Structures of trehalose and other common sugars.

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... is a naturally occurring, nonreducing disaccharide formed by the α,α-1,1 glycosidic linkage of two glucose units (α-D-glucopyranosyl-α-D-glucopyranoside) (Figure 1). This specific bond bends trehalose into a rigid clamshell structure. ...

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... This drawback is often accepted in the medical field in favor of the better stabilization properties and relative inertness of trehalose, which lacks the free aldehyde groups susceptible to unwanted Maillard reactions that are common with other sugars. 4,9,12 Furthermore, as the glycosidic bond is highly stable, trehalose is less susceptible to hydrolysis, thereby making it more inert than sucrose, the other common nonreducing sugar (Figure 1). Nonetheless, when ingested, the trehalose glycosidic bond is hydrolyzed in humans by the intestinal enzyme trehalase to form two molecules of glucose, which are subsequently adsorbed and metabolized. ...

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... than producing linear polymers, trehalose monomers can be cross-linked to form thermoset resins of insoluble polymer networks with outstanding thermomechanical properties ( Figure 10). Out of concern for the environment, a focus on producing thermosets from renewable resources has led multiple scientists to replace petroleum-based polymers with biorenewable stocks, such as saccharides. ...

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... was attributed to the hydrolytic stability of the styrenyl backbone. 81 The Reineke group functionalized trehalose with succinic anhydride for use as a cross-linking hardener for their epoxy-containing trimethylolpropane triglycidyl ether (TTE)-based 82 or epoxidized soy bean oil (ESO)-based 83 thermosets (Figure 11a). The properties of the cured thermosets varied greatly, with T g values of 63 and 3 °C and tensile strengths up to 47 and 1.3 MPa for the TTE-and ESO-based trehalose thermosets, respectively. ...

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... Conversely, in a different study, trehalose cinnamoyl ester (TC) smooth thin films promoted fibroblast cell proliferation, with better results than a standard polystyrene culture plate. 84 TCs were prepared by esterification between trehalose and cinnamoyl chloride, and thin films were prepared by photocuring of the monomer solution, as cinnamoyl undergoes dimerization to form a cyclobutane ring under UV irradiation (Figure 11b). The polymerization is favored with a DS of 4 compared to a DS of 8, due to the larger steric hindrance from the extra cinnamoyl groups in the latter. ...

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... purified hydrogel was obtained as a colorless powder, although this first attempt provided only a modest 17% yield. 65 By increasing the 4-vinylbenzyl chloride to trehalose ratio, greater trehalose modification was achieved, with a preference for the monosubstituted monomer (Figure 12a). The scaled up multigram reaction gave a 76% yield, a large increase from that of the previous synthesis. ...

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... styrenyl trehalose polymer was prepared by FRP and mixed in phosphate-buffered saline (PBS) with an 8-arm PEG bearing PBA at every end group. A gel formed within 5 min, and it was Figure 13. Synthesis of acid-cleavable acetal trehalose hydrogels and their thermoresponsive behavior based on the volume phase transition temperature (VPTT). ...

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... same characteristics also influenced swelling abilities, with low cross-linking, 2-isomers, and higher water content in the solvent system leading to higher swelling capacity. Due to the presence of acetals in the cross-linker, the hydrogel degraded within hours in an acidic solution at room temperature, although no degradation occurred at acidic pH above the VPTT, due to the shrinkage of the hydrogel and masking of the acetals ( Figure 13). 91 To obtain a hydrogel able to degrade at physiological temperatures, hydrophilic comonomers, such as acrylamide (AAm), N-(2-hydroxyethyl)acrylamide (HEAAm), and N,Ndimethylacrylamide (DMAAm), were added in the polymerization feed. ...

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... A final set of degradable chitosan hydrogels was prepared using a diiodotrehalose derivative as the chemical cross-linker; these hydrogels could be fully biodegraded in 96 h by trehalase. 97 Interestingly, O'Shea et al. developed tricomposite hydrogels by thiol−ene reaction using enzyme derived diacrylate trehalose, PEG diacrylate, and trimethylolpropane ethoxylate thiolactate as a thiol-bearing cross-linker (Figure 12b). Within a few minutes of mixing, hydrogels with varied trehalose contents were prepared and their rate of degradation increased proportionally with trehalose amount. ...

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... on the known stabilization ability, hydrophilicity, and biocompatibility of trehalose as a small molecule, many groups hypothesized that incorporating trehalose into a polymer would aid in drug solubility and prevent the aggregation, denaturation, and degradation of proteins. In the following section, the ability of trehalose polymers to stabilize proteins and peptides as excipients, conjugates, and hydrogels ( Figure 14) will be discussed. ...

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... The derived polymers, as well as small molecule trehalose, were applied in 1−80 weight equivalents (wt equiv) to horseradish peroxidase (HRP), β-galactosidase (β-gal), and GOx. The percent original activity of β-gal after three lyophilization cycles or of HRP (Figure 15a) and GOx after heating (70 °C for 30 min) clearly showed that all of the polymer excipient formulations, except for 1 wt equiv of pTrMA with β-gal, significantly increased the remaining enzyme activity (60−100% HRP, 50−100% β-gal, and 80− 95% GOx activity) relative to no excipient or trehalose. Moreover, the polymers were noncytotoxic in vitro on four different cell lines up to 8 mg/mL (Figure 15b) 25 and were later found to also be nontoxic in vivo. ...

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... percent original activity of β-gal after three lyophilization cycles or of HRP (Figure 15a) and GOx after heating (70 °C for 30 min) clearly showed that all of the polymer excipient formulations, except for 1 wt equiv of pTrMA with β-gal, significantly increased the remaining enzyme activity (60−100% HRP, 50−100% β-gal, and 80− 95% GOx activity) relative to no excipient or trehalose. Moreover, the polymers were noncytotoxic in vitro on four different cell lines up to 8 mg/mL (Figure 15b) 25 and were later found to also be nontoxic in vivo. 67 Counterintuitively, initial experiments with trehalose polymers did not appear to have improved stabilization with increasing MW 19 even though concentration clearly played a critical role in stabilizing proteins. ...

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... Pelegri-O'Day et al. found that, while keeping the total amount of polymer or trehalose in solution constant, increasing the MW of trehalose-based polymer excipients resulted in more stable protein formulations. 20 A later study with pTMA showed that the molecular weight effect was only observed at lower concentrations of polymer, with larger polymers requiring a significantly lower concentration in order to fully stabilize the protein insulin when compared with smaller polymers (Figure 16). 26 Due to the polymer backbone connecting individual trehalose molecules, the likelihood of a higher concentration of trehalose molecules in the polymer interacting with the protein surface is increased. ...

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... our group explored the effect of polymer concentration and MW of poly(trehalose methacrylate) on the stabilization of intact insulin, determined by HPLC analysis. This study showed that, for insulin, increasing the MW or concentration led to greater insulin stability against environmental stresses (Figure 16). 26 Based on the similarities in stabilization properties across polymer backbones, it seems likely that excipient formulations of the other trehalose polymers could be similarly optimized to reduce the amount of polymer in solution. ...

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... the second case, the greater nucleophilicity of lysine B29 over the N-terminal amines was exploited by increasing the reaction pH from 8.0 to 9.5 in order to favor single modification of insulin using a nitrophenyl carbonate-activated ATRP initiator as described above (Figure 8b). While the dose of insulin required for each conjugate was higher than that of native insulin, the site-specifically modified insulin required only a 3-fold dosage as compared to the 5-fold dosage of the original conjugate (16 vs 48 vs 80 μg/kg) in order to lower glucose concentrations in mice comparably (Figure 17a). Excitingly, both insulin conjugates stabilized insulin against an accelerated heat stress (90 °C for 30 min) better than unmodified insulin did; by insulin tolerance tests (ITT) in mice, the conjugate retained 100% activity after heat treatment in vivo, while the unmodified protein had 17% activity (Figure 17c). ...

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... the dose of insulin required for each conjugate was higher than that of native insulin, the site-specifically modified insulin required only a 3-fold dosage as compared to the 5-fold dosage of the original conjugate (16 vs 48 vs 80 μg/kg) in order to lower glucose concentrations in mice comparably (Figure 17a). Excitingly, both insulin conjugates stabilized insulin against an accelerated heat stress (90 °C for 30 min) better than unmodified insulin did; by insulin tolerance tests (ITT) in mice, the conjugate retained 100% activity after heat treatment in vivo, while the unmodified protein had 17% activity (Figure 17c). 67 The longer insulin plasma lifetime of the conjugate compared to insulin was confirmed in mice. ...

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... The longer insulin plasma lifetime of the conjugate compared to insulin was confirmed in mice. The trehalose polymer prolonged the plasma lifetime in a comparable fashion to a similarly sized PEG conjugate, suggesting that the polymers have that advantage of PEG (Figure 17b). 67 Disulfide bonds were exploited for nonspecifically or siteselectively conjugated trehalose polymers onto an antibody and Fab, respectively. ...

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... Our group utilized a styrenyl trehalose hydrogel to stabilize phytase, which is an enzyme important to agriculture feed stocks. Variable pressure scanning election microscopy (SEM) was used to characterize the hydrogel, and the images revealed micrometer-sized pores which could easily fit the enzyme (Figure 18a,b). Thus, phytase was entrapped within the network structure at 1, 10, and 40 wt equiv of hydrogel to protein. ...

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... As with the original work, the enzymes were encapsulated in the trehalose hydrogel, exposed to 90 °C for 1 min with 50 wt % water, and then tested for activity. Similar to the original work, with 10 wt equiv, >98% activity was maintained with all enzymes, while only 15−58% enzyme activity was observed when the protein was tested alone (Figure 18c). Notably, phytase and xylanase activity was increased to above 100% in the presence of the gel, possibly due to the gel network and/or trehalose scaffold stabilization enhancing substrate binding or stabilizing the proteins in the activity assay conditions. ...

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... results were also compared to the stability of the enzymes in the presence of the same amount of molecular trehalose (0.54, 2.7, and 5.4 wt equiv), and only the highest concentration consistently retained any significant amount of activity (65−100%) relative to the enzymes alone; all hydrogel concentrations outperformed the equivalent concentrations of free trehalose. Importantly, similar to the original work, sustained quantitative release of phytase was achieved within 4 h at 37 °C (Figure 18d), which is a relevant time frame for the average feed transit in the small intestine of pigs. 24 Langer and co-workers developed three-component trehalose/PEG/TMPE hydrogels with varying amounts (6.25− 100% diacrylate component) of trehalose incorporation, which were found to have faster protein release with increasing trehalose content for both ovalbumin (OVA) and IgG proteins, despite the large difference in size (Figure 19a). ...

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... similar to the original work, sustained quantitative release of phytase was achieved within 4 h at 37 °C (Figure 18d), which is a relevant time frame for the average feed transit in the small intestine of pigs. 24 Langer and co-workers developed three-component trehalose/PEG/TMPE hydrogels with varying amounts (6.25− 100% diacrylate component) of trehalose incorporation, which were found to have faster protein release with increasing trehalose content for both ovalbumin (OVA) and IgG proteins, despite the large difference in size (Figure 19a). 98 This, along with a triphasic release profile, suggested that the initial diffusion release gives way to network degradation-based release and that the higher the amount of trehalose component, the faster this degradation occurs. ...

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... This, along with a triphasic release profile, suggested that the initial diffusion release gives way to network degradation-based release and that the higher the amount of trehalose component, the faster this degradation occurs. Furthermore, HRP was encapsulated in the hydrogel, then exposed to heat (37 °C for up to 12 days), and subsequently recovered to test activity and showed that a higher trehalose content results in higher recovered activity (100% activity for gel with maximum trehalose content vs 50% for gel with half the amount of trehalose vs 7% for gel with 25% amount of trehalose) ( Figure 19b). Conversely, the hydrogels with less trehalose content could destabilize the protein, because hydrolysis of the network exposed carboxylate groups. ...

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... resulting nanogels increased the solution stability of glucagon from less than 24 h at physiological pH to at least 3 weeks. This was demonstrated by the lack of glucagon fibrils in transmission electron microscopy (TEM) images after 7 and 21 days in solution and by the appearance of the fibrils after reduction of the nanogel (Figure 21a−c). The in vitro activity of the thiolated glucagon was found to be similar to that of native glucagon. ...

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... in vitro activity of the thiolated glucagon was found to be similar to that of native glucagon. Glucagon released under mild reducing conditions was fully active (Figure 21d). 58 Wang et al. prepared SENs for the stabilization of GOx using statistical or block copolymers. ...