmatic example of a commercially available and easy-to-synthesize hydrogelator with a molecular weight much lower than that of most other phenylboronic acid-containing LMW hydrogelators. This is the first LMW gelator solely based on phenylboronic acid and without more prominent substituents (such as peptide (29–31) or fatty chain (32) based LMW gelators). Moreover, only the meta isomer of PBA lacks a crystal structure determined by single-crystal XRD.

PBA Hydrogels Show a Network of Cross-Linked Fibers with Amorphous and Crystalline Phases

Our SAXS measurements (Figures 2A and S1) showed scattering in the Porod regime [I(q) ∝ q–4] at a 0.04–1 nm–1 q range, corresponding to a 6–150 nm length scale, indicating scattering at flat interfaces between the PBA phase and the aqueous phase; that is, at the length scale 6–150 nm, the PBA phase was homogeneous.

Figure 2

Figure 2. SAXS (A) and WAXS (B) diffractograms of a 2.7 mg/mL PBA hydrogel sample, TEM (C,D) images of gelator crystalline and amorphous phases, respectively, SEM (E,F) images of the corresponding dried gel, and fluorescence confocal microscopy (G,H) images of the gel stained with Nile red (further experimental details on 2A-H in Supporting Information).

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At shorter length scales, below 6 nm (q > 1 nm–1), scattering deviated from the Porod regime [I(q) ∝ q–2] at the high q limit. This deviation indicated that the PBA phase was amorphous but no longer homogeneous at those length scales. As such, the scattering in the corresponding q range was dominated by the contribution from the density fluctuations.
The scattering data could thus be fitted using the model composed of the power-law term for the low q region and the Ornstein–Zernike term for the high q region (details about the model and values of the fit parameters are available in Supporting Information). The WAXS measurement (Figure 2B) revealed several reflections, indicating crystalline domains. The degree of crystallinity, calculated as the ratio between the sum of the areas of the crystalline peaks and the whole area under the curve, was 52–53%, depending on whether the first intensive peak at q = 0.36 A–1 was counted or not. The estimated size of the crystalline domains was approximately 20 nm, according to the Scherrer equation. Because the crystallite size was much smaller than the size of the fibers, we can assume that the fibers were composed of small crystallites connected by the amorphous phase.
As expected, based on WAXS, we observed both crystalline (Figure 2C) and amorphous (Figure 2D) phases in high-resolution TEM images of PBA xerogel samples. Fourier transform (FT) analysis of the micrograph in Figure 2C (inset) was difficult because overlaying lamellar structures had various spatial orientations, albeit with periodical 1.1 and 1.5 nm spacings. Moreover, the 1.1 nm spacing matched the periodicity clearly visible in the lamellar structure of the crystal. This periodic 1.1 nm spacing had two maxima in FT, resulting from different in-plane crystal orientations, and was close to the 1.05 nm d-spacing observed by WAXS analysis.
On a larger scale, the fibrous morphology of the PBA hydrogel was confirmed by SEM. As shown in Figure 2E,F, the fibers varied in both thickness (10–400 nm) and spatial orientation, displaying branching (marked by yellow arrows in Figure 2E). At an even lower magnification, the microscopic structure of PBA hydrogels was further studied by confocal laser scanning microscopy (CLSM) and polarized light microscopy. CLSM analysis of the PBA hydrogel stained with Nile red revealed a structure similar to that observed by SEM, but with fibers of variable thickness and with noticeable curving of the thicker fibers (Figure 2G,H). Although PBA is a LMW gelator, its fibers effectively absorbed the fluorescent dye without disturbing its structure.

PBA Hydrogels Are Formed by Spontaneous Precipitation from a Supersaturated Solution

The PBA hydrogel gradually dissolved in water as the temperature increased, and the density of the gelator network decreased during this dissolution, as determined by polarized light microscopy (Figure 3A). The DSC cooling (Figure 3C) curves showed that the gelation temperature in the undisturbed sample strongly depended on the gelator concentration c (31.4, 39.8, and 49.4 °C for 2.04, 2.70, and 3.54 mg/mL of PBA, respectively), as often reported for LMW gelators, but rarely explained. Among the exceptions, Ferry and Eldridge, (33) who studied gelation of gelatin, pointed out that the variation of the gel–sol transition temperature as a function of gelator concentration can be expressed using the van’t Hoff equation
ln⁡⁡c2c1=ΔHtR(1T2−1T1)
(1)
where T1 and T2 are the sol-to-gel phase transition temperatures at gelator concentrations c1 and c2, respectively, ΔHt is the transition enthalpy, and R is the gas constant. As previously show, eq 1 is also applicable to LMW gelators. (34) The resulting data provided a transition enthalpy ΔHt = −25.0 ± 0.8 kJ mol–1 (the plot of ln c vs T–1 is shown in Figure S2), corresponding to the formation of ca. 1 hydrogen bond per 1 gelator molecule. (33) Moreover, the calculated IR spectra of the PBA dimer more closely matched the measured IR spectra of the PBA gel than the IR spectra of the PBA unimer. This enhanced agreement provides convincing evidence of the crucial involvement of hydrogen bonds in the gel formation process (see Supporting Information Figure S3A,B).

Figure 3

Figure 3. Gradual dissolution of the PBA hydrogel with the increase in temperature under polarized light microscopy (A; left to right: 80, 86, 88 °C), heating (B) and cooling (C) DSC curves of the PBA hydrogel at different PBA concentrations, and cooling rheology of PBA hydrogels (D–G), showing the variation of the PBA hydrogel storage modulus (G′) as a function of temperature at different PBA (D) and urea (F) concentrations and the variation of the storage (G′) and loss (G″) moduli of the PBA hydrogel as a function of temperature at 2.70 mg/mL PBA (E) and 3.5 mg/mL urea (G).

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Although the gelation temperature also varied with the concentration in the heating curves (Figure 3B), the heating and cooling curves differed in both gelation temperatures and shape (tailing).
The tails of the heating curves matched at all concentrations, most likely because the amount of the gelator that can be dissolved (and hence the absorbed heat) is limited by its solubility at a given temperature. Similar differences in the shape of DSC heating and cooling curves have been previously observed in supersaturated solutions (35) and undercooled melts. (36) Furthermore, other researchers have suggested that a gel prepared by cooling a solution is first in a supersaturated state, which then spontaneously crystallizes and/or precipitates as an amorphous mass, thereby yielding the gel. (37) We therefore hypothesize that the PBA gelator easily forms a supersaturated solution, which, at some critical point during cooling, precipitates as a mixture of amorphous and crystalline phases, favoring one-dimensional aggregation. In line with the above, eq 1 also describes the critical crystallization temperature of supersaturated solutions. (38)

Viscoelastic Properties of PBA Hydrogels Lie in the Range of Soft Tissues

Elastic moduli of the extracellular matrix vary widely between the brain (1–3 kPa), muscles (23–42 kPa), blood vessels (1.16–860 MPa), tendons (136–820 MPa), and bones (15–40 GPa); therefore, changing the elastic modulus of the gel is critical for different applications by mimicking the mechanical properties of different tissues and organs and facilitating cell adhesion, migration, proliferation, and differentiation. (39,40) Increasing the PBA concentration increases the storage modulus of the hydrogel over the whole range of temperatures below the gel point (Figure 3D,E). At higher temperatures, in the dissolved state of the gel, the graphs show a “noisy” region because the moduli are lower than the limit of detection of rheometry, which was thus disregarded. As expected, increasing the PBA concentration also led to a denser gelator network. This network consists of fiber-like microcrystallites connected by the amorphous solid phase of PBA (see Figure 2C,D). Combined, they act as elastic chains in a classical elastomer network. Hence, at higher concentrations, PBA yields stiffer elastic gels with a higher storage modulus (G′) (Figure 3D).
The curves of the loss modulus (G″) (Figure S4) display similar trends and shapes to those of the storage modulus (G′), albeit with lower values in the whole temperature range, as exemplified in Figure 3E. At higher PBA concentrations and therefore denser gels, the internal friction in and between PBA fibers also increases, thus increasing G″.
The comparison of the results from the DSC cooling and rheology experiments shows marked differences in gelation temperatures. Yet, the rates of temperature change differed only slightly between DSC and rheology. Based on the rheology data, measured as a cooling run (see the G′/G″ crossover example at 2.70 mg/mL PBA in Figure 3E and the crossover plots of the other samples in Figure S5), the gelation temperatures were 48.5, 62.5, and 64.8 °C at 2.04, 2.70, and 3.54 mg/mL PBA, respectively. In contrast, the DSC curves (Figure 3B,C) show transitions at 31.4, 39.8, and 49.4 °C in the cooling run (as peaks) and at 52, 58, and 64.5 °C (broader maxima) in the heating run. Nevertheless, in the DSC experiments, the samples remained undisturbed and hence in the state of a supersaturated solution. Conversely, in the rheology experiment, the samples were disturbed by mechanical oscillations, which triggered crystallization and thus prevented supersaturation. For these reasons, the gelation temperatures assessed by rheology in the cooling run are much closer to the gel-to-sol transition temperature determined in DSC heating curves, albeit not completely identical because DSC directly detects the heat of melting but not the mechanical reversal of gelation.
The fibers still exist during dissolution, whereas their mechanical network is already disconnected (see Figure 3A). By varying the PBA concentration, we were able to tune the moduli of the gels at physiological temperature (at 37 °C) by 2 orders of magnitude, from 2.5 to 103 kPa (Table S1). Considering this range, PBA hydrogels have a high potential for biomedical applications, including tissue scaffolds. To further test the tunability of PBA hydrogels, we assessed the effect of urea on the viscoelastic properties of these gels because urea is a well-known, nontoxic chaotropic agent.

Urea Decreases the Elastic and Loss Moduli of PBA Hydrogels

Adding urea to a PBA hydrogel changes its mechanical properties. At 33.3 mg/mL, urea prevented the formation of the gel even after cooling to 6 °C overnight in a refrigerator, whereas at lower concentrations, up to 10 mg/mL of urea, the PBA gel was formed at room temperature. Figure 3F shows the variation of the storage modulus of 2.7 mg/mL PBA gels doped with 0, 3.5, or 10.4 mg/mL urea as a function of temperature (for loss modulus see Figure S6). As in neat PBA, the loss modulus (G″) curves of these doped samples also displayed trends and shapes similar to those of G″ shown in Figure 3E (undoped sample) but lower values with increasing doping across the temperature range, as also shown for storage modulus in Figures 3F and S7. The PBA gelation temperatures were determined from rheology as the crossover points of storage and loss modulus, as explained in detail above (see example in Figure 3G; the plots of the crossovers of the remaining samples are shown in Figure S7). In urea-doped samples, the gelation temperatures were 62.6, 60.6, and 56 °C for 0, 3.5, and 10.4 mg/mL urea, respectively, highlighting a clear trend, that is, the decrease in gelation temperature with the increase in urea concentration (see Table S2 in Supporting Information). These changes in the physical properties and melting temperature of PBA hydrogels upon urea addition could be caused either by the chaotropic effect of urea, which can disrupt hydrogen bonding (via urea-PBA bridging), or by the lone electron pairs of urea (especially on the carbonyl O atom), which can interact with boron on PBA via donor–acceptor bonding. Nevertheless, further experimental research is needed to confirm these assumptions.
At body temperature, the storage moduli (G′) of the urea-doped hydrogels ranged from 63.4 to 30.4 kPa. Their values depended on the concentration of urea (Table S2 in Supporting Information). These findings underscore the possibility of tuning the viscoelastic properties of these hydrogels by external chemical stimuli, thereby opening up opportunities for preparing tissue scaffolds and modulating stem cell differentiation. (41,42)

Mechanical and Rheological Properties of the Gels at Room Temperature

Figure 4A shows the variation of the storage and loss moduli as a function of oscillation strain for representative urea-free samples (for samples with urea, see Figure S8A). The data indicate good stability (constancy of storage modulus G′) until a deformation amplitude of ca. 0.1%, whereas considerable stability persists until 1%, above which deformation a rapid mechanical destruction occurs. In the “nondestructive” deformation range from 0.002 to 1%, the loss modulus G″ gradually increases with the deformation amplitude, thus indicating an increasing contribution of disentanglement and friction of the interlocked fibers. Above the strain amplitude of 1%, as the gel is being mechanically destroyed, G″ rapidly decreases together with G′. The differences in trends between all samples were small, but the absolute values of the moduli (G′, G″) depended on the concentration of PBA and of the urea additive (as already discussed above). In view of the nearly identical trends in the destructive strain sweep tests, that is, of the nearly identical values of the deformation at break (1%), the moduli of the different gels can be directly correlated with gel strength, expressed as stress at break (=deformation_at_break * modulus) or as toughness (area below the deformation-dependent curve: stress = deformation * modulus). (43) The stiffest gels (higher G′) of the series were automatically also the strongest.

Figure 4

Figure 4. (A) Strain sweeps for networks at 30 °C with different concentrations of PBA; (B) variation of the storage modulus G′ and of the loss modulus G″ as a function of frequency at 30 °C, with deformation amplitude 0.01%, for samples with different concentrations of PBA. Data points in all graphs: G′: filled symbols; G″, open symbols.

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Figure 4B illustrates the variation of the storage and loss moduli as a function of frequency of representative urea-free samples (for samples with urea, see Figure S8B). In the whole range from 0.01 to 100 Hz, the storage modulus G′ did not depended on the frequency and as always higher than G″. These results indicate that the material is neither in a transitioning state and nor solid-like. Lower frequencies were not studied because they would have required long experimental times, thus entailing a high risk of partial drying of the samples (and of “false modulus increase”) during the measurements. Given the low applied deformation amplitude, the data from 0.1 to 0.01 Hz were increasingly noisy. The loss modulus G″ steadily decreased with the increase in frequency, most likely because disentanglement and subsequent sliding (and friction) of interlocked fibers are more difficult at high frequencies.

PBA Hydrogels Respond to Multiple Chemical Stimuli

We assessed the sol–gel reactivity of PBA hydrogel samples to four chemical stimuli: (i) after adding 50 μL (1 equiv) of a 0.2 M NaOH solution, the gel dissolved within 15 min; (ii) after adding 50 μL (1 equiv) of a 0.2 M aqueous solution of hydrochloric acid to this solution, the gel formed again immediately, showing its chemically triggered reversible sol–gel transition; (iii) after adding 20 μL (6 equiv) of a 10% hydrogen peroxide solution, the gel irreversibly dissolved in approximately 1 h, as expected because arylboronic acids are known to react with hydrogen peroxide, producing phenol; (44) (iv) after adding 20 mg (approximately 1.3 equiv) of (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD), the gel also dissolved in approximately 1 h (Figure 5A), by forming a host–guest complex, as confirmed by NMR (Figure 6).

Figure 5

Figure 5. (A) Triggering the gel–sol transition of PBA by NaOH/HCl, H2O2, and CD. (B) Photos of selective absorption of Nile red and methylene blue at 0 and 2 h after adding dyes and mixtures of PBA and dyes of different molar equivalents at room temperature.

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Figure 6

Figure 6. (A) 1H ROESY NMR spectrum of PBA/cyclodextrine complex, (B) detail of 1H ROESY NMR spectrum of interactions of PBA aromatic hydrogens with cyclodextrine and (C) 1H DOSY NMR spectrum confirming formation of host-guest complex (numbering corresponds to the proton assignments as indicated on the chemical structure of PBA and cyclodextrine).

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In host–guest chemistry, β-cyclodextrin is a well-known compound for its ability to form complexes with small and relatively nonpolar molecules, such as ibuprofen, (45) solubilizing them. Introducing macromolecular cavities into gelators could provide them with host–guest responsiveness, but this approach remains challenging because LMW gelators tend to lose their gelating properties upon structural modifications. (46) In further research, by preparing soluble host–guest complexes of LMW gelators, we may prepare systems responsive to compounds capable of strongly interacting with cyclodextrin, thus releasing the gelator and gelating the solvent.

PBA Hydrogels Selectively Absorb Dyes

As a fraction of PBA was present in anionic form in PBA hydrogels, the hydrogel selectively absorbed the cationic dye methylene blue over the anionic dye Congo red. Figure 5B shows efficient uptake of methylene blue, which is accumulated in the gel near its surface. Confocal fluorescence microscopy (Figure S9) using the cationic fluorescent dye Nile red and the anionic fluorescent dye fluorescein showed a more detailed image of their distribution in the system: Nile red was absorbed efficiently, whereas fluorescein remained in solution and was not absorbed by the nanofibers. (36)

NMR Confirms the Formation of PBA/HP-β-CD Host–Guest Complexes

To confirm that adding 2-hydroxypropyl-β-cyclodextrin dissolves the gel through the formation of host–guest complexes, a sample prepared in D2O was analyzed by NMR (Figure 6). Because the peaks of PBA isobutoxy groups and hydrogens of HP-β-CD overlap, 1H shifts corresponding to PBA were assigned from H–H COSY. The ROESY spectra showed strong interactions of aromatic hydrogens with either PBA O–CH2 hydrogens (3.95 ppm) or HP-β-CD hydrogens. They also clearly showed interactions between all aromatic hydrogens of PBA and the internal hydrogen of the HP-β-CD cavity (3.75 ppm), corroborating the formation of the host–guest complex. Given the absence of any interaction between cyclodextrin hydrogens and isobutoxy CH hydrogens of PBA in ROESY, we assumed that the isobutoxy group was oriented outside of the cavity. Despite striking differences between the molar masses of PBA (194 g/mol) and HP-β-CD (approximately 1500 g/mol, depending on the degree of derivatization), diffusion ordered spectroscopy (DOSY) showed virtually identical diffusion coefficients, highlighting PBA binding to HP-β-CD. The decreased diffusion coefficient of PBA in HP-β-CD also indicated the formation of the host–guest complex.
These NMR findings contradict prior research on the complexation of phenylboronic acids with β-CD. In previous studies, the interactions of β-CD hydroxyl groups with boronic acid prevailed, and the formation of host–guest complexes was not shown by either rotating-frame Overhauser effect spectroscopy (ROESY) or DOSY. (47) Nevertheless, this discrepancy may be explained by cyclodextrin derivatization by 2-hydroxypropyl groups, which prevents interactions with sugar diols because they become inaccessible. Therefore, unlike previously published ROESY and DOSY data, our NMR findings confirm that PBA/HP-β-CD host–guest complexes are formed when adding 2-hydroxypropyl-β-cyclodextrin to a PBA gel.

Conclusions

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PBA is a simple LMW gelator capable of gelating water at low concentrations into a network of cross-linked nanofibers with amorphous and crystalline phases as shown by electron microscopy and by SAXS and WAXS measurements. The viscoelastic properties of PBA hydrogels lie in the range of soft tissues, and the moduli of these gels can be tailored in a wide range of 2 orders of magnitude, from 2.5 to 103 kPa, by changing the concentration of PBA. Furthermore, adding urea, which is biocompatible, decreases the elastic and loss moduli of PBA hydrogels at a given concentration. In turn, increasing the urea concentration enables us to tune the gelation temperature between 62 and 56 °C and the elastic modulus G′ (at body temperature) between 63.4 and 30.4 kPa. Therefore, PBA has a high potential as a biodegradable, multistimuli-responsive, LMW hydrogelator for bioapplications, capable of selective absorption of cationic compounds, as shown for two cationic and two anionic dyes. The gelator can be dissolved by adding hydrogen peroxide, sodium hydroxide, and 2-hydroxypropyl-β-cyclodextrin, thus demonstrating the host-guess stimuli-responsive properties of the PBA gelator.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsanm.3c03259.

  • Fit of the SAXS data and components of the used model, IR spectra, rheological data, and CLSM images (PDF)

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Author Information

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  • Corresponding Author
  • Authors
    • Martin Orságh - Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Hlavova 2030, 128 00 Prague 2, Czech Republic;  Orcidhttps://orcid.org/0000-0003-1145-6137
    • Beata Strachota - Institute of Macromolecular Chemistry AS CR, Heyrovsky Sq. 2, 162 00 Prague 6, Czech Republic;  Orcidhttps://orcid.org/0000-0001-5163-9304
    • Ewa Pavlova - Institute of Macromolecular Chemistry AS CR, Heyrovsky Sq. 2, 162 00 Prague 6, Czech Republic
    • Jiří Pánek - Institute of Macromolecular Chemistry AS CR, Heyrovsky Sq. 2, 162 00 Prague 6, Czech Republic;  Orcidhttps://orcid.org/0000-0001-5816-6298
    • Agnieszka Adamczyk-Woźniak - Department of Physical Chemistry, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland;  Orcidhttps://orcid.org/0000-0002-0571-0197
    • Andrzej Sporzyński - Department of Physical Chemistry, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland;  Faculty of Agriculture and Forestry, University of Warmia and Mazury, Oczapowskiego 8, 10-719 Olsztyn, Poland;  Orcidhttps://orcid.org/0000-0001-8405-3297
    • Paweł Leszczyński - Department of Physical Chemistry, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
    • Miroslav Štěpánek - Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Hlavova 2030, 128 00 Prague 2, Czech Republic;  Orcidhttps://orcid.org/0000-0002-7636-7234
  • Author Contributions

    M.O. investigation, data curation, formal analysis, visualization, writing─original draft, and writing─review and editing; B.S. investigation, data curation, writing─original draft, and writing─review and editing; E.P. investigation; J.P. investigation; A.A.-W investigation; A.S. investigation; P.L. investigation; M.Š. investigation, data curation, writing─original draft, and writing─review and editing; M.U. conceptualization, methodology, data curation, visualization, resources, supervision, writing─original draft, writing─review and editing, project administration, and funding acquisition.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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The authors acknowledge the financial support from the Ministry of Education, Youth, and Sport of the Czech Republic projects: LTAIN19078 within the Inter-Excellence Program and Operational Program Research, Development and Education: “Excellent Research Teams” (Project No. CZ.02.1.01/0.0/0.0/15_003/0000417-CUCAM). The authors thank Dr. Carlos V. Melo for editing the manuscript.

References

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    Biomacromolecules (2015), 16 (12), 3731-3739CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
    Coassembly behavior of the double hydrophilic block copolymer poly(4-hydroxystyrene)-block-poly(ethylene oxide) (PHOS-PEO) with three amphiphilic phenylboronic acids (PBA) differing in hydrophobicity, 4-dodecyloxyphenylboronic acid (C12), 4-octyloxyphenylboronic acid (C8), and 4-isobutoxyphenylboronic acid (i-Bu) was studied in alk. aq. solns. and in mixts. of NaOHaq/THF by spin-echo 1H NMR spectroscopy, dynamic and electrophoretic light scattering, and SAXS. The study reveals that only the coassembly of C12 with PHOS-PEO provides spherical nanoparticles with intermixed PHOS and PEO blocks, contg. densely packed C12 micelles. NMR measurements have shown that spatial proximity of PHOS-PEO and C12 leads to the formation of ester bonds between -OH of PHOS block and hydroxyl groups of -B(OH)2. Due to the presence of PBA moieties, the release of compds. with 1,2- or 1,3-dihydroxy groups loaded in the coassembled PHOS-PEO/PBA nanoparticles by covalent binding to PBA can be triggered by addn. of a surplus of glucose that bind to PBA competitively. The latter feature has been confirmed by fluorescence measurements using Alizarin Red as a model compd. Nanoparticles were proved to exhibit swelling in response to glucose as detected by light scattering.
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  15. 15
    Zhao, F.; Wu, D.; Yao, D.; Guo, R.; Wang, W.; Dong, A.; Kong, D.; Zhang, J. An Injectable Particle-Hydrogel Hybrid System for Glucose-Regulatory Insulin Delivery. Acta Biomater. 2017, 64, 334– 345,  DOI: 10.1016/j.actbio.2017.09.044
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    15
    An injectable particle-hydrogel hybrid system for glucose-regulatory insulin delivery
    Zhao, Fuli; Wu, Di; Yao, Dan; Guo, Ruiwei; Wang, Weiwei; Dong, Anjie; Kong, Deling; Zhang, Jianhua
    Acta Biomaterialia (2017), 64 (), 334-345CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
    Long-term and daily s.c. injections of insulin for the treatment of insulin-dependent diabetic patients often lead to poor patient compliance and undesired complications. Phenylboronic acid (PBA)-based polymeric hydrogels have been widely considered as one of the most promising insulin delivery system to replace the frequent insulin injections. However, their applications are limited by clin. irrelevant glucose-responsive range, slow response rate, low tissue-adhesiveness and poor biodegradability, undesirable leakage at normoglycemic state. Herein, we report a novel implantable insulin hydrogel for glucose-regulated delivery of insulin based on a unique particle-hydrogel hybrid platform featuring fast glucose responsiveness at physiol. pH, shear-thinning behavior for injection, tissue-adhesive function for long-lasting adherence, and full biodegradability for safe use. The system was thoroughly characterized both in vitro and in vivo and was demonstrated to hold these unique functions. Using streptozotocin-induced diabetic mice as a model, it was shown that a single s.c. injection of the insulin-loaded particle-hydrogel formulation led to quasi-steady-state blood glucose levels within the normal range for about two weeks. In addn., the prepn. of the formulation only involved simple mixing and self-assembling processes, and thus it had great scalability and reproducibility for practical use. The highly feasible prepn., excellent performance, inherent biocompatibility and biodegradability make this novel composite hydrogel promising platform for diabetes therapy. Phenylboronic acid (PBA)-based polymeric hydrogels have been widely considered as one of the most promising insulin delivery system to replace the frequent insulin injections. However, these hydrogels, mostly based on a variety of PBA-contg. acrylamide monomers, are still far from clin. reality. Building upon a unique particle-hydrogel hybrid platform, herein we report a novel implantable insulin storage and delivery system with multifunctionalities including fast glucose-sensitiveness at physiol. pH, shear-thinning behavior for injection, tissue-adhesive function for long-lasting adherence, biodegradable materials for safe use and well-controlled insulin release. These unique functions were demonstrated through research both in vitro and in vivo. In addn., the prepn. of the formulation was simple, and thus it had great scalability and reproducibility for practical use.
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  16. 16
    Tao, N.; Li, G.; Liu, M.; Gao, W.; Wu, H. Preparation of Dual Responsive Low-Molecular-Weight Hydrogel for Long-Lasting Drug Delivery. Tetrahedron 2017, 73 (22), 3173– 3180,  DOI: 10.1016/j.tet.2017.04.051
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    16
    Preparation of dual responsive low-molecular-weight hydrogel for long-lasting drug delivery
    Tao, Ning; Li, Guotao; Liu, Miaochang; Gao, Wenxia; Wu, Huayue
    Tetrahedron (2017), 73 (22), 3173-3180CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
    A novel low-mol.-wt. hydrogel (LMWG) was fabricated by oligopeptide and phenylboronic acid to obtain a smart mol. hydrogel with dual glucose and pH response for long-term drug delivery in this study. Dual glucose and pH responsiveness of the blank mol. hydrogel was first evaluated by online tracking the dynamics curves using UV spectroscopy. Model drugs of phenformin for antidiabetes and doxorubicin for anticancer were selected to evaluate the drug carry and glucose/pH responsive drug release of the mol. hydrogel. The results showed the drug-loaded LMWG had good sustaining and long-lasting drug delivery in physiol. or pathol. environment.
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  17. 17
    Wu, X.; Chen, X.-X.; Song, B.-N.; Huang, Y.-J.; Ouyang, W.-J.; Li, Z.; James, T. D.; Jiang, Y.-B. Direct Sensing of Fluoride in Aqueous Solutions Using a Boronic Acid Based Sensor. Chem. Commun. 2014, 50 (90), 13987– 13989,  DOI: 10.1039/C4CC04542D
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    Direct sensing of fluoride in aqueous solutions using a boronic acid based sensor
    Wu, Xin; Chen, Xuan-Xuan; Song, Bing-Nan; Huang, Yan-Jun; Ouyang, Wen-Juan; Li, Zhao; James, Tony D.; Jiang, Yun-Bao
    Chemical Communications (Cambridge, United Kingdom) (2014), 50 (90), 13987-13989CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    Binding of the fluoride ion triggers aggregation of a pyreneboronic acid-catechol ensemble in acidic aq. solns., giving rise to intense excimer emission, allowing for sensitive fluoride ion sensing at ppm levels, with an apparent fluoride binding const. higher than 103 M-1 which is unprecedented for boronic acid sensors in water.
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  18. 18
    Martínez-Aguirre, M. A.; Villamil-Ramos, R.; Guerrero-Alvarez, J. A.; Yatsimirsky, A. K. Substituent Effects and PH Profiles for Stability Constants of Arylboronic Acid Diol Esters. J. Org. Chem. 2013, 78 (10), 4674– 4684,  DOI: 10.1021/jo400617j
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    Substituent Effects and pH Profiles for Stability Constants of Arylboronic Acid Diol Esters
    Martinez-Aguirre, Mayte A.; Villamil-Ramos, Raul; Guerrero-Alvarez, Jorge A.; Yatsimirsky, Anatoly K.
    Journal of Organic Chemistry (2013), 78 (10), 4674-4684CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    Stability consts. of boronic acid diol esters in aq. soln. have been detd. potentiometrically for a series of meta-, para-substituted phenylboronic acids and diols of variable acidity. The consts. β11-1 for reactions between neutral forms of reactants producing the anionic ester plus proton follow the Hammett equation with ρ depending on pKa of diol and varying from 2.0 for glucose to 1.29 for 4-nitrocatechol. Obsd. stability consts. (Kobs) measured by UV-vis and fluorometric titrns. at variable pH for esters of 4,5-dihydroxy-1,3-benzenedisulfonate (Tiron) generally agree with those expected on the basis of β11-1 values, but the direct fitting of Kobs vs. pH profiles gives shifted pKa values both for boronic acids and diol as a result of significant interdependence of fitting parameters. The substituent effects on absorption and fluorescence spectra of Tiron arylboronate esters are characterized. The Kobs for Tiron detd. by 11B NMR titrns. are approx. 1 order of magnitude smaller than those detd. by UV-vis titrns. under identical conditions. A general equation, which makes possible an est. of β11-1 for any pair of boronic acid and diol from their pKa values, is proposed on the basis of established Broensted-type correlation of Hammett parameters for β11-1 with acidity of diols. The equation allows one to calc. stability consts. expected only on basis of acid-base properties of the components, thus permitting more strict evaluation of contributions of addnl. factors such as steric or charge effects to the ester stability.
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  19. 19
    Brooks, W. L. A.; Deng, C. C.; Sumerlin, B. S. Structure–Reactivity Relationships in Boronic Acid–Diol Complexation. ACS Omega 2018, 3 (12), 17863– 17870,  DOI: 10.1021/acsomega.8b02999
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    19
    Structure-Reactivity Relationships in Boronic Acid-Diol Complexation
    Brooks, William L. A.; Deng, Christopher C.; Sumerlin, Brent S.
    ACS Omega (2018), 3 (12), 17863-17870CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)
    Boronic acids have found widespread use in the field of biomaterials, primarily through their ability to bind with biol. relevant 1,2- and 1,3-diols, including saccharides and peptidoglycans, or with polyols to prep. hydrogels with dynamic covalent or responsive behavior. Despite a wide range of boronic acid architectures that have been previously considered, there is a need for greater understanding of the structure-reactivity relationships that govern binding affinity to diols. In this study, various boronic acids and other organoboron compds. were investigated to det. their pKa and their binding consts. with the biol. relevant diols including sorbitol, fructose, and glucose. Boronic acid pKa values were detd. through spectroscopic titrn., whereas binding consts. were detd. by fluorescence spectroscopy during competitive binding studies. Key structure-reactivity relationships clearly indicated that both boronic acid structure and soln. pH must be carefully considered. By considering a variety of boronic acids with systematically varied electronics and sterics, these results provide guidance during selection of organoboron compds. in sensing, delivery, and materials chem.
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  20. 20
    Tomsho, J. W.; Pal, A.; Hall, D. G.; Benkovic, S. J. Ring Structure and Aromatic Substituent Effects on the p K a of the Benzoxaborole Pharmacophore. ACS Med. Chem. Lett. 2012, 3 (1), 48– 52,  DOI: 10.1021/ml200215j
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    20
    Ring Structure and Aromatic Substituent Effects on the pKa of the Benzoxaborole Pharmacophore
    Tomsho, John W.; Pal, Arnab; Hall, Dennis G.; Benkovic, Stephen J.
    ACS Medicinal Chemistry Letters (2012), 3 (1), 48-52CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
    In this work, we present an investigation into the phys. properties of a unique class of arom. boronic acids, the benzoxaboroles. Using spectrophotometric methods, the ionization consts. of a family of substituted benzoxaboroles are detd. Heterocyclic ring modifications are examd. to det. their effects on the ionization of the boronic acid moiety. It is also shown that the substituent effects about the arom. ring follow a Hammett relationship with the compds.' measured pKa values. Finally, these substituent effects are also shown to extend to the sugar binding properties of these compds. under physiol. relevant conditions. Combined, these data will inform medicinal chemists wishing to tailor the ionization and/or ability of this class of compd. to bind diol-contg. biomols.
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  21. 21
    Vrbata, D.; Uchman, M. Preparation of Lactic Acid- and Glucose-Responsive Poly(ε-Caprolactone)- b -Poly(Ethylene Oxide) Block Copolymer Micelles Using Phenylboronic Ester as a Sensitive Block Linkage. Nanoscale 2018, 10 (18), 8428– 8442,  DOI: 10.1039/C7NR09427B
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    21
    Preparation of lactic acid- and glucose-responsive poly(.vepsiln.-caprolactone)-b-poly(ethylene oxide) block copolymer micelles using phenylboronic ester as a sensitive block linkage
    Vrbata, David; Uchman, Mariusz
    Nanoscale (2018), 10 (18), 8428-8442CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
    The present study describes the synthesis, self-assembly and responsiveness to glucose and lactic acid of biocompatible and biodegradable block copolymer micelles using phenylboronic ester as the linkage between hydrophobic PCL and hydrophilic PEO. The PCL block with pendant phenylboronic acid (PCLBA) was synthesized by combining ε-CL ROP, using 4-hydroxymethyl(phenylboronic) acid pinacolate as the initiator, and pinacol deprotection. The glucose-terminated PEO was prepd. by 1,3-dipolar, Cu(I)-catalyzed, alkyne-azide cycloaddn. of α-methoxy-ω-propargyl poly(ethylene oxide) and 1-azido-1-deoxy-D-glucopyranose. PCLBA and PEOGlc blocks were linked in NaOH acetone soln., which was indirectly confirmed by Alizarin Red S fluorescence and directly by 1H NMR spectroscopy. Dialysis against Milli-Q water induced the self-assembly of PCLBA-b-PEOGlc nanoparticles, which were characterized by SLS and DLS and by cryo-TEM. Furthermore, the microscopic properties of the charged interface between the hydrophobic PCLBA core and the hydrophilic PEOGlc shell were examd. Subsequently, the nanoparticles were transferred to a PBS soln. supplemented with different conc. of glucose to simulate the physiol. conditions in blood or lactic acid to simulate acidic cytosolic or endosomal conditions in tumor cells. Adding a surplus of glucose or lactic acid, which competitively binds to PBA, removes the stabilizing hydrophilic PEOGlc blocks, thereby triggering marked nanoparticle aggregation.
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  22. 22
    Vrbata, D.; Kereiche, S.; Kalíková, K.; Uchman, M. Stimuli-Responsive Multifunctional Micelles of ABC vs. ACB Triblock Terpolymers Using Reversible Covalent Bonding of Phenylboronic Acid: Controlled Synthesis, Self-Assembly and Model Drug Release. J. Mol. Liq. 2021, 335, 116528,  DOI: 10.1016/j.molliq.2021.116528
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    22
    Stimuli-responsive multifunctional micelles of ABC vs. ACB triblock terpolymers using reversible covalent bonding of phenylboronic acid: controlled synthesis, self-assembly and model drug release
    Vrbata, David; Kereiche, Sami; Kalikova, Kveta; Uchman, Mariusz
    Journal of Molecular Liquids (2021), 335 (), 116528CODEN: JMLIDT; ISSN:0167-7322. (Elsevier B.V.)
    We report the synthesis and self-assembly of well-defined, amphiphilic, biodegradable and glucose- and pH-responsive ABC and ACB triblock terpolymer multifunctional micelles in aq. media using blocks consisting of poly(ethylene oxide) (PEO), poly(ε-caprolactone) (PCL), and boronic acid-functionalised poly(ε-caprolactone) (PBA). The terpolymers were synthesized by sequential ring-opening polymn. (ROP) and functionalised using phenylboronic acid pinacolate via alkyne - azide cycloaddn. (CuAAC). Lastly, the pinacole groups were deprotected by mild acidic catalysis to introduce phenylboronic acid for controlled drug solubilisation and delivery. ABC and ACB triblock terpolymers self-assembled into various multifunctional micelles in aq. media depending on the state of the phenylboronic acid (pinacol protected, BAPin vs. deprotected, BA) and on the prepn. procedure, as shown by dynamic and static light scattering (DLS and SLS) and by cryogenic transmission electron microscopy (cryo-TEM). The fluorescence probe Alizarin Red S (ARS) was used as a model drug, which covalently binds to BA, and its uptake was monitored by fluorescence spectroscopy and high-performance liq. chromatog. (HPLC). When adding a surplus of glucose, which competitively binds to BA, ARS was released as a function of micelle morphol. (core-shell corona (ABC) vs. mixed-shell (ACB) micelles). When transferring ARS-loaded nanoparticles to phosphate buffer saline (PBS) solns. at different pH values (7.4 and 5 or 3) simulating physiol. and tumor conditions, resp., ABC micelles released ARS only at low pH, while ACB micelles released ARS in response to glucose and to both low and physiol. pH values. Therefore, in this system, ABC micelles are better suited for drug delivery to tumor cells than their ACB counterparts because they retain their cargo in PBS at high glucose concns. but release it under acidic conditions, which occur in hypoxic cancer cells, thus highlighting the potential of ABC micelles for targeted drug delivery in the context of cancer therapy.
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    Celenza, G.; Vicario, M.; Bellio, P.; Linciano, P.; Perilli, M.; Oliver, A.; Blazquez, J.; Cendron, L.; Tondi, D. Phenylboronic acid derivatives as validated leads active in clinical strains overexpressing KPC-2: a step against bacterial resistance. Chemmedchem 2018, 13, 713– 724,  DOI: 10.1002/cmdc.201700788
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    Phenylboronic Acid Derivatives as Validated Leads Active in Clinical Strains Overexpressing KPC-2: A Step against Bacterial Resistance
    Celenza, Giuseppe; Vicario, Mattia; Bellio, Pierangelo; Linciano, Pasquale; Perilli, Mariagrazia; Oliver, Antonio; Blazquez, Jesus; Cendron, Laura; Tondi, Donatella
    ChemMedChem (2018), 13 (7), 713-724CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The emergence and dissemination of multidrug resistant (MDR) pathogens resistant to nearly all available antibiotics poses a significant threat in clin. therapy. Among them, Klebsiella pneumoniae clin. isolates overexpressing KPC-2 carbapenemase are the most worrisome, extending bacterial resistance to last-resort carbapenems. In this study, we investigate the mol. recognition requirements in the KPC-2 active site by small phenylboronic acid derivs. Four new phenylboronic acid derivs. were designed and tested against KPC-2. For the most active, despite their simple chem. structures, nanomolar affinity was achieved. The new derivs. restored susceptibility to meropenem in clin. strains overexpressing KPC-2. Moreover, no cytotoxicity was detected in cell-viability assays, which further validated the designed leads. Two crystallog. binary complexes of the best inhibitors binding KPC-2 were obtained at high resoln. Kinetic descriptions of slow binding, time-dependent inhibition, and interaction geometries in KPC-2 were fully investigated. This study will ultimately lead toward the optimization and development of more-effective KPC-2 inhibitors.
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    Rit, T.; Ghosh, T.; Bhowmik, S.; Patidar, M. K.; Das, A. K. Dynamic Multicomponent Reactions-Directed Self-Assembled G-quadruplex Inherent Antibacterial Hydrogel. Langmuir 2023, 39 (18), 6466– 6475,  DOI: 10.1021/acs.langmuir.3c00392
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    24
    Dynamic Multicomponent Reactions-Directed Self-Assembled G-quadruplex Inherent Antibacterial Hydrogel
    Rit, Tanmay; Ghosh, Tapas; Bhowmik, Sourav; Patidar, Mukesh K.; Das, Apurba K.
    Langmuir (2023), 39 (18), 6466-6475CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
    Nowadays, inherent antibacterial hydrogels have gained significant attention due to their utilization against infectious bacteria. Herein, we focus on the development of an injectable, self-healable, dynamic, and G-quadruplex hydrogel with inherent antibacterial activity. The dynamic self-assembled hydrogel is constructed upon multicomponent reactions (MCR) among guanosine, 2-formylphenylboronic acid, and amino acid/peptides in the presence of potassium ions. The role of amino acid/peptides in the formation of the G-quadruplex hydrogel is studied in detail. The G-quadruplex structure is formed via the π-π stacking of G-quartets. The formation of G-quadruplex is investigated by thioflavin T binding assay, CD spectroscopy, and PXRD. The formation of the dynamic imino-boronate bond in the hydrogels is well characterized by temp.-dependent 11B NMR (VT-NMR) and FT-IR spectroscopy. Furthermore, HR-TEM images and rheol. expts. reveal the fibrillar networks and viscoelastic property of the hydrogels. The presence of the dynamic imino-boronate ester bonds makes the hydrogel injectable and self-healable in nature. These dynamic G-quadruplex hydrogels show potential antibacterial activity against a series of Gram-pos. and Gram-neg. bacteria. The hydrogels have been used for the entrapment and sustained release of an anticancer drug doxorubicin over 48 h at different pHs (4.8, 7.4, and 8.5) and temp. without the influence of any external stimuli. Such injectable and self-healable hydrogels could be used in various applications in the field of biomedical science.
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    Baker, S. J.; Ding, C. Z.; Akama, T.; Zhang, Y.-K.; Hernandez, V.; Xia, Y. Therapeutic potential of boron-containing compounds. Future Med. Chem. 2009, 1 (7), 1275– 1288,  DOI: 10.4155/fmc.09.71
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    Therapeutic potential of boron-containing compounds
    Baker, Stephen J.; Ding, Charles Z.; Akama, Tsutomu; Zhang, Yong-Kang; Hernandez, Vincent; Xia, Yi
    Future Medicinal Chemistry (2009), 1 (7), 1275-1288CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)
    A review. Relative to C, H, N, and O2, very little is currently known about B in therapeutics. In addn., there are very few boron-contg. natural products identified to date to serve as leads for medicinal chemists. Perceived risks of using B and lack of synthetic methods to handle boron-contg. compds. have caused the medicinal chem. community to shy away from using the atom. However, phys., chem. and biol. properties of B offer medicinal chemists a rare opportunity to explore and pioneer new areas of drug discovery. B therapeutics are emerging that show different modes of inhibition against a variety of biol. targets. With one B-contg. therapeutic agent on the market and several more in various stages of clin. trials, the occurrence of this class of compd. is likely to grow over the next decade and B could become widely accepted as a useful element in future drug discovery.
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    Marasovic, M.; Ivankovic, S.; Stojkovic, R.; Djermic, D.; Galic, B.; Milos, M. In vitro and in vivo antitumour effects of phenylboronic acid against mouse mammary adenocarcinoma 4T1 and squamous carcinoma SCCVII cells. J. Enzyme Inhib. Med. Chem. 2017, 32 (1), 1299– 1304,  DOI: 10.1080/14756366.2017.1384823
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    26
    In vitro and in vivo antitumour effects of phenylboronic acid against mouse mammary adenocarcinoma 4T1 and squamous carcinoma SCCVII cells
    Marasovic, Maja; Ivankovic, Sinisa; Stojkovic, Ranko; Djermic, Damir; Galic, Borivoj; Milos, Mladen
    Journal of Enzyme Inhibition and Medicinal Chemistry (2017), 32 (1), 1299-1304CODEN: JEIMAZ; ISSN:1475-6366. (Taylor & Francis Ltd.)
    The cytotoxic activity of phenylboroxine acid was evaluated in vitro on mouse mammary adenocarcinoma 4T1, mouse squamous cell carcinoma SCCVII, hamster lung fibroblast V79 and mouse dermal fibroblasts L929 cell lines. The cytotoxic effects were dose dependent for all tested tumor and non-tumor cell lines. Under in vivo conditions, three application routes of phenylboronic acid were studied: intra-peritoneal (i.p.), intra-tumor (i.t.) and per-oral. After tumor transplantation in syngeneic mice, phenylboronic acid was shown to slow the growth of both tumor cell lines (4T1 and SCCVII) compared with the control. The inhibitory effects were pronounced during the application of phenylboronic acid. For both tested tumor cell lines, the most prominent antitumor effect was obtained by i.p. administration, followed significantly by oral administration.
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    Adamczyk-Woźniak, A.; Kaczorowska, E.; Kredátusova, J.; Madura, I.; Marek, P. H.; Matuszewska, A.; Sporzyński, A.; Uchman, M. Dehydration of Ortho -Meta - and Para -Alkoxy Phenylboronic Acids to Their Corresponding Boroxines. Eur. J. Inorg. Chem. 2018, 2018 (13), 1492– 1498,  DOI: 10.1002/ejic.201701485
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    27
    Dehydration of ortho-, meta- and para-Alkoxy Phenylboronic Acids to their Corresponding Boroxines
    Adamczyk-Wozniak, Agnieszka; Kaczorowska, Ewa; Kredatusova, Jana; Madura, Izabela; Marek, Paulina H.; Matuszewska, Alicja; Sporzynski, Andrzej; Uchman, Mariusz
    European Journal of Inorganic Chemistry (2018), 2018 (13), 1492-1498CODEN: EJICFO; ISSN:1434-1948. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The authors detd. and compared properties such as pKa and thermal stability of isomeric isobutoxyphenylboronic acids (ortho-, meta-, para-). Mol. and crystal structures of the para isomer were detd. by single crystal XRD methods. DSC and TGA measurements were carried out on all isomers to study their dehydration as well as thermal stability. The position of the substituent in phenylboronic acids influences their acidity as well as possible formation of the corresponding boroxines.
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    Sporzyński, A.; Leszczyński, P. Solubility of Phenylboronic Compounds in Water. Mediterr. J. Chem. 2017, 6 (5), 200,  DOI: 10.13171/mjc65/01711021733-sporzynsky
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    Solubility of phenylboronic compounds in water
    Leszczynski, Pawel; Sporzynski, Andrzej
    Mediterranean Journal of Chemistry (2017), 6 (5), 200-207CODEN: MJCEAF; ISSN:2028-3997. (Mediterranean Journal of Chemistry)
    Soly. of six phenylboronic compds. in water was investigated using different methods. The results are consistent with each other, although for particular compds. selected methods should be preferred. The soly. of the investigated compds. is low, with the value of ca. 2 g/100 cm3 H2O at 20°C for unsubstituted phenylboronic acid. The unsubstituted benzoxaborole is less sol. than phenylboronic acid. Introduction of OiBu, COOH and CF3 groups into the Ph ring decreases soly. in comparison with unsubstituted phenylboronic acid, esp. for the alkoxy substituent.
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  29. 29
    Xu, L.; Hu, Y.; Liu, M.; Chen, J.; Huang, X.; Gao, W.; Wu, H. Gelation properties and glucose-sensitive behavior of phenylboronic acid based low-molecular-weight organogels. Tetrahedron 2015, 71, 2079– 2088,  DOI: 10.1016/j.tet.2015.02.050
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    Gelation properties and glucose-sensitive behavior of phenylboronic acid based low-molecular-weight organogels
    Xu, Long; Hu, Yalong; Liu, Miaochang; Chen, Jiuxi; Huang, Xiaobo; Gao, Wenxia; Wu, Huayue
    Tetrahedron (2015), 71 (14), 2079-2088CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
    A series of phenylboronic acid (PBA)-based low-mol.-wt. gelators with different hydrocarbon chain lengths (C2-C11) were designed and synthesized. These gelators gelated five solvents efficiently at relatively low concn. with interesting aggregates of nanofibers, thin films, spherical thin shells, and microspheres piled with nanofibers. The gelation ability increased with the chain length increasing up to C11, which has the lowest crit. gelation concn. (CGC) of 0.19 wt %. FTIR and 1H NMR measurements suggested that van der Waals of alkyl chains, H-bonding, and π-π stacking interactions had an important contribution in gelation process and self-assembly. For all the gelators, their glucose-response increased along with the increasing concn. of glucose soln. However, the recognition and responsive rate to glucose were weakened gradually with the alkyl chain length increasing for the gelators. Therefore, glucose-sensitivity of these PBA-based organogels could be modulated through alkyl chain length.
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  30. 30
    Mandal, D.; Mandal, S. K.; Ghosh, M.; Das, P. K. Phenylboronic Acid Appended Pyrene-Based Low-Molecular-Weight Injectable Hydrogel: Glucose-Stimulated Insulin Release. Chem. ─Eur. J. 2015, 21, 12042– 12052,  DOI: 10.1002/chem.201501170
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    30
    Phenylboronic Acid Appended Pyrene-Based Low-Molecular-Weight Injectable Hydrogel: Glucose-Stimulated Insulin Release
    Mandal, Deep; Mandal, Subhra Kanti; Ghosh, Moumita; Das, Prasanta Kumar
    Chemistry - A European Journal (2015), 21 (34), 12042-12052CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A pyrene-contg. phenylboronic acid (PBA) functionalized low-mol.-wt. hydrogelator was synthesized with the aim to develop glucose-sensitive insulin release. The gelator showed the solvent imbibing ability in aq. buffer solns. of pH values, ranging from 8-12, whereas the sodium salt of the gelator formed a hydrogel at physiol. pH 7.4 with a min. gelation concn. (MGC) of 5 mg mL-1. The aggregation behavior of this thermoreversible hydrogel was studied by using microscopic and spectroscopic techniques, including transmission electron microscopy, FTIR, UV/Vis, luminescence, and CD spectroscopy. These investigations revealed that hydrogen bonding, π-π stacking, and van der Waals interactions are the key factors for the self-assembled gelation. The diol-sensitive PBA part and the pyrene unit in the gelator were judiciously used in fluorimetric sensing of minute amts. of glucose at physiol. pH. The morphol. change of the gel due to addn. of glucose was investigated by SEM, which denoted the glucose-responsive swelling of the hydrogel. A rheol. study indicated the loss of the rigidity of the native gel in the presence of glucose. Hence, the glucose-induced swelling of the hydrogel was exploited in the controlled release of insulin from the hydrogel. The insulin-loaded hydrogel showed thixotropic self-recovery property, which hoisted it as an injectable soft composite. Encouragingly, the gelator was found to be compatible with HeLa cells.
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  31. 31
    Gao, W.; Liang, Y.; Peng, X.; Hu, Y.; Zhang, L.; Wu, H.; He, B. In situ injection of phenylboronic acid based low molecular weight gels for efficient chemotherapy. Biomaterials 2016, 105, 1– 11,  DOI: 10.1016/j.biomaterials.2016.07.025
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    In situ injection of phenylboronic acid based low molecular weight gels for efficient chemotherapy
    Gao, Wenxia; Liang, Yan; Peng, Xinyu; Hu, Yalong; Zhang, Longgui; Wu, Huayue; He, Bin
    Biomaterials (2016), 105 (), 1-11CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
    Injectable low mol. wt. gels (LMWGs) based on the derivs. of phenylboronic acid were prepd. and used as substrates for efficient in situ chemotherapy. The gelators as well as LMWGs were characterized by 1H NMR, UV-vis, FTIR, MS and SEM. Anticancer drug doxorubicin hydrochloride (DOX) was encapsulated in the gels. The rheol. properties and rapid recovery capability of both blank and drug-loaded gels were tested. The LMWGs were non-toxic to both 3T3 fibroblasts and 4T1 breast cancer cells. The gels were formed rapidly after injected in vivo. The in vivo anticancer activities of DOX-loaded LMWGs were investigated in breast cancer bearing mice. The intratumoral injection of DOX loaded LMWGs with dose of 30 mg/kg revealed that the gels could coat around the tumor tissues to release DOX sustainingly and maintain effective DOX concn. for chemotherapy. The systemic toxicity of DOX was reduced significantly with the in situ administration of LMWGs formulations. The injectable LMWGs exhibited excellent therapeutic efficacy and low side effects in local chemotherapy. A series of phenylboronic acid (PBA)-based low-mol.-wt. gelators with different hydrocarbon chain lengths (C2-C11) were designed and synthesized. These gelators gelated five solvents efficiently at relatively low concn. with interesting aggregates of nanofibers, thin films, spherical thin shells, and microspheres piled with nanofibers. The gelation ability increased with the chain length increasing up to C11, which has the lowest crit. gelation concn. (CGC) of 0.19 wt %. FTIR and 1H NMR measurements suggested that van der Waals of alkyl chains, H-bonding, and π-π stacking interactions had an important contribution in gelation process and self-assembly. For all the gelators, their glucose-response increased along with the increasing concn. of glucose soln. However, the recognition and responsive rate to glucose were weakened gradually with the alkyl chain length increasing for the gelators. Therefore, glucose-sensitivity of these PBA-based organogels could be modulated through alkyl chain length.
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  32. 32
    He, J.; Hu, Y.; Wu, F.; He, B.; Gao, W. Control of MSC Differentiation by Tuning the Alkyl Chain Length of Phenylboroinc Acid Based Low-molecular-weight Gelators. J. Bionic Eng. 2018, 15, 682– 692,  DOI: 10.1007/s42235-018-0056-2
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    Eldridge, J. E.; Ferry, J. D. Studies of the Cross-Linking Process in Gelatin Gels. III. Dependence of Melting Point on Concentration and Molecular Weight. J. Phys. Chem. 1954, 58 (11), 992– 995,  DOI: 10.1021/j150521a013
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    The cross-linking process in gelatin gels. III. Dependence of melting point on concentration and molecular weight
    Eldridge, John E.; Ferry, John D.
    Journal of Physical Chemistry (1954), 58 (), 992-6CODEN: JPCHAX; ISSN:0022-3654.
    cf. C.A. 46, 1846d; preceding abstr. The m. ps. of solns. of 5 degraded gelatin samples with mol. wts. ranging from 33,000 to 72,000 were measured over a concn. range from 20 to 60 g./l. A nearly linear relation was found between the logarithm of the gelatin concn. and the reciprocal abs. temp. of melting. The relation between the logarithm of the mol. wt. and the reciprocal of the abs. temp. of melting was also nearly linear except for the sample of lowest mol. wt. Annealed gels had generally higher m. ps. than gels formed by quick chilling. The exptl. results were discussed in relation to the cross-linking process considered responsible for the gelation of gelatin solns. Exothermic heats of reaction ranging from 50 to 220 kcal./mole were calcd. for the formation of cross links if these are assumed to result from a binary assocn. of polymer chains.
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    Murata, K.; Aoki, M.; Suzuki, T.; Harada, T.; Kawabata, H.; Komori, T.; Ohseto, F.; Ueda, K.; Shinkai, S. Thermal and Light Control of the Sol-Gel Phase Transition in Cholesterol-Based Organic Gels. Novel Helical Aggregation Modes As Detected by Circular Dichroism and Electron Microscopic Observation. J. Am. Chem. Soc. 1994, 116 (15), 6664– 6676,  DOI: 10.1021/ja00094a023
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    34
    Thermal and Light Control of the Sol-Gel Phase Transition in Cholesterol-Based Organic Gels. Novel Helical Aggregation Modes As Detected by Circular Dichroism and Electron Microscopic Observation
    Murata, Kazutaka; Aoki, Masayoshi; Suzuki, Tsuyoshi; Harada, Takaaki; Kawabata, Hirosuke; Komori, Takashi; Ohseto, Fumio; Ueda, Keiko; Shinkai, Seiji
    Journal of the American Chemical Society (1994), 116 (15), 6664-76CODEN: JACSAT; ISSN:0002-7863.
    Nineteen cholesterol derivs. contg. a variety of azobenzene moieties coupled to C-3 of a steroidal moiety through an ester linkage were synthesized. We employed two different esterification methods by which cholesterol derivs. with the natural (S)-configuration at C-3 and those with the inverted (R)-configuration at C-3 were obtained. Among them, cholesterol derivs. I (R = Me, Et, Pr, Bu, decyl) and II (R = Me, Et, Pr, Bu, pentyl, decyl) bearing a p-alkoxyazobenzene moiety acted as excellent thermally-reversible gelators of various org. fluids, but the gelation ability is fairly different between I and II; I could gelatinize hydrocarbons, e.g. n-hexane, n-octane, and toluene, halogen solvents, e.g. 1,2-dichloroethane and dichloromethane, ethers, e.g. di-Et ether and THF, and alcs., e.g. ethanol and 1-butanol, whereas II could gelatinize ketones, methanol, and polysiloxanes. In general, the soly. of II in apolar solvents is superior to that of I, so I is useful for gelation of apolar solvents whereas II is useful for gelation of polar solvents. The sol-gel phase transition is sensitively "read-out" by a change in the CD spectrum: the gel phase is CD-active, whereas the sol phase is totally CD-silent. These results mean that dipoles in the azobenzene moiety are oriented in a clockwise (in R-chirality) or anticlockwise (in S-chirality) direction when they interact in the excited state. Strangely, we accidentally found that the CD sign of the gels prepd. from I (R = Pr, Bu) and III (azobenzene-linked cholesterol deriv. with p-NMe2) is frequently inverted. After careful examn. of the gel prepn. conditions, we found that inversion takes place only when the cooling speed is fast. The scanning electron microscopic studies established that gelators form three-dimensional networks with helical fibrils. In the III gel prepd. from cyclohexane, the gel with R-chirality in CD possesses a right-handed helix, whereas the gel with S-chirality in the CD possesses a left-handed helix. The sol-gel phase transition was also induced by photoresponsive cis-trans isomerism of the azobenzene moiety; the gel formed from the trans-isomer was efficiently converted to the sol when trans-to-cis isomerization was photochem. induced, and this process can be repeated reversibly. The photoinduced sol-gel phase transition was also "read-out" as a change in CD spectroscopy.
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    Alhalaweh, A.; Alzghoul, A.; Bergström, C. A. Molecular Drivers of Crystallization Kinetics for Drugs in Supersaturated Aqueous Solutions. J. Pharm. Sci. 2019, 108 (1), 252– 259,  DOI: 10.1016/j.xphs.2018.11.006
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    Molecular drivers of crystallization kinetics for drugs in supersaturated aqueous solutions
    Alhalaweh, Amjad; Alzghoul, Ahmad; Bergstroem, Christel A. S.
    Journal of Pharmaceutical Sciences (Philadelphia, PA, United States) (2019), 108 (1), 252-259CODEN: JPMSAE; ISSN:0022-3549. (Elsevier Inc.)
    In this study, we explore mol. properties of importance in soln.-mediated crystn. occurring in supersatd. aq. drug solns. Furthermore, we contrast the identified mol. properties with those of importance for crystn. occurring in the solid state. A literature data set of 54 structurally diverse compds., for which crystn. kinetics from supersatd. aq. solns. and in melt-quenched solids were reported, was used to identify mol. drivers for crystn. kinetics obsd. in soln. and contrast these to those obsd. for solids. The compds. were divided into fast, moderate, and slow crystallizers, and in silico classification was developed using a mol. K-nearest neighbor model. The topol. equiv. of Grav3 (related to mol. size and shape) was identified as the most important mol. descriptor for soln. crystn. kinetics; the larger this descriptor, the slower the crystn. Two electrotopol. descriptors (the atom-type E-state index for -Caa groups and the sum of abs. values of pi Fukui(+) indexes on C) were found to sep. the moderate and slow crystallizers in the soln. The larger these descriptors, the slower the crystn. With these 3 descriptors, the computational model correctly sorted the crystn. tendencies from solns. with an overall classification accuracy of 77% (test set).
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  36. 36
    Raina, S. A.; Van Eerdenbrugh, B.; Alonzo, D. E.; Mo, H.; Zhang, G. G. Z.; Gao, Y.; Taylor, L. S. Trends in the Precipitation and Crystallization Behavior of Supersaturated Aqueous Solutions of Poorly Water-Soluble Drugs Assessed Using Synchrotron Radiation. J. Pharm. Sci. 2015, 104 (6), 1981– 1992,  DOI: 10.1002/jps.24423
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    Trends in the Precipitation and Crystallization Behavior of Supersaturated Aqueous Solutions of Poorly Water-Soluble Drugs Assessed Using Synchrotron Radiation
    Raina, Shweta A.; Van Eerdenbrugh, Bernard; Alonzo, David E.; Mo, Huaping; Zhang, Geoff G. Z.; Gao, Yi; Taylor, Lynne S.
    Journal of Pharmaceutical Sciences (2015), 104 (6), 1981-1992CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)
    Amorphous materials are high-energy solids that can potentially enhance the bioavailability of poorly sol. compds. A major impediment to their widespread use as a formulation platform is the tendency of amorphous materials to crystallize. The aim of this study was to evaluate the relative crystn. tendency of six structural analogs belonging to the dihydropyridine class, in an aq. environment in the absence and presence of polymers, using wide-angle X-ray scattering synchrotron radiation and polarized light microscopy. The crystn. behavior of ppts. generated from supersatd. solns. of the active pharmaceutical ingredients was found to be highly variable ranging from immediate to several hours in the absence of polymers. Polymers with intermediate hydrophilicity/hydrophobicity were found to substantially delay crystn., whereas strongly hydrophilic or hydrophobic polymers were largely ineffective. NMR spectroscopy expts. supported the supposition that polymers need to have affinity for both the drug-rich ppt. and the aq. phase in order to be effective crystn. inhibitors. This study highlights the variability in the crystn. tendency of different compds. and provides insight into the mechanism of inhibition by polymeric additives. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.
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    Sangeetha, N. M.; Maitra, U. Supramolecular Gels: Functions and Uses. Chem. Soc. Rev. 2005, 34 (10), 821,  DOI: 10.1039/b417081b
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    Supramolecular gels: Functions and uses
    Sangeetha, Neralagatta M.; Maitra, Uday
    Chemical Society Reviews (2005), 34 (10), 821-836CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    In recent years there has been immense interest in studying gels derived from low mol. mass gelators (supramol., or simply mol. gels). The motivation for this is not only to understand the fundamental aggregate structures in the gels at different length scales, but also to explore their potential for futuristic technol. applications. Gels have been made sensitive to external stimuli like light and chem. entities by incorporating a spectroscopically active or a receptor unit as part of the gelator mol. This makes them suitable for applications such as sensing and actuating. The diversity of gel structural architectures has allowed them to be utilized as templates to prep. novel inorg. superstructures for possible applications in catalysis and sepn. Gels derived from liq. crystals (anisotropy gels) that can act as dynamically functional materials have been prepd., for example, for (re-writable) information recording. Supramol. gels can be important in controlled release applications, in oil recovery, for gelling cryogenic fuels etc. They can also serve as media for a range of applications. This tutorial review highlights some of the instructive work done by various groups to develop smart and functional gels, and covers a wide spectrum of scientific interest ranging from medicine to materials science.
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    Schall, J. M.; Capellades, G.; Myerson, A. S. Methods for Estimating Supersaturation in Antisolvent Crystallization Systems. CrystEngComm 2019, 21 (38), 5811– 5817,  DOI: 10.1039/C9CE00843H
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    Methods for estimating supersaturation in antisolvent crystallization systems
    Schall, Jennifer M.; Capellades, Gerard; Myerson, Allan S.
    CrystEngComm (2019), 21 (38), 5811-5817CODEN: CRECF4; ISSN:1466-8033. (Royal Society of Chemistry)
    The mole fraction and activity coeff.-dependent (MFAD) supersatn. expression is the least-assumptive, practical choice for calcg. supersatn. in solvent mixts. This paper reviews the basic thermodn. derivation of the supersatn. expression, revisits common simplifying assumptions, and discusses the shortcomings of those assumptions for the design of industrial crystn. processes. A step-by-step methodol. for estg. the activity-dependent supersatn. is provided with focus on ternary systems. This method requires only soly. data and thermal property data from a single differential scanning calorimetry (DSC) expt. Two case studies are presented, where common simplifications to the MFAD supersatn. expression are evaluated: (1) for various levels of supersatn. of L-asparagine monohydrate in water-isopropanol mixts. and (2) for the dynamic and steady-state mixed-suspension, mixed-product removal (MSMPR) crystn. of a proprietary API in water-ethanol-tetrahydrofuran solvent mixts. When compared to the MFAD supersatn. estn., it becomes clear that errors in excess of 190% may be introduced in the estn. of the crystn. driving force by making unnecessary simplifications to the supersatn. expression. These errors can result in addnl. parameter regression errors - sometimes by nearly an order of magnitude - for nucleation and growth kinetic parameters, limiting the accurate simulation of dynamic and steady-state crystn. systems.
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    Yi, B.; Xu, Q.; Liu, W. An overview of substrate stiffness guided cellular response and its applications in tissue regeneration. Bioact. Mater. 2022, 15, 82– 102,  DOI: 10.1016/j.bioactmat.2021.12.005
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    An overview of substrate stiffness guided cellular response and its applications in tissue regeneration
    Yi, Bingcheng; Xu, Qi; Liu, Wei
    Bioactive Materials (2022), 15 (), 82-102CODEN: BMIAD4; ISSN:2452-199X. (Elsevier B.V.)
    A review. Cell-matrix interactions play a crit. role in tissue repair and regeneration. With gradual uncovering of substrate mech. characteristics that can affect cell-matrix interactions, much progress has been made to unravel substrate stiffness-mediated cellular response as well as its underlying mechanisms. Yet, as a part of cell-matrix interaction biol., this field remains in its infancy, and the detailed mol. mechanisms are still elusive regarding scaffold-modulated tissue regeneration. This review provides an overview of recent progress in the area of the substrate stiffness-mediated cellular responses, including (1) the phys. detn. of substrate stiffness on cell fate and tissue development; (2) the current exploited approaches to manipulate the stiffness of scaffolds; (3) the progress of recent researches to reveal the role of substrate stiffness in cellular responses in some representative tissue-engineered regeneration varying from stiff tissue to soft tissue. This article aims to provide an up-to-date overview of cell mechanobiol. research in substrate stiffness mediated cellular response and tissue regeneration with insightful information to facilitate interdisciplinary knowledge transfer and enable the establishment of prognostic markers for the design of suitable biomaterials.
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    Jiao, T.; Rodney, J.; Clifton, G. L. C.; Hopkins, R. A. Measurements of the Effects of Decellularization on Viscoelastic Properties of Tissues in Ovine. Baboon, and Human Heart Valves. Tissue Eng., Part A 2012, 18, 423,  DOI: 10.1089/ten.TEA.2010.0677
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    40
    Measurements of the Effects of Decellularization on Viscoelastic Properties of Tissues in Ovine, Baboon, and Human Heart Valves
    Jiao, Tong; Clifton, Rodney J.; Converse, Gabriel L.; Hopkins, Richard A.
    Tissue Engineering, Part A (2012), 18 (3 and 4), 423-431CODEN: TEPAB9; ISSN:1937-3341. (Mary Ann Liebert, Inc.)
    In the development of tissue-engineered heart valves based on allograft decellularized extracellular matrix scaffolds, the material properties of the implant should be ideally comparable to the native semilunar valves. This investigation of the viscoelastic properties of the three functional aortic/pulmonary valve tissues (leaflets, sinus wall, and great vessel wall) was undertaken to establish normative values for fresh samples of human valves and to compare these properties after various steps in creating scaffolds for subsequent bioreactor-based seeding protocols. Torsional wave methods were used to measure the viscoelastic properties. Since preclin. surgical implant validation studies require relevant animal models, the tests reported here also include results for three pairs of both ovine and baboon aortic and pulmonary valves. For human aortic valves, four cryopreserved valves were compared with four decellularized scaffolds. Because of organ and heart valve transplant scarcity for pulmonary valves, only three cryopreserved and two decellularized pulmonary valves were tested. Leaflets are relatively soft. Loss angles are similar for all tissue samples. Regardless of species, the decellularization process used in this study has little effect on viscoelastic properties.
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    Charrier, E. E.; Pogoda, K.; Wells, R. G.; Janmey, P. A. Control of Cell Morphology and Differentiation by Substrates with Independently Tunable Elasticity and Viscous Dissipation. Nat. Commun. 2018, 9 (1), 449,  DOI: 10.1038/s41467-018-02906-9
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    Control of cell morphology and differentiation by substrates with independently tunable elasticity and viscous dissipation
    Charrier Elisabeth E; Pogoda Katarzyna; Janmey Paul A; Charrier Elisabeth E; Wells Rebecca G; Pogoda Katarzyna
    Nature communications (2018), 9 (1), 449 ISSN:.
    The mechanical properties of extracellular matrices can control the function of cells. Studies of cellular responses to biomimetic soft materials have been largely restricted to hydrogels and elastomers that have stiffness values independent of time and extent of deformation, so the substrate stiffness can be unambiguously related to its effect on cells. Real tissues, however, often have loss moduli that are 10 to 20% of their elastic moduli and behave as viscoelastic solids. The response of cells to a time-dependent viscous loss is largely uncharacterized because appropriate viscoelastic materials are lacking for quantitative studies. Here we report the synthesis of soft viscoelastic solids in which the elastic and viscous moduli can be independently tuned to produce gels with viscoelastic properties that closely resemble those of soft tissues. Systematic alteration of the hydrogel viscosity demonstrates the time dependence of cellular mechanosensing and the influence of viscous dissipation on cell phenotype.
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    He, J.; Hu, Y.; Wu, F.; He, B.; Gao, W. Control of MSC Differentiation by Tuning the Alkyl Chain Length of Phenylboroinc Acid Based Low-Molecular-Weight Gelators. J. Bionic Eng. 2018, 15 (4), 682– 692,  DOI: 10.1007/s42235-018-0056-2
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    Landel, R. F.; Nielsen, L. E. Mechanical Properties of Polymers and Composites, 2nd ed.; Marcel Dekker, Inc.: New York, Basel, 1994; ISBN 0-8247-8964-4.
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    Elumalai, V.; Hansen, J. H. A Scalable and Green One-Minute Synthesis of Substituted Phenols. RSC Adv. 2020, 10 (66), 40582– 40587,  DOI: 10.1039/D0RA08580D
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    A scalable and green one-minute synthesis of substituted phenols
    Elumalai, Vijayaragavan; Hansen, Joern H.
    RSC Advances (2020), 10 (66), 40582-40587CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
    A mild, green and highly efficient protocol was developed for the synthesis of substituted phenols ArOH [Ar = Ph, 2-ClC6H4, 2,4,6-tri-BrC6H2, etc.] via ipso-hydroxylation of arylboronic acids in ethanol. The method utilized the combination of aq. hydrogen peroxide as the oxidant and H2O2/HBr as the reagent under unprecedentedly simple and convenient conditions. A wide range of arylboronic acids were smoothly transformed into substituted phenols ArOH in very good to excellent yields without chromatog. purifn. The reaction was scalable up to at least 5 g at room temp. with one-minute reaction time and can be combined in a one-pot sequence with bromination and Pd-catalyzed cross-coupling to generate more diverse, highly substituted phenols ArOH [Ar = 2,4-di-Me-4,6-di-PhC6H, 2,4,6-tri-PhC6H2, 2,4,6-tri-(4-N≡C6H4)C6H2].
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  • Abstract

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    Figure 1

    Figure 1. Arylboronic acids of interest: (A) 3-isobutoxyphenylboronic acid (PBA); (B) Wulff type acid; and (C) benzoxaborole.

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    Figure 2

    Figure 2. SAXS (A) and WAXS (B) diffractograms of a 2.7 mg/mL PBA hydrogel sample, TEM (C,D) images of gelator crystalline and amorphous phases, respectively, SEM (E,F) images of the corresponding dried gel, and fluorescence confocal microscopy (G,H) images of the gel stained with Nile red (further experimental details on 2A-H in Supporting Information).

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    Figure 3

    Figure 3. Gradual dissolution of the PBA hydrogel with the increase in temperature under polarized light microscopy (A; left to right: 80, 86, 88 °C), heating (B) and cooling (C) DSC curves of the PBA hydrogel at different PBA concentrations, and cooling rheology of PBA hydrogels (D–G), showing the variation of the PBA hydrogel storage modulus (G′) as a function of temperature at different PBA (D) and urea (F) concentrations and the variation of the storage (G′) and loss (G″) moduli of the PBA hydrogel as a function of temperature at 2.70 mg/mL PBA (E) and 3.5 mg/mL urea (G).

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    Figure 4

    Figure 4. (A) Strain sweeps for networks at 30 °C with different concentrations of PBA; (B) variation of the storage modulus G′ and of the loss modulus G″ as a function of frequency at 30 °C, with deformation amplitude 0.01%, for samples with different concentrations of PBA. Data points in all graphs: G′: filled symbols; G″, open symbols.

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    Figure 5

    Figure 5. (A) Triggering the gel–sol transition of PBA by NaOH/HCl, H2O2, and CD. (B) Photos of selective absorption of Nile red and methylene blue at 0 and 2 h after adding dyes and mixtures of PBA and dyes of different molar equivalents at room temperature.

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    Figure 6

    Figure 6. (A) 1H ROESY NMR spectrum of PBA/cyclodextrine complex, (B) detail of 1H ROESY NMR spectrum of interactions of PBA aromatic hydrogens with cyclodextrine and (C) 1H DOSY NMR spectrum confirming formation of host-guest complex (numbering corresponds to the proton assignments as indicated on the chemical structure of PBA and cyclodextrine).

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      Matuszewska, Alicja; Uchman, Mariusz; Adamczyk-Wozniak, Agnieszka; Sporzynski, Andrzej; Pispas, Stergios; Kovacik, Lubomir; Stepanek, Miroslav
      Biomacromolecules (2015), 16 (12), 3731-3739CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
      Coassembly behavior of the double hydrophilic block copolymer poly(4-hydroxystyrene)-block-poly(ethylene oxide) (PHOS-PEO) with three amphiphilic phenylboronic acids (PBA) differing in hydrophobicity, 4-dodecyloxyphenylboronic acid (C12), 4-octyloxyphenylboronic acid (C8), and 4-isobutoxyphenylboronic acid (i-Bu) was studied in alk. aq. solns. and in mixts. of NaOHaq/THF by spin-echo 1H NMR spectroscopy, dynamic and electrophoretic light scattering, and SAXS. The study reveals that only the coassembly of C12 with PHOS-PEO provides spherical nanoparticles with intermixed PHOS and PEO blocks, contg. densely packed C12 micelles. NMR measurements have shown that spatial proximity of PHOS-PEO and C12 leads to the formation of ester bonds between -OH of PHOS block and hydroxyl groups of -B(OH)2. Due to the presence of PBA moieties, the release of compds. with 1,2- or 1,3-dihydroxy groups loaded in the coassembled PHOS-PEO/PBA nanoparticles by covalent binding to PBA can be triggered by addn. of a surplus of glucose that bind to PBA competitively. The latter feature has been confirmed by fluorescence measurements using Alizarin Red as a model compd. Nanoparticles were proved to exhibit swelling in response to glucose as detected by light scattering.
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    15. 15
      Zhao, F.; Wu, D.; Yao, D.; Guo, R.; Wang, W.; Dong, A.; Kong, D.; Zhang, J. An Injectable Particle-Hydrogel Hybrid System for Glucose-Regulatory Insulin Delivery. Acta Biomater. 2017, 64, 334– 345,  DOI: 10.1016/j.actbio.2017.09.044
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      15
      An injectable particle-hydrogel hybrid system for glucose-regulatory insulin delivery
      Zhao, Fuli; Wu, Di; Yao, Dan; Guo, Ruiwei; Wang, Weiwei; Dong, Anjie; Kong, Deling; Zhang, Jianhua
      Acta Biomaterialia (2017), 64 (), 334-345CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
      Long-term and daily s.c. injections of insulin for the treatment of insulin-dependent diabetic patients often lead to poor patient compliance and undesired complications. Phenylboronic acid (PBA)-based polymeric hydrogels have been widely considered as one of the most promising insulin delivery system to replace the frequent insulin injections. However, their applications are limited by clin. irrelevant glucose-responsive range, slow response rate, low tissue-adhesiveness and poor biodegradability, undesirable leakage at normoglycemic state. Herein, we report a novel implantable insulin hydrogel for glucose-regulated delivery of insulin based on a unique particle-hydrogel hybrid platform featuring fast glucose responsiveness at physiol. pH, shear-thinning behavior for injection, tissue-adhesive function for long-lasting adherence, and full biodegradability for safe use. The system was thoroughly characterized both in vitro and in vivo and was demonstrated to hold these unique functions. Using streptozotocin-induced diabetic mice as a model, it was shown that a single s.c. injection of the insulin-loaded particle-hydrogel formulation led to quasi-steady-state blood glucose levels within the normal range for about two weeks. In addn., the prepn. of the formulation only involved simple mixing and self-assembling processes, and thus it had great scalability and reproducibility for practical use. The highly feasible prepn., excellent performance, inherent biocompatibility and biodegradability make this novel composite hydrogel promising platform for diabetes therapy. Phenylboronic acid (PBA)-based polymeric hydrogels have been widely considered as one of the most promising insulin delivery system to replace the frequent insulin injections. However, these hydrogels, mostly based on a variety of PBA-contg. acrylamide monomers, are still far from clin. reality. Building upon a unique particle-hydrogel hybrid platform, herein we report a novel implantable insulin storage and delivery system with multifunctionalities including fast glucose-sensitiveness at physiol. pH, shear-thinning behavior for injection, tissue-adhesive function for long-lasting adherence, biodegradable materials for safe use and well-controlled insulin release. These unique functions were demonstrated through research both in vitro and in vivo. In addn., the prepn. of the formulation was simple, and thus it had great scalability and reproducibility for practical use.
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    16. 16
      Tao, N.; Li, G.; Liu, M.; Gao, W.; Wu, H. Preparation of Dual Responsive Low-Molecular-Weight Hydrogel for Long-Lasting Drug Delivery. Tetrahedron 2017, 73 (22), 3173– 3180,  DOI: 10.1016/j.tet.2017.04.051
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      16
      Preparation of dual responsive low-molecular-weight hydrogel for long-lasting drug delivery
      Tao, Ning; Li, Guotao; Liu, Miaochang; Gao, Wenxia; Wu, Huayue
      Tetrahedron (2017), 73 (22), 3173-3180CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
      A novel low-mol.-wt. hydrogel (LMWG) was fabricated by oligopeptide and phenylboronic acid to obtain a smart mol. hydrogel with dual glucose and pH response for long-term drug delivery in this study. Dual glucose and pH responsiveness of the blank mol. hydrogel was first evaluated by online tracking the dynamics curves using UV spectroscopy. Model drugs of phenformin for antidiabetes and doxorubicin for anticancer were selected to evaluate the drug carry and glucose/pH responsive drug release of the mol. hydrogel. The results showed the drug-loaded LMWG had good sustaining and long-lasting drug delivery in physiol. or pathol. environment.
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    17. 17
      Wu, X.; Chen, X.-X.; Song, B.-N.; Huang, Y.-J.; Ouyang, W.-J.; Li, Z.; James, T. D.; Jiang, Y.-B. Direct Sensing of Fluoride in Aqueous Solutions Using a Boronic Acid Based Sensor. Chem. Commun. 2014, 50 (90), 13987– 13989,  DOI: 10.1039/C4CC04542D
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      17
      Direct sensing of fluoride in aqueous solutions using a boronic acid based sensor
      Wu, Xin; Chen, Xuan-Xuan; Song, Bing-Nan; Huang, Yan-Jun; Ouyang, Wen-Juan; Li, Zhao; James, Tony D.; Jiang, Yun-Bao
      Chemical Communications (Cambridge, United Kingdom) (2014), 50 (90), 13987-13989CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      Binding of the fluoride ion triggers aggregation of a pyreneboronic acid-catechol ensemble in acidic aq. solns., giving rise to intense excimer emission, allowing for sensitive fluoride ion sensing at ppm levels, with an apparent fluoride binding const. higher than 103 M-1 which is unprecedented for boronic acid sensors in water.
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    18. 18
      Martínez-Aguirre, M. A.; Villamil-Ramos, R.; Guerrero-Alvarez, J. A.; Yatsimirsky, A. K. Substituent Effects and PH Profiles for Stability Constants of Arylboronic Acid Diol Esters. J. Org. Chem. 2013, 78 (10), 4674– 4684,  DOI: 10.1021/jo400617j
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      18
      Substituent Effects and pH Profiles for Stability Constants of Arylboronic Acid Diol Esters
      Martinez-Aguirre, Mayte A.; Villamil-Ramos, Raul; Guerrero-Alvarez, Jorge A.; Yatsimirsky, Anatoly K.
      Journal of Organic Chemistry (2013), 78 (10), 4674-4684CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      Stability consts. of boronic acid diol esters in aq. soln. have been detd. potentiometrically for a series of meta-, para-substituted phenylboronic acids and diols of variable acidity. The consts. β11-1 for reactions between neutral forms of reactants producing the anionic ester plus proton follow the Hammett equation with ρ depending on pKa of diol and varying from 2.0 for glucose to 1.29 for 4-nitrocatechol. Obsd. stability consts. (Kobs) measured by UV-vis and fluorometric titrns. at variable pH for esters of 4,5-dihydroxy-1,3-benzenedisulfonate (Tiron) generally agree with those expected on the basis of β11-1 values, but the direct fitting of Kobs vs. pH profiles gives shifted pKa values both for boronic acids and diol as a result of significant interdependence of fitting parameters. The substituent effects on absorption and fluorescence spectra of Tiron arylboronate esters are characterized. The Kobs for Tiron detd. by 11B NMR titrns. are approx. 1 order of magnitude smaller than those detd. by UV-vis titrns. under identical conditions. A general equation, which makes possible an est. of β11-1 for any pair of boronic acid and diol from their pKa values, is proposed on the basis of established Broensted-type correlation of Hammett parameters for β11-1 with acidity of diols. The equation allows one to calc. stability consts. expected only on basis of acid-base properties of the components, thus permitting more strict evaluation of contributions of addnl. factors such as steric or charge effects to the ester stability.
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    19. 19
      Brooks, W. L. A.; Deng, C. C.; Sumerlin, B. S. Structure–Reactivity Relationships in Boronic Acid–Diol Complexation. ACS Omega 2018, 3 (12), 17863– 17870,  DOI: 10.1021/acsomega.8b02999
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      19
      Structure-Reactivity Relationships in Boronic Acid-Diol Complexation
      Brooks, William L. A.; Deng, Christopher C.; Sumerlin, Brent S.
      ACS Omega (2018), 3 (12), 17863-17870CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)
      Boronic acids have found widespread use in the field of biomaterials, primarily through their ability to bind with biol. relevant 1,2- and 1,3-diols, including saccharides and peptidoglycans, or with polyols to prep. hydrogels with dynamic covalent or responsive behavior. Despite a wide range of boronic acid architectures that have been previously considered, there is a need for greater understanding of the structure-reactivity relationships that govern binding affinity to diols. In this study, various boronic acids and other organoboron compds. were investigated to det. their pKa and their binding consts. with the biol. relevant diols including sorbitol, fructose, and glucose. Boronic acid pKa values were detd. through spectroscopic titrn., whereas binding consts. were detd. by fluorescence spectroscopy during competitive binding studies. Key structure-reactivity relationships clearly indicated that both boronic acid structure and soln. pH must be carefully considered. By considering a variety of boronic acids with systematically varied electronics and sterics, these results provide guidance during selection of organoboron compds. in sensing, delivery, and materials chem.
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    20. 20
      Tomsho, J. W.; Pal, A.; Hall, D. G.; Benkovic, S. J. Ring Structure and Aromatic Substituent Effects on the p K a of the Benzoxaborole Pharmacophore. ACS Med. Chem. Lett. 2012, 3 (1), 48– 52,  DOI: 10.1021/ml200215j
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      20
      Ring Structure and Aromatic Substituent Effects on the pKa of the Benzoxaborole Pharmacophore
      Tomsho, John W.; Pal, Arnab; Hall, Dennis G.; Benkovic, Stephen J.
      ACS Medicinal Chemistry Letters (2012), 3 (1), 48-52CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
      In this work, we present an investigation into the phys. properties of a unique class of arom. boronic acids, the benzoxaboroles. Using spectrophotometric methods, the ionization consts. of a family of substituted benzoxaboroles are detd. Heterocyclic ring modifications are examd. to det. their effects on the ionization of the boronic acid moiety. It is also shown that the substituent effects about the arom. ring follow a Hammett relationship with the compds.' measured pKa values. Finally, these substituent effects are also shown to extend to the sugar binding properties of these compds. under physiol. relevant conditions. Combined, these data will inform medicinal chemists wishing to tailor the ionization and/or ability of this class of compd. to bind diol-contg. biomols.
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    21. 21
      Vrbata, D.; Uchman, M. Preparation of Lactic Acid- and Glucose-Responsive Poly(ε-Caprolactone)- b -Poly(Ethylene Oxide) Block Copolymer Micelles Using Phenylboronic Ester as a Sensitive Block Linkage. Nanoscale 2018, 10 (18), 8428– 8442,  DOI: 10.1039/C7NR09427B
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      21
      Preparation of lactic acid- and glucose-responsive poly(.vepsiln.-caprolactone)-b-poly(ethylene oxide) block copolymer micelles using phenylboronic ester as a sensitive block linkage
      Vrbata, David; Uchman, Mariusz
      Nanoscale (2018), 10 (18), 8428-8442CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
      The present study describes the synthesis, self-assembly and responsiveness to glucose and lactic acid of biocompatible and biodegradable block copolymer micelles using phenylboronic ester as the linkage between hydrophobic PCL and hydrophilic PEO. The PCL block with pendant phenylboronic acid (PCLBA) was synthesized by combining ε-CL ROP, using 4-hydroxymethyl(phenylboronic) acid pinacolate as the initiator, and pinacol deprotection. The glucose-terminated PEO was prepd. by 1,3-dipolar, Cu(I)-catalyzed, alkyne-azide cycloaddn. of α-methoxy-ω-propargyl poly(ethylene oxide) and 1-azido-1-deoxy-D-glucopyranose. PCLBA and PEOGlc blocks were linked in NaOH acetone soln., which was indirectly confirmed by Alizarin Red S fluorescence and directly by 1H NMR spectroscopy. Dialysis against Milli-Q water induced the self-assembly of PCLBA-b-PEOGlc nanoparticles, which were characterized by SLS and DLS and by cryo-TEM. Furthermore, the microscopic properties of the charged interface between the hydrophobic PCLBA core and the hydrophilic PEOGlc shell were examd. Subsequently, the nanoparticles were transferred to a PBS soln. supplemented with different conc. of glucose to simulate the physiol. conditions in blood or lactic acid to simulate acidic cytosolic or endosomal conditions in tumor cells. Adding a surplus of glucose or lactic acid, which competitively binds to PBA, removes the stabilizing hydrophilic PEOGlc blocks, thereby triggering marked nanoparticle aggregation.
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    22. 22
      Vrbata, D.; Kereiche, S.; Kalíková, K.; Uchman, M. Stimuli-Responsive Multifunctional Micelles of ABC vs. ACB Triblock Terpolymers Using Reversible Covalent Bonding of Phenylboronic Acid: Controlled Synthesis, Self-Assembly and Model Drug Release. J. Mol. Liq. 2021, 335, 116528,  DOI: 10.1016/j.molliq.2021.116528
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      22
      Stimuli-responsive multifunctional micelles of ABC vs. ACB triblock terpolymers using reversible covalent bonding of phenylboronic acid: controlled synthesis, self-assembly and model drug release
      Vrbata, David; Kereiche, Sami; Kalikova, Kveta; Uchman, Mariusz
      Journal of Molecular Liquids (2021), 335 (), 116528CODEN: JMLIDT; ISSN:0167-7322. (Elsevier B.V.)
      We report the synthesis and self-assembly of well-defined, amphiphilic, biodegradable and glucose- and pH-responsive ABC and ACB triblock terpolymer multifunctional micelles in aq. media using blocks consisting of poly(ethylene oxide) (PEO), poly(ε-caprolactone) (PCL), and boronic acid-functionalised poly(ε-caprolactone) (PBA). The terpolymers were synthesized by sequential ring-opening polymn. (ROP) and functionalised using phenylboronic acid pinacolate via alkyne - azide cycloaddn. (CuAAC). Lastly, the pinacole groups were deprotected by mild acidic catalysis to introduce phenylboronic acid for controlled drug solubilisation and delivery. ABC and ACB triblock terpolymers self-assembled into various multifunctional micelles in aq. media depending on the state of the phenylboronic acid (pinacol protected, BAPin vs. deprotected, BA) and on the prepn. procedure, as shown by dynamic and static light scattering (DLS and SLS) and by cryogenic transmission electron microscopy (cryo-TEM). The fluorescence probe Alizarin Red S (ARS) was used as a model drug, which covalently binds to BA, and its uptake was monitored by fluorescence spectroscopy and high-performance liq. chromatog. (HPLC). When adding a surplus of glucose, which competitively binds to BA, ARS was released as a function of micelle morphol. (core-shell corona (ABC) vs. mixed-shell (ACB) micelles). When transferring ARS-loaded nanoparticles to phosphate buffer saline (PBS) solns. at different pH values (7.4 and 5 or 3) simulating physiol. and tumor conditions, resp., ABC micelles released ARS only at low pH, while ACB micelles released ARS in response to glucose and to both low and physiol. pH values. Therefore, in this system, ABC micelles are better suited for drug delivery to tumor cells than their ACB counterparts because they retain their cargo in PBS at high glucose concns. but release it under acidic conditions, which occur in hypoxic cancer cells, thus highlighting the potential of ABC micelles for targeted drug delivery in the context of cancer therapy.
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    23. 23
      Celenza, G.; Vicario, M.; Bellio, P.; Linciano, P.; Perilli, M.; Oliver, A.; Blazquez, J.; Cendron, L.; Tondi, D. Phenylboronic acid derivatives as validated leads active in clinical strains overexpressing KPC-2: a step against bacterial resistance. Chemmedchem 2018, 13, 713– 724,  DOI: 10.1002/cmdc.201700788
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      Phenylboronic Acid Derivatives as Validated Leads Active in Clinical Strains Overexpressing KPC-2: A Step against Bacterial Resistance
      Celenza, Giuseppe; Vicario, Mattia; Bellio, Pierangelo; Linciano, Pasquale; Perilli, Mariagrazia; Oliver, Antonio; Blazquez, Jesus; Cendron, Laura; Tondi, Donatella
      ChemMedChem (2018), 13 (7), 713-724CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The emergence and dissemination of multidrug resistant (MDR) pathogens resistant to nearly all available antibiotics poses a significant threat in clin. therapy. Among them, Klebsiella pneumoniae clin. isolates overexpressing KPC-2 carbapenemase are the most worrisome, extending bacterial resistance to last-resort carbapenems. In this study, we investigate the mol. recognition requirements in the KPC-2 active site by small phenylboronic acid derivs. Four new phenylboronic acid derivs. were designed and tested against KPC-2. For the most active, despite their simple chem. structures, nanomolar affinity was achieved. The new derivs. restored susceptibility to meropenem in clin. strains overexpressing KPC-2. Moreover, no cytotoxicity was detected in cell-viability assays, which further validated the designed leads. Two crystallog. binary complexes of the best inhibitors binding KPC-2 were obtained at high resoln. Kinetic descriptions of slow binding, time-dependent inhibition, and interaction geometries in KPC-2 were fully investigated. This study will ultimately lead toward the optimization and development of more-effective KPC-2 inhibitors.
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    24. 24
      Rit, T.; Ghosh, T.; Bhowmik, S.; Patidar, M. K.; Das, A. K. Dynamic Multicomponent Reactions-Directed Self-Assembled G-quadruplex Inherent Antibacterial Hydrogel. Langmuir 2023, 39 (18), 6466– 6475,  DOI: 10.1021/acs.langmuir.3c00392
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      Dynamic Multicomponent Reactions-Directed Self-Assembled G-quadruplex Inherent Antibacterial Hydrogel
      Rit, Tanmay; Ghosh, Tapas; Bhowmik, Sourav; Patidar, Mukesh K.; Das, Apurba K.
      Langmuir (2023), 39 (18), 6466-6475CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
      Nowadays, inherent antibacterial hydrogels have gained significant attention due to their utilization against infectious bacteria. Herein, we focus on the development of an injectable, self-healable, dynamic, and G-quadruplex hydrogel with inherent antibacterial activity. The dynamic self-assembled hydrogel is constructed upon multicomponent reactions (MCR) among guanosine, 2-formylphenylboronic acid, and amino acid/peptides in the presence of potassium ions. The role of amino acid/peptides in the formation of the G-quadruplex hydrogel is studied in detail. The G-quadruplex structure is formed via the π-π stacking of G-quartets. The formation of G-quadruplex is investigated by thioflavin T binding assay, CD spectroscopy, and PXRD. The formation of the dynamic imino-boronate bond in the hydrogels is well characterized by temp.-dependent 11B NMR (VT-NMR) and FT-IR spectroscopy. Furthermore, HR-TEM images and rheol. expts. reveal the fibrillar networks and viscoelastic property of the hydrogels. The presence of the dynamic imino-boronate ester bonds makes the hydrogel injectable and self-healable in nature. These dynamic G-quadruplex hydrogels show potential antibacterial activity against a series of Gram-pos. and Gram-neg. bacteria. The hydrogels have been used for the entrapment and sustained release of an anticancer drug doxorubicin over 48 h at different pHs (4.8, 7.4, and 8.5) and temp. without the influence of any external stimuli. Such injectable and self-healable hydrogels could be used in various applications in the field of biomedical science.
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      Baker, S. J.; Ding, C. Z.; Akama, T.; Zhang, Y.-K.; Hernandez, V.; Xia, Y. Therapeutic potential of boron-containing compounds. Future Med. Chem. 2009, 1 (7), 1275– 1288,  DOI: 10.4155/fmc.09.71
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      Therapeutic potential of boron-containing compounds
      Baker, Stephen J.; Ding, Charles Z.; Akama, Tsutomu; Zhang, Yong-Kang; Hernandez, Vincent; Xia, Yi
      Future Medicinal Chemistry (2009), 1 (7), 1275-1288CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)
      A review. Relative to C, H, N, and O2, very little is currently known about B in therapeutics. In addn., there are very few boron-contg. natural products identified to date to serve as leads for medicinal chemists. Perceived risks of using B and lack of synthetic methods to handle boron-contg. compds. have caused the medicinal chem. community to shy away from using the atom. However, phys., chem. and biol. properties of B offer medicinal chemists a rare opportunity to explore and pioneer new areas of drug discovery. B therapeutics are emerging that show different modes of inhibition against a variety of biol. targets. With one B-contg. therapeutic agent on the market and several more in various stages of clin. trials, the occurrence of this class of compd. is likely to grow over the next decade and B could become widely accepted as a useful element in future drug discovery.
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    26. 26
      Marasovic, M.; Ivankovic, S.; Stojkovic, R.; Djermic, D.; Galic, B.; Milos, M. In vitro and in vivo antitumour effects of phenylboronic acid against mouse mammary adenocarcinoma 4T1 and squamous carcinoma SCCVII cells. J. Enzyme Inhib. Med. Chem. 2017, 32 (1), 1299– 1304,  DOI: 10.1080/14756366.2017.1384823
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      26
      In vitro and in vivo antitumour effects of phenylboronic acid against mouse mammary adenocarcinoma 4T1 and squamous carcinoma SCCVII cells
      Marasovic, Maja; Ivankovic, Sinisa; Stojkovic, Ranko; Djermic, Damir; Galic, Borivoj; Milos, Mladen
      Journal of Enzyme Inhibition and Medicinal Chemistry (2017), 32 (1), 1299-1304CODEN: JEIMAZ; ISSN:1475-6366. (Taylor & Francis Ltd.)
      The cytotoxic activity of phenylboroxine acid was evaluated in vitro on mouse mammary adenocarcinoma 4T1, mouse squamous cell carcinoma SCCVII, hamster lung fibroblast V79 and mouse dermal fibroblasts L929 cell lines. The cytotoxic effects were dose dependent for all tested tumor and non-tumor cell lines. Under in vivo conditions, three application routes of phenylboronic acid were studied: intra-peritoneal (i.p.), intra-tumor (i.t.) and per-oral. After tumor transplantation in syngeneic mice, phenylboronic acid was shown to slow the growth of both tumor cell lines (4T1 and SCCVII) compared with the control. The inhibitory effects were pronounced during the application of phenylboronic acid. For both tested tumor cell lines, the most prominent antitumor effect was obtained by i.p. administration, followed significantly by oral administration.
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    27. 27
      Adamczyk-Woźniak, A.; Kaczorowska, E.; Kredátusova, J.; Madura, I.; Marek, P. H.; Matuszewska, A.; Sporzyński, A.; Uchman, M. Dehydration of Ortho -Meta - and Para -Alkoxy Phenylboronic Acids to Their Corresponding Boroxines. Eur. J. Inorg. Chem. 2018, 2018 (13), 1492– 1498,  DOI: 10.1002/ejic.201701485
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      Dehydration of ortho-, meta- and para-Alkoxy Phenylboronic Acids to their Corresponding Boroxines
      Adamczyk-Wozniak, Agnieszka; Kaczorowska, Ewa; Kredatusova, Jana; Madura, Izabela; Marek, Paulina H.; Matuszewska, Alicja; Sporzynski, Andrzej; Uchman, Mariusz
      European Journal of Inorganic Chemistry (2018), 2018 (13), 1492-1498CODEN: EJICFO; ISSN:1434-1948. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The authors detd. and compared properties such as pKa and thermal stability of isomeric isobutoxyphenylboronic acids (ortho-, meta-, para-). Mol. and crystal structures of the para isomer were detd. by single crystal XRD methods. DSC and TGA measurements were carried out on all isomers to study their dehydration as well as thermal stability. The position of the substituent in phenylboronic acids influences their acidity as well as possible formation of the corresponding boroxines.
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      Sporzyński, A.; Leszczyński, P. Solubility of Phenylboronic Compounds in Water. Mediterr. J. Chem. 2017, 6 (5), 200,  DOI: 10.13171/mjc65/01711021733-sporzynsky
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      Solubility of phenylboronic compounds in water
      Leszczynski, Pawel; Sporzynski, Andrzej
      Mediterranean Journal of Chemistry (2017), 6 (5), 200-207CODEN: MJCEAF; ISSN:2028-3997. (Mediterranean Journal of Chemistry)
      Soly. of six phenylboronic compds. in water was investigated using different methods. The results are consistent with each other, although for particular compds. selected methods should be preferred. The soly. of the investigated compds. is low, with the value of ca. 2 g/100 cm3 H2O at 20°C for unsubstituted phenylboronic acid. The unsubstituted benzoxaborole is less sol. than phenylboronic acid. Introduction of OiBu, COOH and CF3 groups into the Ph ring decreases soly. in comparison with unsubstituted phenylboronic acid, esp. for the alkoxy substituent.
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    29. 29
      Xu, L.; Hu, Y.; Liu, M.; Chen, J.; Huang, X.; Gao, W.; Wu, H. Gelation properties and glucose-sensitive behavior of phenylboronic acid based low-molecular-weight organogels. Tetrahedron 2015, 71, 2079– 2088,  DOI: 10.1016/j.tet.2015.02.050
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      29
      Gelation properties and glucose-sensitive behavior of phenylboronic acid based low-molecular-weight organogels
      Xu, Long; Hu, Yalong; Liu, Miaochang; Chen, Jiuxi; Huang, Xiaobo; Gao, Wenxia; Wu, Huayue
      Tetrahedron (2015), 71 (14), 2079-2088CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
      A series of phenylboronic acid (PBA)-based low-mol.-wt. gelators with different hydrocarbon chain lengths (C2-C11) were designed and synthesized. These gelators gelated five solvents efficiently at relatively low concn. with interesting aggregates of nanofibers, thin films, spherical thin shells, and microspheres piled with nanofibers. The gelation ability increased with the chain length increasing up to C11, which has the lowest crit. gelation concn. (CGC) of 0.19 wt %. FTIR and 1H NMR measurements suggested that van der Waals of alkyl chains, H-bonding, and π-π stacking interactions had an important contribution in gelation process and self-assembly. For all the gelators, their glucose-response increased along with the increasing concn. of glucose soln. However, the recognition and responsive rate to glucose were weakened gradually with the alkyl chain length increasing for the gelators. Therefore, glucose-sensitivity of these PBA-based organogels could be modulated through alkyl chain length.
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    30. 30
      Mandal, D.; Mandal, S. K.; Ghosh, M.; Das, P. K. Phenylboronic Acid Appended Pyrene-Based Low-Molecular-Weight Injectable Hydrogel: Glucose-Stimulated Insulin Release. Chem. ─Eur. J. 2015, 21, 12042– 12052,  DOI: 10.1002/chem.201501170
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      30
      Phenylboronic Acid Appended Pyrene-Based Low-Molecular-Weight Injectable Hydrogel: Glucose-Stimulated Insulin Release
      Mandal, Deep; Mandal, Subhra Kanti; Ghosh, Moumita; Das, Prasanta Kumar
      Chemistry - A European Journal (2015), 21 (34), 12042-12052CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A pyrene-contg. phenylboronic acid (PBA) functionalized low-mol.-wt. hydrogelator was synthesized with the aim to develop glucose-sensitive insulin release. The gelator showed the solvent imbibing ability in aq. buffer solns. of pH values, ranging from 8-12, whereas the sodium salt of the gelator formed a hydrogel at physiol. pH 7.4 with a min. gelation concn. (MGC) of 5 mg mL-1. The aggregation behavior of this thermoreversible hydrogel was studied by using microscopic and spectroscopic techniques, including transmission electron microscopy, FTIR, UV/Vis, luminescence, and CD spectroscopy. These investigations revealed that hydrogen bonding, π-π stacking, and van der Waals interactions are the key factors for the self-assembled gelation. The diol-sensitive PBA part and the pyrene unit in the gelator were judiciously used in fluorimetric sensing of minute amts. of glucose at physiol. pH. The morphol. change of the gel due to addn. of glucose was investigated by SEM, which denoted the glucose-responsive swelling of the hydrogel. A rheol. study indicated the loss of the rigidity of the native gel in the presence of glucose. Hence, the glucose-induced swelling of the hydrogel was exploited in the controlled release of insulin from the hydrogel. The insulin-loaded hydrogel showed thixotropic self-recovery property, which hoisted it as an injectable soft composite. Encouragingly, the gelator was found to be compatible with HeLa cells.
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    31. 31
      Gao, W.; Liang, Y.; Peng, X.; Hu, Y.; Zhang, L.; Wu, H.; He, B. In situ injection of phenylboronic acid based low molecular weight gels for efficient chemotherapy. Biomaterials 2016, 105, 1– 11,  DOI: 10.1016/j.biomaterials.2016.07.025
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      31
      In situ injection of phenylboronic acid based low molecular weight gels for efficient chemotherapy
      Gao, Wenxia; Liang, Yan; Peng, Xinyu; Hu, Yalong; Zhang, Longgui; Wu, Huayue; He, Bin
      Biomaterials (2016), 105 (), 1-11CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      Injectable low mol. wt. gels (LMWGs) based on the derivs. of phenylboronic acid were prepd. and used as substrates for efficient in situ chemotherapy. The gelators as well as LMWGs were characterized by 1H NMR, UV-vis, FTIR, MS and SEM. Anticancer drug doxorubicin hydrochloride (DOX) was encapsulated in the gels. The rheol. properties and rapid recovery capability of both blank and drug-loaded gels were tested. The LMWGs were non-toxic to both 3T3 fibroblasts and 4T1 breast cancer cells. The gels were formed rapidly after injected in vivo. The in vivo anticancer activities of DOX-loaded LMWGs were investigated in breast cancer bearing mice. The intratumoral injection of DOX loaded LMWGs with dose of 30 mg/kg revealed that the gels could coat around the tumor tissues to release DOX sustainingly and maintain effective DOX concn. for chemotherapy. The systemic toxicity of DOX was reduced significantly with the in situ administration of LMWGs formulations. The injectable LMWGs exhibited excellent therapeutic efficacy and low side effects in local chemotherapy. A series of phenylboronic acid (PBA)-based low-mol.-wt. gelators with different hydrocarbon chain lengths (C2-C11) were designed and synthesized. These gelators gelated five solvents efficiently at relatively low concn. with interesting aggregates of nanofibers, thin films, spherical thin shells, and microspheres piled with nanofibers. The gelation ability increased with the chain length increasing up to C11, which has the lowest crit. gelation concn. (CGC) of 0.19 wt %. FTIR and 1H NMR measurements suggested that van der Waals of alkyl chains, H-bonding, and π-π stacking interactions had an important contribution in gelation process and self-assembly. For all the gelators, their glucose-response increased along with the increasing concn. of glucose soln. However, the recognition and responsive rate to glucose were weakened gradually with the alkyl chain length increasing for the gelators. Therefore, glucose-sensitivity of these PBA-based organogels could be modulated through alkyl chain length.
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    32. 32
      He, J.; Hu, Y.; Wu, F.; He, B.; Gao, W. Control of MSC Differentiation by Tuning the Alkyl Chain Length of Phenylboroinc Acid Based Low-molecular-weight Gelators. J. Bionic Eng. 2018, 15, 682– 692,  DOI: 10.1007/s42235-018-0056-2
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      Eldridge, J. E.; Ferry, J. D. Studies of the Cross-Linking Process in Gelatin Gels. III. Dependence of Melting Point on Concentration and Molecular Weight. J. Phys. Chem. 1954, 58 (11), 992– 995,  DOI: 10.1021/j150521a013
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      The cross-linking process in gelatin gels. III. Dependence of melting point on concentration and molecular weight
      Eldridge, John E.; Ferry, John D.
      Journal of Physical Chemistry (1954), 58 (), 992-6CODEN: JPCHAX; ISSN:0022-3654.
      cf. C.A. 46, 1846d; preceding abstr. The m. ps. of solns. of 5 degraded gelatin samples with mol. wts. ranging from 33,000 to 72,000 were measured over a concn. range from 20 to 60 g./l. A nearly linear relation was found between the logarithm of the gelatin concn. and the reciprocal abs. temp. of melting. The relation between the logarithm of the mol. wt. and the reciprocal of the abs. temp. of melting was also nearly linear except for the sample of lowest mol. wt. Annealed gels had generally higher m. ps. than gels formed by quick chilling. The exptl. results were discussed in relation to the cross-linking process considered responsible for the gelation of gelatin solns. Exothermic heats of reaction ranging from 50 to 220 kcal./mole were calcd. for the formation of cross links if these are assumed to result from a binary assocn. of polymer chains.
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    34. 34
      Murata, K.; Aoki, M.; Suzuki, T.; Harada, T.; Kawabata, H.; Komori, T.; Ohseto, F.; Ueda, K.; Shinkai, S. Thermal and Light Control of the Sol-Gel Phase Transition in Cholesterol-Based Organic Gels. Novel Helical Aggregation Modes As Detected by Circular Dichroism and Electron Microscopic Observation. J. Am. Chem. Soc. 1994, 116 (15), 6664– 6676,  DOI: 10.1021/ja00094a023
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      34
      Thermal and Light Control of the Sol-Gel Phase Transition in Cholesterol-Based Organic Gels. Novel Helical Aggregation Modes As Detected by Circular Dichroism and Electron Microscopic Observation
      Murata, Kazutaka; Aoki, Masayoshi; Suzuki, Tsuyoshi; Harada, Takaaki; Kawabata, Hirosuke; Komori, Takashi; Ohseto, Fumio; Ueda, Keiko; Shinkai, Seiji
      Journal of the American Chemical Society (1994), 116 (15), 6664-76CODEN: JACSAT; ISSN:0002-7863.
      Nineteen cholesterol derivs. contg. a variety of azobenzene moieties coupled to C-3 of a steroidal moiety through an ester linkage were synthesized. We employed two different esterification methods by which cholesterol derivs. with the natural (S)-configuration at C-3 and those with the inverted (R)-configuration at C-3 were obtained. Among them, cholesterol derivs. I (R = Me, Et, Pr, Bu, decyl) and II (R = Me, Et, Pr, Bu, pentyl, decyl) bearing a p-alkoxyazobenzene moiety acted as excellent thermally-reversible gelators of various org. fluids, but the gelation ability is fairly different between I and II; I could gelatinize hydrocarbons, e.g. n-hexane, n-octane, and toluene, halogen solvents, e.g. 1,2-dichloroethane and dichloromethane, ethers, e.g. di-Et ether and THF, and alcs., e.g. ethanol and 1-butanol, whereas II could gelatinize ketones, methanol, and polysiloxanes. In general, the soly. of II in apolar solvents is superior to that of I, so I is useful for gelation of apolar solvents whereas II is useful for gelation of polar solvents. The sol-gel phase transition is sensitively "read-out" by a change in the CD spectrum: the gel phase is CD-active, whereas the sol phase is totally CD-silent. These results mean that dipoles in the azobenzene moiety are oriented in a clockwise (in R-chirality) or anticlockwise (in S-chirality) direction when they interact in the excited state. Strangely, we accidentally found that the CD sign of the gels prepd. from I (R = Pr, Bu) and III (azobenzene-linked cholesterol deriv. with p-NMe2) is frequently inverted. After careful examn. of the gel prepn. conditions, we found that inversion takes place only when the cooling speed is fast. The scanning electron microscopic studies established that gelators form three-dimensional networks with helical fibrils. In the III gel prepd. from cyclohexane, the gel with R-chirality in CD possesses a right-handed helix, whereas the gel with S-chirality in the CD possesses a left-handed helix. The sol-gel phase transition was also induced by photoresponsive cis-trans isomerism of the azobenzene moiety; the gel formed from the trans-isomer was efficiently converted to the sol when trans-to-cis isomerization was photochem. induced, and this process can be repeated reversibly. The photoinduced sol-gel phase transition was also "read-out" as a change in CD spectroscopy.
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    35. 35
      Alhalaweh, A.; Alzghoul, A.; Bergström, C. A. Molecular Drivers of Crystallization Kinetics for Drugs in Supersaturated Aqueous Solutions. J. Pharm. Sci. 2019, 108 (1), 252– 259,  DOI: 10.1016/j.xphs.2018.11.006
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      35
      Molecular drivers of crystallization kinetics for drugs in supersaturated aqueous solutions
      Alhalaweh, Amjad; Alzghoul, Ahmad; Bergstroem, Christel A. S.
      Journal of Pharmaceutical Sciences (Philadelphia, PA, United States) (2019), 108 (1), 252-259CODEN: JPMSAE; ISSN:0022-3549. (Elsevier Inc.)
      In this study, we explore mol. properties of importance in soln.-mediated crystn. occurring in supersatd. aq. drug solns. Furthermore, we contrast the identified mol. properties with those of importance for crystn. occurring in the solid state. A literature data set of 54 structurally diverse compds., for which crystn. kinetics from supersatd. aq. solns. and in melt-quenched solids were reported, was used to identify mol. drivers for crystn. kinetics obsd. in soln. and contrast these to those obsd. for solids. The compds. were divided into fast, moderate, and slow crystallizers, and in silico classification was developed using a mol. K-nearest neighbor model. The topol. equiv. of Grav3 (related to mol. size and shape) was identified as the most important mol. descriptor for soln. crystn. kinetics; the larger this descriptor, the slower the crystn. Two electrotopol. descriptors (the atom-type E-state index for -Caa groups and the sum of abs. values of pi Fukui(+) indexes on C) were found to sep. the moderate and slow crystallizers in the soln. The larger these descriptors, the slower the crystn. With these 3 descriptors, the computational model correctly sorted the crystn. tendencies from solns. with an overall classification accuracy of 77% (test set).
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    36. 36
      Raina, S. A.; Van Eerdenbrugh, B.; Alonzo, D. E.; Mo, H.; Zhang, G. G. Z.; Gao, Y.; Taylor, L. S. Trends in the Precipitation and Crystallization Behavior of Supersaturated Aqueous Solutions of Poorly Water-Soluble Drugs Assessed Using Synchrotron Radiation. J. Pharm. Sci. 2015, 104 (6), 1981– 1992,  DOI: 10.1002/jps.24423
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      Trends in the Precipitation and Crystallization Behavior of Supersaturated Aqueous Solutions of Poorly Water-Soluble Drugs Assessed Using Synchrotron Radiation
      Raina, Shweta A.; Van Eerdenbrugh, Bernard; Alonzo, David E.; Mo, Huaping; Zhang, Geoff G. Z.; Gao, Yi; Taylor, Lynne S.
      Journal of Pharmaceutical Sciences (2015), 104 (6), 1981-1992CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)
      Amorphous materials are high-energy solids that can potentially enhance the bioavailability of poorly sol. compds. A major impediment to their widespread use as a formulation platform is the tendency of amorphous materials to crystallize. The aim of this study was to evaluate the relative crystn. tendency of six structural analogs belonging to the dihydropyridine class, in an aq. environment in the absence and presence of polymers, using wide-angle X-ray scattering synchrotron radiation and polarized light microscopy. The crystn. behavior of ppts. generated from supersatd. solns. of the active pharmaceutical ingredients was found to be highly variable ranging from immediate to several hours in the absence of polymers. Polymers with intermediate hydrophilicity/hydrophobicity were found to substantially delay crystn., whereas strongly hydrophilic or hydrophobic polymers were largely ineffective. NMR spectroscopy expts. supported the supposition that polymers need to have affinity for both the drug-rich ppt. and the aq. phase in order to be effective crystn. inhibitors. This study highlights the variability in the crystn. tendency of different compds. and provides insight into the mechanism of inhibition by polymeric additives. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.
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    37. 37
      Sangeetha, N. M.; Maitra, U. Supramolecular Gels: Functions and Uses. Chem. Soc. Rev. 2005, 34 (10), 821,  DOI: 10.1039/b417081b
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      Supramolecular gels: Functions and uses
      Sangeetha, Neralagatta M.; Maitra, Uday
      Chemical Society Reviews (2005), 34 (10), 821-836CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      In recent years there has been immense interest in studying gels derived from low mol. mass gelators (supramol., or simply mol. gels). The motivation for this is not only to understand the fundamental aggregate structures in the gels at different length scales, but also to explore their potential for futuristic technol. applications. Gels have been made sensitive to external stimuli like light and chem. entities by incorporating a spectroscopically active or a receptor unit as part of the gelator mol. This makes them suitable for applications such as sensing and actuating. The diversity of gel structural architectures has allowed them to be utilized as templates to prep. novel inorg. superstructures for possible applications in catalysis and sepn. Gels derived from liq. crystals (anisotropy gels) that can act as dynamically functional materials have been prepd., for example, for (re-writable) information recording. Supramol. gels can be important in controlled release applications, in oil recovery, for gelling cryogenic fuels etc. They can also serve as media for a range of applications. This tutorial review highlights some of the instructive work done by various groups to develop smart and functional gels, and covers a wide spectrum of scientific interest ranging from medicine to materials science.
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    38. 38
      Schall, J. M.; Capellades, G.; Myerson, A. S. Methods for Estimating Supersaturation in Antisolvent Crystallization Systems. CrystEngComm 2019, 21 (38), 5811– 5817,  DOI: 10.1039/C9CE00843H
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      Methods for estimating supersaturation in antisolvent crystallization systems
      Schall, Jennifer M.; Capellades, Gerard; Myerson, Allan S.
      CrystEngComm (2019), 21 (38), 5811-5817CODEN: CRECF4; ISSN:1466-8033. (Royal Society of Chemistry)
      The mole fraction and activity coeff.-dependent (MFAD) supersatn. expression is the least-assumptive, practical choice for calcg. supersatn. in solvent mixts. This paper reviews the basic thermodn. derivation of the supersatn. expression, revisits common simplifying assumptions, and discusses the shortcomings of those assumptions for the design of industrial crystn. processes. A step-by-step methodol. for estg. the activity-dependent supersatn. is provided with focus on ternary systems. This method requires only soly. data and thermal property data from a single differential scanning calorimetry (DSC) expt. Two case studies are presented, where common simplifications to the MFAD supersatn. expression are evaluated: (1) for various levels of supersatn. of L-asparagine monohydrate in water-isopropanol mixts. and (2) for the dynamic and steady-state mixed-suspension, mixed-product removal (MSMPR) crystn. of a proprietary API in water-ethanol-tetrahydrofuran solvent mixts. When compared to the MFAD supersatn. estn., it becomes clear that errors in excess of 190% may be introduced in the estn. of the crystn. driving force by making unnecessary simplifications to the supersatn. expression. These errors can result in addnl. parameter regression errors - sometimes by nearly an order of magnitude - for nucleation and growth kinetic parameters, limiting the accurate simulation of dynamic and steady-state crystn. systems.
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    39. 39
      Yi, B.; Xu, Q.; Liu, W. An overview of substrate stiffness guided cellular response and its applications in tissue regeneration. Bioact. Mater. 2022, 15, 82– 102,  DOI: 10.1016/j.bioactmat.2021.12.005
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      An overview of substrate stiffness guided cellular response and its applications in tissue regeneration
      Yi, Bingcheng; Xu, Qi; Liu, Wei
      Bioactive Materials (2022), 15 (), 82-102CODEN: BMIAD4; ISSN:2452-199X. (Elsevier B.V.)
      A review. Cell-matrix interactions play a crit. role in tissue repair and regeneration. With gradual uncovering of substrate mech. characteristics that can affect cell-matrix interactions, much progress has been made to unravel substrate stiffness-mediated cellular response as well as its underlying mechanisms. Yet, as a part of cell-matrix interaction biol., this field remains in its infancy, and the detailed mol. mechanisms are still elusive regarding scaffold-modulated tissue regeneration. This review provides an overview of recent progress in the area of the substrate stiffness-mediated cellular responses, including (1) the phys. detn. of substrate stiffness on cell fate and tissue development; (2) the current exploited approaches to manipulate the stiffness of scaffolds; (3) the progress of recent researches to reveal the role of substrate stiffness in cellular responses in some representative tissue-engineered regeneration varying from stiff tissue to soft tissue. This article aims to provide an up-to-date overview of cell mechanobiol. research in substrate stiffness mediated cellular response and tissue regeneration with insightful information to facilitate interdisciplinary knowledge transfer and enable the establishment of prognostic markers for the design of suitable biomaterials.
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    40. 40
      Jiao, T.; Rodney, J.; Clifton, G. L. C.; Hopkins, R. A. Measurements of the Effects of Decellularization on Viscoelastic Properties of Tissues in Ovine. Baboon, and Human Heart Valves. Tissue Eng., Part A 2012, 18, 423,  DOI: 10.1089/ten.TEA.2010.0677
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      40
      Measurements of the Effects of Decellularization on Viscoelastic Properties of Tissues in Ovine, Baboon, and Human Heart Valves
      Jiao, Tong; Clifton, Rodney J.; Converse, Gabriel L.; Hopkins, Richard A.
      Tissue Engineering, Part A (2012), 18 (3 and 4), 423-431CODEN: TEPAB9; ISSN:1937-3341. (Mary Ann Liebert, Inc.)
      In the development of tissue-engineered heart valves based on allograft decellularized extracellular matrix scaffolds, the material properties of the implant should be ideally comparable to the native semilunar valves. This investigation of the viscoelastic properties of the three functional aortic/pulmonary valve tissues (leaflets, sinus wall, and great vessel wall) was undertaken to establish normative values for fresh samples of human valves and to compare these properties after various steps in creating scaffolds for subsequent bioreactor-based seeding protocols. Torsional wave methods were used to measure the viscoelastic properties. Since preclin. surgical implant validation studies require relevant animal models, the tests reported here also include results for three pairs of both ovine and baboon aortic and pulmonary valves. For human aortic valves, four cryopreserved valves were compared with four decellularized scaffolds. Because of organ and heart valve transplant scarcity for pulmonary valves, only three cryopreserved and two decellularized pulmonary valves were tested. Leaflets are relatively soft. Loss angles are similar for all tissue samples. Regardless of species, the decellularization process used in this study has little effect on viscoelastic properties.
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      Charrier, E. E.; Pogoda, K.; Wells, R. G.; Janmey, P. A. Control of Cell Morphology and Differentiation by Substrates with Independently Tunable Elasticity and Viscous Dissipation. Nat. Commun. 2018, 9 (1), 449,  DOI: 10.1038/s41467-018-02906-9
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      Control of cell morphology and differentiation by substrates with independently tunable elasticity and viscous dissipation
      Charrier Elisabeth E; Pogoda Katarzyna; Janmey Paul A; Charrier Elisabeth E; Wells Rebecca G; Pogoda Katarzyna
      Nature communications (2018), 9 (1), 449 ISSN:.
      The mechanical properties of extracellular matrices can control the function of cells. Studies of cellular responses to biomimetic soft materials have been largely restricted to hydrogels and elastomers that have stiffness values independent of time and extent of deformation, so the substrate stiffness can be unambiguously related to its effect on cells. Real tissues, however, often have loss moduli that are 10 to 20% of their elastic moduli and behave as viscoelastic solids. The response of cells to a time-dependent viscous loss is largely uncharacterized because appropriate viscoelastic materials are lacking for quantitative studies. Here we report the synthesis of soft viscoelastic solids in which the elastic and viscous moduli can be independently tuned to produce gels with viscoelastic properties that closely resemble those of soft tissues. Systematic alteration of the hydrogel viscosity demonstrates the time dependence of cellular mechanosensing and the influence of viscous dissipation on cell phenotype.
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    42. 42
      He, J.; Hu, Y.; Wu, F.; He, B.; Gao, W. Control of MSC Differentiation by Tuning the Alkyl Chain Length of Phenylboroinc Acid Based Low-Molecular-Weight Gelators. J. Bionic Eng. 2018, 15 (4), 682– 692,  DOI: 10.1007/s42235-018-0056-2
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      Landel, R. F.; Nielsen, L. E. Mechanical Properties of Polymers and Composites, 2nd ed.; Marcel Dekker, Inc.: New York, Basel, 1994; ISBN 0-8247-8964-4.
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      Elumalai, V.; Hansen, J. H. A Scalable and Green One-Minute Synthesis of Substituted Phenols. RSC Adv. 2020, 10 (66), 40582– 40587,  DOI: 10.1039/D0RA08580D
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      A scalable and green one-minute synthesis of substituted phenols
      Elumalai, Vijayaragavan; Hansen, Joern H.
      RSC Advances (2020), 10 (66), 40582-40587CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
      A mild, green and highly efficient protocol was developed for the synthesis of substituted phenols ArOH [Ar = Ph, 2-ClC6H4, 2,4,6-tri-BrC6H2, etc.] via ipso-hydroxylation of arylboronic acids in ethanol. The method utilized the combination of aq. hydrogen peroxide as the oxidant and H2O2/HBr as the reagent under unprecedentedly simple and convenient conditions. A wide range of arylboronic acids were smoothly transformed into substituted phenols ArOH in very good to excellent yields without chromatog. purifn. The reaction was scalable up to at least 5 g at room temp. with one-minute reaction time and can be combined in a one-pot sequence with bromination and Pd-catalyzed cross-coupling to generate more diverse, highly substituted phenols ArOH [Ar = 2,4-di-Me-4,6-di-PhC6H, 2,4,6-tri-PhC6H2, 2,4,6-tri-(4-N≡C6H4)C6H2].
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      The 1:1 β-CD/ibuprofen complex formation was studied by means of theor. (DFT calcns.) and exptl. (NMR) methods. The results show that both enantiomeric forms of ibuprofen can freely enter and leave the host cavity. According to the DFT computations, the binding mode I (less polar part of the ibuprofen mol. inserted into the host cavity) appears to be the preferable mode of binding of the guest ibuprofen mols. inside the β-CD host cavity. This type of binding corresponds to the exptl. observations: the 2D-ROESY spectrum of ibuprofen with β-CD shows only those crosspeaks discussed for binding mode I.
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