Revealing the trehalose mediated inhibition of protein aggregation through lysozyme–silver nanoparticle interaction

Siddhanta, Soumik; Barman, Ishan; Narayana, Chandrabhas

doi:10.1039/c5sm01896j

Cited by 29 publications

(29 citation statements)

References 49 publications

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“…Trehalose has long been used as a bioprotectant for pharmaceutically relevant molecules including globular proteins during desiccation or lyophilization . In addition to being a nonreducing sugar, trehalose is known to stabilize proteins through a combination of vitrification, water replacement, and water entrapment mechanisms, while exerts substantive protective action against oxidative stress . Given the considerable protein content of mucin, we hypothesized that trehalose‐induced prevention of adverse nanoparticle interactions combined with conservation of the coordinated water molecules will enhance mucus dispersion and, thus, retain the intrinsic matrix hydration.…”

Section: Introductionmentioning

confidence: 99%

“…Several laboratries, including our own, have harnessed SERS in elucidating an array of biomolecule–nanoparticle interactions . Of particular relevance, we have used these spectral tools to uncover the effect of trehalose‐rich microenvironment on protein–nanoparticle interactions . Since the mucus presents a complex matrix of mucin glycoproteins, globular proteins, and other organic plus inorganic entities, it necessitates the use of a nondestructive, molecular‐specific analytical tool such as SERS.…”

Section: Introductionmentioning

confidence: 99%

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Shedding Light on the Trehalose‐Enabled Mucopermeation of Nanoparticles with Label‐Free Raman Spectroscopy

Siddhanta

Bhattacharjee

Harrison

et al. 2019

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Nanoparticle‐based drug delivery systems have attracted significant interest owing to their promise as tunable platforms that offer improved intracellular release of cargo therapeutics. However, significant challenges remain in maintaining the physiological stability of the mucosal matrix due to the nanoparticle‐induced reduction in the matrix diffusivity and promotion of mucin aggregation. Such aggregation also adversely impacts the permeability of the nanoparticles, and thus, diminishes the efficacy of nanoparticle‐based formulations. Here, an entirely complementary approach is proposed to the existing nanoparticle functionalization methods to address these challenges by using trehalose, a naturally occurring disaccharide that offers exceptional protein stabilization. Plasmon‐enhanced Raman spectroscopy and far‐red fluorescence emission of the plasmonic silver nanoparticulate clusters are harnessed to create a unique dual‐functional, aggregating, and imaging agent that obviates the need of an additional reporter to investigate mucus–nanoparticle interactions. These spectroscopy‐based density mapping tools uncover the mechanism of mucus–nanoparticle interactions and establish the protective role of trehalose microenvironment in minimizing the nanoparticle aggregation. Thus, in contrast to the prevailing belief, these results demonstrate that nonfunctionalized nanoparticles may rapidly penetrate through mucus barriers, and by leveraging the bioprotectant attributes of trehalose, an in vivo milieu for efficient mucosal drug delivery can be generated.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Shedding Light on the Trehalose‐Enabled Mucopermeation of Nanoparticles with Label‐Free Raman Spectroscopy

Siddhanta

Bhattacharjee

Harrison

et al. 2019

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“…Similar, although less pronounced solubility problems were already observed with the original CPDs 2 at high concentrations, particularly in conjugation with some but not all proteins. To increase solubility of functional systems, PEGylation and the attachment of trehalose have received much attention. Glycosylation with other carbohydrates such as glucose and galactose has been successful as well, although direct applications to CPPs are remarkably rare and fully developped only recently in a breakthrough report from the Deming group .…”

Section: Introductionmentioning

confidence: 99%

Glycosylated Cell‐Penetrating Poly(disulfide)s: Multifunctional Cellular Uptake at High Solubility

Morelli

Bartolami

Sakai

et al. 2018

Helvetica Chimica Acta

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In memory of Ronald BreslowThe glycosylation of cell-penetrating poly(disulfide)s (CPDs) is introduced to increase the solubility of classical CPDs and to achieve multifunctional cellular uptake. With the recently developed sidechain engineering, CPDs decorated with a-D-glucose (Glu), b-D-galactose (Gal), D-trehalose (Tre), and triethyleneglycol (TEG) were readily accessible. Confocal laser scanning microscopy images of HeLa Kyoto cells incubated with the new CPDs at 2.5 lM revealed efficient uptake into cytosol and nucleoli of all glycosylated CPDs, whereas the original CPDs and TEGylated CPDs showed much precipitation into fluorescent aggregates at these high concentrations. Flow cytometry analysis identified Glu-CPDs as most active, closely followed by Gal-CPDs and Tre-CPDs, and all clearly more active than nonglycosylated CPDs. In the MTT assay, all glyco-CPDs were non-toxic at concentrations as high as 2.5 lM. Consistent with thiol-mediated uptake, glycosylated CPDs remained dependent on thiols on the cell surface for dynamic covalent exchange, their removal with Ellman's reagent DTNB efficiently inhibited uptake. Multifunctionality was demonstrated by inhibition of Glu-CPDs with D-glucose (IC 50 ca. 20 mM). Insensitivity toward L-glucose and D-galactose and insensitivity of conventional CPDs toward D-glucose supported that glucose-mediated uptake of the multifunctional Glu-CPDs involves selective recognition by glucose receptors at the cell surface. Weaker but significant sensitivity of Gal-CPDs toward D-galactose but not D-glucose was noted (IC 50 ca. 110 mM). Biotinylation of Glu-CPDs resulted in the efficient delivery of streptavidin together with a fluorescent model substrate. Protein delivery with Glu-CPDs was more efficient than with conventional CPDs and remained sensitive to DTNB and D-glucose, i.e., multifunctional.

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“…High levels of intra‐ and extracellular trehalose enable these organisms to better survive environmental stresses, including cold, heat, desiccation, and reactive oxygen species . Although the mechanisms by which trehalose protects these organisms from damage have not been fully elucidated, it is hypothesized that this disaccharide partially replaces the shell of water around cellular components, including proteins and lipid membranes . In doing so, trehalose helps maintain membrane integrity and protein structure; the sugar also forms a stable glass (a liquid of high viscosity) at room temperature; thus reducing the rates of damaging biochemical reactions .…”

Section: Introductionmentioning

confidence: 99%

“…Although the mechanisms by which trehalose protects these organisms from damage have not been fully elucidated, it is hypothesized that this disaccharide partially replaces the shell of water around cellular components, including proteins and lipid membranes . In doing so, trehalose helps maintain membrane integrity and protein structure; the sugar also forms a stable glass (a liquid of high viscosity) at room temperature; thus reducing the rates of damaging biochemical reactions . The protective properties of trehalose and its lack of cellular toxicity have generated interest in its use as a general cellular protectant for mammalian cells exposed to stressful conditions …”

Section: Introductionmentioning

confidence: 99%

Esterified Trehalose Analogues Protect Mammalian Cells from Heat Shock

et al. 2017

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Trehalose is a disaccharide produced by many organisms to better enable them to survive environmental stresses, including heat, cold, desiccation, and reactive oxygen species. Mammalian cells do not naturally biosynthesize trehalose; however, when introduced into mammalian cells, trehalose provides protection from damage associated with freezing and drying. One of the major difficulties in using trehalose as a cellular protectant for mammalian cells is the delivery of this disaccharide into the intracellular environment; mammalian cell membranes are impermeable to the hydrophilic sugar trehalose. A panel of cell-permeable trehalose analogues, in which the hydrophilic hydroxyl groups of trehalose are masked as esters, have been synthesized and the ability of these analogues to load trehalose into mammalian cells has been evaluated. Two of these analogues deliver millimolar concentrations of free trehalose into a variety of mammalian cells. Critically, Jurkat cells incubated with these analogues show improved survival after heat shock, relative to untreated Jurkat cells. The method reported herein thus paves the way for the use of esterified analogues of trehalose as a facile means to deliver high concentrations of trehalose into mammalian cells for use as a cellular protectant.

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Revealing the trehalose mediated inhibition of protein aggregation through lysozyme–silver nanoparticle interaction

Cited by 29 publications

References 49 publications

Shedding Light on the Trehalose‐Enabled Mucopermeation of Nanoparticles with Label‐Free Raman Spectroscopy

Shedding Light on the Trehalose‐Enabled Mucopermeation of Nanoparticles with Label‐Free Raman Spectroscopy

Glycosylated Cell‐Penetrating Poly(disulfide)s: Multifunctional Cellular Uptake at High Solubility

Esterified Trehalose Analogues Protect Mammalian Cells from Heat Shock

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