A specific inhibitory effect of multivalent trehalose toward Aβ(1-40) aggregation

Wada, Masaya; Miyazawa, Yuta; Miura, Yoshiko

doi:10.1039/c1py00072a

Cited by 31 publications

(49 citation statements)

References 42 publications

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“…27 Due to practical considerations for our study, an approach was taken to monofunctionalize trehalose modeled from the procedure of Miura et al with important improvements (Scheme 1). 23 Triphenylphosphine-iodine was used to produce a mixture of three species, diiodo-, monoiodo-, and unmodified trehalose. This mixture was acetylated and the desired per-acetylated monoiodo-trehalose 2 was obtained after column chromatography in 24% yield.…”

Section: Resultsmentioning

confidence: 99%

“…21,22 Wada et al have demonstrated that a statistical co-polymer of trehalose and acrylamide inhibits the aggregation of amyloid β peptide, associated with Alzheimer’s disease. 23 More recently, Maynard et al reported that lysozyme covalently attached to p -formylpolystyrene modified with trehalose via an acetonide moiety is capable of imparting both lyo- and heat protectant properties to this enzyme. 24 …”

Section: Introductionmentioning

confidence: 99%

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Poly(trehalose): Sugar-Coated Nanocomplexes Promote Stabilization and Effective Polyplex-Mediated siRNA Delivery

et al. 2013

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When nanoparticles interact with their environment, the nature of that interaction is governed largely by the properties of its outermost surface layer. Here, we exploit the exceptional properties of a common disaccharide, trehalose, which is well known for its unique biological stabilization effects. To this end, we have developed a synthetic procedure that readily affords a polymer of this disaccharide, poly(methacrylamidotrehalose) or “poly(trehalose)” and diblock copolycations containing this polymer with 51 repeat units chain extended with aminoethylmethacrylate (AEMA) at three degrees of polymerization (n=34, 65, and 84). Two series of experiments were conducted to study these di block copolymers in detail and to compare their properties to two control polymer [PEG-P(AEMA) and P(AEMA)]. First, we demonstrate that the poly(trehalose)-coating ensures colloidal stability of polyplexes containing siRNA in the presence of high salt concentrations and serum proteins. Poly(trehalose) retains the ability of trehalose to lower the phase transition energy associated with water freezing and can protect siRNA polyplexes during freeze-drying allowing complete nanoparticle resuspension without loss of biological function. Second, we show that siRNA polyplexes coated with poly(trehalose) have exceptional cellular internalization into glioblastoma cells that proceeds with zero-order kinetics. Moreover, the amount of siRNA delivered by poly(trehalose) block copolycations can be controlled by the siRNA concentration in cell culture media. Using confocal microscopy we show that trehalose-coated polyplexes undergo active trafficking in cytoplasm upon internalization and significant siRNA-induced target gene down-regulation was achieved with an IC50 of 19 nM. These findings coupled with a negligible cytotoxicity suggests that poly(trehalose) has the potential to serve as an important component of therapeutic nanoparticle formulations of nucleic acids and has great promise to be extended as a new coating for other nano-based technologies and macromolecules, in particular, those related to nanomedicine applications.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Poly(trehalose): Sugar-Coated Nanocomplexes Promote Stabilization and Effective Polyplex-Mediated siRNA Delivery

et al. 2013

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“…22, 28 Others have shown that polymers with trehalose side chains can inhibit amyloid formation and form stable nanoparticles for nucleic acid delivery. 29–31 We hypothesized that trehalose glycopolymers would also stabilize proteins in vivo similar to PEG. In the study described here, for the first time we demonstrate that the trehalose glycopolymer can maintain the plasma protein concentration within the therapeutic window over an extended period of time and also stabilize a protein therapeutic at elevated temperature and under mechanical stress.…”

Section: Introductionmentioning

confidence: 99%

Trehalose Glycopolymer Enhances Both Solution Stability and Pharmacokinetics of a Therapeutic Protein

et al. 2017

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Biocompatible polymers such as poly(ethylene glycol) (PEG) have been successfully conjugated to therapeutic proteins to enhance their pharmacokinetics. However, many of these polymers, including PEG, only improve the in vivo lifetimes and do not protect proteins against inactivation during storage and transportation. Herein, we report a polymer with trehalose side chains (PolyProtek) that is capable of improving both the external stability and the in vivo plasma half-life of a therapeutic protein. Insulin was employed as a model biologic, and high performance liquid chromatography and dynamic light scattering confirmed that addition of trehalose glycopolymer as an excipient or covalent conjugation prevented thermal or agitation-induced aggregation of insulin. The insulin-trehalose glycopolymer conjugate also showed significantly prolonged plasma circulation time in mice, similar to the analogous insulin-PEG conjugate. The insulin-trehalose glycopolymer conjugate was active as tested by insulin tolerance tests in mice and retained bioactivity even after exposure to high temperatures. The trehalose glycopolymer was shown to be non-toxic to mice up to at least 1.6 mg/kg dosage. These results together suggest that the trehalose glycopolymer should be further explored as an alternative to PEG for long circulating protein therapeutics.

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“…For instance, α,α‐trehalose is known to prevent aggregation, fusion, and lysis of lipid membranes and proteins . Hence there is much interest in the synthesis of trehalose‐based polymers . Several polymers having pendant trehalose units have been synthesized (Figure a), and these trehalosylated polymers have been shown to stabilize proteins against various stresses and prevent aggregation of amyloid beta .…”

Section: Introductionmentioning

confidence: 99%

Crystal‐to‐Crystal Synthesis of Helically Ordered Polymers of Trehalose by Topochemical Polymerization

2020

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The synthesis of crystalline helical polymers of trehalose via topochemical azide–alkyne cycloaddition (TAAC) of a trehalose‐based monomer is presented. An unsymmetrical trehalose derivative having azide and alkyne crystallizes in two different forms having almost similar packing. Upon heating, both the crystals undergo TAAC reaction to form crystalline polymers. Powder X‐ray diffraction (PXRD) studies revealed that the monomers in both the crystals polymerize in a crystal‐to‐crystal fashion; circular dichroism (CD) studies of the product crystals revealed that the formed polymer is helically ordered. This solvent‐free, catalyst‐free polymerization method that eliminates the tedious purification of the polymeric product exemplifies the advantage of topochemical polymerization reaction over traditional solution‐phase polymerization.

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A specific inhibitory effect of multivalent trehalose toward Aβ(1-40) aggregation

Cited by 31 publications

References 42 publications

Poly(trehalose): Sugar-Coated Nanocomplexes Promote Stabilization and Effective Polyplex-Mediated siRNA Delivery

Poly(trehalose): Sugar-Coated Nanocomplexes Promote Stabilization and Effective Polyplex-Mediated siRNA Delivery

Trehalose Glycopolymer Enhances Both Solution Stability and Pharmacokinetics of a Therapeutic Protein

Crystal‐to‐Crystal Synthesis of Helically Ordered Polymers of Trehalose by Topochemical Polymerization

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