An Aromatic Micelle-Based Saccharide Cluster with Changeable Fluorescent Color and its Protein Interactions

Article abstract of DOI:10.1002/anie.202102547

To develop a new type of synthetic saccharide clusters with changeable fluorescent colors, we herein designed a multisaccharide-coated aromatic micelle. The new cluster forms in water through the quantitative assembly of bent polyaromatic amphiphiles bearing three mannose groups. The spherical assembly, with a 2 nm-sized polyaromatic core and ca. 18 saccharide pendants, is stable even under high dilution conditions (up to 0.02 mM). The emission intensity and color of the saccharide cluster can be altered from moderate blue (Φ_F=19 %) to strong red, orange, and green (Φ_F up to 67 %) upon encapsulation of hydrophobic fluorescent dyes in water. Moreover, the present fluorescent clusters, both with and without the dyes, display selective interactions with mannose-binding proteins in vitro.

Full text of DOI:10.1002/anie.202102547

Angewandte
Communications
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How to cite:
International Edition: doi.org/10.1002/anie.202102547
German Edition: doi.org/10.1002/ange.202102547
Saccharide Clusters
An Aromatic Micelle-Based Saccharide Cluster with Changeable
Fluorescent Color and its Protein Interactions
Haruna Narita, Lorenzo Catti, and Michito Yoshizawa*
Abstract: To develop a new type of synthetic saccharide
clusters with changeable fluorescent colors, we herein designed
a multisaccharide-coated aromatic micelle. The new cluster
forms in water through the quantitative assembly of bent
polyaromatic amphiphiles bearing three mannose groups. The
spherical assembly, with a 2 nm-sized polyaromatic core and
ca. 18 saccharide pendants, is stable even under high dilution
conditions (up to 0.02 mM). The emission intensity and color
of the saccharide cluster can be altered from moderate blue
(FF = 19%) to strong red, orange, and green (FF up to 67%)
upon encapsulation of hydrophobic fluorescent dyes in water.
Moreover, the present fluorescent clusters, both with and
without the dyes, display selective interactions with mannose-
binding proteins in vitro.
S
accharide clusters are essential bioarchitectures capable of
interacting with protein surfaces with high specificity.[1,2] The
majority of natural clusters possess relatively large and
complex multisaccharide frameworks so that their total
syntheses remain difficult. From the viewpoints of basic
biochemical research and medical applications, several types
of synthetic saccharide clusters have been developed, such as
(i) covalent dendrimer-shaped and macrocycle-based clus-
ters,[3,4] (ii) metal nanoparticle-based clusters,[5] (iii) non-
covalent micellar and vesicle-like clusters,[6,7] and (iv) metal-
organic framework (MOF)-type clusters (Figure 1a–d).[8] The
attachment and incorporation of fluorophores within the
clusters have been demonstrated to provide clusters with
photofunctions.[9] However, both covalent as well as non-
covalent saccharide clusters displaying high emissivity with
various emission colors are scarcely reported so far, owing to
aggregation-caused quenching (ACQ) or the heavy metal
effect.[10] Highly photofunctional and selectively biointerac-
tive clusters would be valuable tools for the non-covalent
labeling of proteins and cell-surfaces under fluorescent
microscopy, and potentially useful as sensors for specific
proteins.
Figure 1. a) Dendrimer-shaped, b) metal nanoparticle-based, c) micel-
lar, and d) MOF-type saccharide clusters, and e) a new saccharide
cluster based on an aromatic micelle. f) Bent amphiphile MA with
mannose groups, designed herein, and AA and SA reported previously.
g) Optimized structure of MA.
For the design of a novel saccharide cluster with strong
and changeable fluorescent color, we took inspiration from an
aromatic micelle, composed of bent polyaromatic amphi-
philes AA with hydrophilic ammonium groups on the convex
side (Figure 1 f).[11] The rational replacement of the two ionic
substituents with three monosaccharide groups generates an
aqueous multisaccharide-coated aromatic micelle possessing
a polyaromatic cavity (Figure 1e), yielding a novel saccharide
cluster with the desired photofunctions. This marks the first
synthetic success to decorate aromatic micelles with biofunc-
tional groups and the first elucidation of their interactions
with proteins in vitro, as part of our ongoing efforts towards
biocompatible nanocontainers.[12]
Here we report the synthesis of bent polyaromatic am-
phiphile MA with three mannose-based pendants (Fig-
ure 1 f,g) and the quantitative formation of new multiman-
nose-coated aromatic micelle (MA)n in water. The present
saccharide cluster displays the following five features: 1) the
spherical polyaromatic core (ca. 2 nm in diameter) is sur-
rounded by ca. 18 mannose groups; 2) the self-assembled
structure is stable enough under high dilution conditions (up
to 0.02 mM based on MA); 3) cluster (MA)n emits blue
fluorescence with moderate quantum yield (FF = 19%); 4)
the emission color can be altered to strong red, orange, and
green (FF = 41–67%) upon encapsulation of fluorescent dyes
[*] H. Narita, Prof. Dr. M. Yoshizawa
Laboratory for Chemistry and Life Science, Institute of Innovative
Research, Tokyo Institute of Technology
4259 Nagatsuta, Midori-ku, Yokohama 226-8503 (Japan)
E-mail: yoshizawa.m.ac@m.titech.ac.jp
Dr. L. Catti
WPI Nano Life Science Institute, Kanazawa University
Kakuma-machi, Kanazawa 920-1192 (Japan)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202102547.
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(e.g., squaraines, rubrene, and coumarins), without typical
covalent functionalization; 5) selective interactions are found
between mannose-binding proteins (i.e., concanavalin A) and
the clusters with/without fluorescent dyes.
stacked polyaromatic core of (MA)6 is thoroughly coated by
18 mannose-based pendants.
Spectroscopic analyses of (MA)n revealed its moderate
emissivity and relatively high stability against low concen-
tration. The UV/Vis absorption bands of (MA)n in H2O were
slightly red-shifted (Dlmax =+ 5 nm) relative to those of MA
in CH3OH, implying anthracene-based p-stacking interac-
tions (Figure 3a). The emission bands of (MA)n were
Mannose-attached amphiphile MAwas synthesized in two
steps from our bent building block[12] and the quantitative
formation of mannose cluster (MA)n in water was revealed by
NMR, DLS, and AFM analyses. Etherification of 1,5-di(9-
anthryl)-2,3,4-trihydroxybenzene with a tetra-O-acetylman-
nose derivative (39% yield) and subsequent deprotection
(84% yield) gave rise to MA.[13,14] Stirring a suspension of
MA (0.4 mg, 0.4 mmol) in D2O (0.4 mL) at 1008C for 30 min
resulted in a clear, colorless solution including cluster (MA)n.
1
Whereas the H NMR spectrum of MA in CD3OD showed
five sharp aromatic signals and complicated mannose signals
in the ranges of 8.5–6.9 and 4.9–3.0 ppm, respectively, that of
the product in D2O was extremely broadened (Figure 2a,b).
The broad signals sharpen at elevated temperatures (e.g.,
608C, Figure 2c), suggesting that the motion of the polyar-
omatic panels of MA is restricted in the assembled state on
the NMR timescale.[15] The selective formation of well-
defined cluster (MA)n (n = ca. 6) was confirmed by particle
size analyses. The DLS chart of (MA)n in water indicated the
formation of small particles with an average polyaromatic-
core diameter of ca. 2 nm (Figure 2d). The AFM image of
(MA)n on mica displayed the presence of spherical particles
with an average outer shell diameter of 2.6 Æ 0.6 nm (Fig-
ure 2e,f). Molecular modeling studies suggested the dominant
formation of a spherical hexamer of MA (Figure 2g), whose
core and outer diameters (i.e., 1.9 and 3.1 nm) are comparable
to those of the DLS and AFM data, respectively. The partially
Figure 3. a) UV/Vis spectra (r.t., 0.1 mM based on MA) of (MA)n in
H2O and MA in CH3OH and, b) their fluorescence spectra
(lex =366 nm). c) Fluorescence quantum yields (r.t., lex =366 nm) of
MA, AA, and SA in the monomeric (CH3OH, 0.1 mM) and micellar
states (H2O, 0.1 or 1.0 mM based on the monomers).
observed at lmax = 435 nm with apparent red-shifts (Dlmax
=
+ 17 nm) and broadening, as compared with those of MA
(Figure 3b).[16] The fluorescent quantum yields (FF) of (MA)n
and MA were estimated to be 19 and 41%, respectively
(Figure 3c). Notably, the FF of (MA)n is 5- and 19-times
higher than that of analogous micelles (AA)n and (SA)n with
ionic substituents, respectively (Figure 3c).[13] The observed,
enhanced emission of (MA)n most probably stems from
restricted p-stacking interactions between the polyaromatic
panels,[17] owing to the sterically hindered saccharide groups.
The concentration-dependent emission study in water indi-
cated the critical micelle concentration (CMC) of MA being
0.02 mM (Figure S23), which is ca. 50 times smaller than that
of (AA)n.[11] The observed, increased stability of (MA)n
against dilution is derived from the non-repulsive, nonionic
hydrophilic groups.
Emission color and intensity of (MA)n could be altered
upon encapsulation of various water-insoluble fluorescent
dyes, through mainly the hydrophobic effect in water. Such
facile, non-covalent modifications have been rarely demon-
strated with the previous covalent and non-covalent clus-
ters.[9] For instance, red-fluorescent saccharide clusters were
facilely prepared employing hydrophobic squaraine dye Squ
and dicyanomethylenepyran dye DCM. When a mixture of
MA (0.2 mg, 0.2 mmol) and Squ (0.01 equiv) was manually
ground for 1 min, followed by sequential water addition
(2.0 mL), centrifugation, and filtration, a clear aqueous
solution of (MA)n·(Squ)m in pale blue was obtained (Fig-
ure 4a,b).[18] The host–guest structure was confirmed by the
UV/Vis spectrum, where a new absorption band derived from
encapsulated (Squ)m was observed at 684 nm (Figure 4c). The
DLS analysis indicated the selective formation of small
particles with a core diameter of 2.1 nm, implying the
presence of (MA)6·Squ (Figure S28 and S29).
Figure 2. 1H NMR spectra (500 MHz, 1.0 mM based on MA) of a) MA
in CD3OD and b) (MA)n in D2O at r.t., and c) (MA)n in D2O at 608C.
d) DLS chart (r.t., H2O, 0.1 mM based on MA) of (MA)n. e) AFM
image (r.t., dry, mica) of (MA)n and f) the selected height profiles.
g) An optimized structure of (MA)6.
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irradiation at 500 nm (Figure 4c,d). The nonionic and steri-
cally demanding features of the hydrophilic substituents
effectively enhanced emissivity of the present multisacchar-
ide-coated host–guest complexes, via the suppression of usual
ACQ, found in micelles (AA)n and (SDS)n (Figure 4e).
In the same way, strong orange and green fluorescent
clusters were also obtained in water by the treatment of
(MA)n with rubrene (Rub) and coumarin 7 (C7), respectively.
The obtained, pale red solution of (MA)n·(Rub)m displayed
broad absorption bands in the range of 430 to 580 nm and
fluorescence bands at lmax = 558 nm with high quantum yield
(FF = 62%), corresponding to the encapsulated (Rub)m (Fig-
ure 4g,h). Interestingly, the encapsulation efficiency and FF
of (MA)n·(Rub)m are 2.0- and 6.1-times higher than those of
(AA)n·(Rub)m under the same conditions.[18] Complex
(MA)n·(C7)m emitted green fluorescence with good quantum
yield (FF = 44%, respectively; Figure 4e,h). The orange and
green emissions were quantified by the CIE diagram (Fig-
ure 4 f).
Finally, multimannose cluster (MA)n and its host–guest
complex exhibited selective interaction abilities toward the
outer surface of a mannose-binding protein, concanavalin A
(ConA),[19] in water at room temperature. The multipoint
surface-surface interactions can be visualized through aggre-
gation-based colloid formation.[9] When an aqueous solution
of (MA)n (1.0 mL; 0.1 mM based on MA) was added to
a clear solution of ConA (2.0 mL; 0.5 mM) in HEPES buffer,
the resultant solution gradually became opaque, suggesting
the formation of colloidal aggregates comprising the proteins
and clusters, monitored by UV/Vis turbidity analysis (Fig-
ure 5a).[13] Upon addition of excess a-methyl mannopyrano-
side (MM) as an inhibitor, the opaque solution turned clear
due to the dissociation of the aggregates, indicating the
surface-surface interactions between (MA)n and (ConA)p.
The exterior mannose groups of (MA)n are essential for the
interactions and accordingly analogue (AA)n showed no
Figure 4. a) Preparation of clusters (MA)n·(dye)m with various emission
colors, through (i) grinding, (ii) water addition, (iii) centrifugation, and
(iv) filtration. b) Fluorescence dyes studied herein. c) UV/Vis spectra
(H2O, r.t., 0.1 mM based on MA) of (MA)n and (MA)n·(DCM or Squ)m,
and d) their fluorescence spectra (lex =366, 500, and 680 nm, respec-
tively). e) Fluorescence quantum yields (H2O, r.t., 0.1 or 1.0 mM based
on the monomers) of (MA)n, (AA)n, and (SDS)n including Squ, Rub,
and C7 dyes. f) CIE chromaticity diagram of (MA)n·(dye)m. g) UV/Vis
spectra (H2O, r.t., 0.1 mM based on MA) of (MA)n·(Rub or C7)m and
h) their fluorescence spectra (lex =465 and 440 nm, respectively).
Complex (MA)n·(Squ)m exhibited strong red emission
(FF = 41%) with a sharp band (lmax = 702 nm) upon irradi-
ation at 680 nm (Figure 4d). In contrast, host–guest com-
plexes (AA)n·(Squ)m and (SDS)n·(Squ)m,[13] prepared by the
same protocol using amphiphiles AA or SDS and Squ,
showed weak emission (FF = 7 and 0.1%, respectively;
Figure 4e). Therefore, the facile preparation and intense
emission of new fluorescent saccharide clusters were simulta-
neously accomplished by the present system. The CIE
chromaticity diagram clarified the distinct change in the
emission color of (MA)n from blue (x, y = 0.16, 0.12) to red (x,
y = 0.74, 0.27) upon encapsulation of Squ (Figure 4 f). Stron-
ger red emission (lmax = 617 nm, FF = 55%) was generated
from an aqueous pale red solution of (MA)n·(DCM)m,
prepared from MA and DCM by the grinding method, upon
Figure 5. Turbidity measurements (H2O, r.t., HEPES buffer,
ldet. =366 nm) of a) ConA after addition of (MA)n (0.1 mM based on
MA) and b) PNA after addition of (MA)n (0.2 mM based on MA).
Inhibitor MM or D-(+)-galactose was added to the mixtures at 15 min.
Fluorescence spectra (H2O, r.t., lex =366 or 465 nm) and photographs
(lex =365 or 470 nm) of cluster-protein complexes c) (MA)n·(ConA)p
and d) [(MA)n·(Rub)m]·(ConA)p.
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aggregate formation (Figure S35).[20] In addition, no protein-
cluster interaction was observed by the treatment of (MA)n
(0.2 mM based on MA) with a galactose-binding protein
(PNA)[19] under similar conditions, even when using twice the
amount of (MA)n (Figure 5b).
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More importantly, the selective protein-cluster interac-
tions were also detected with different fluorescence colors in
water. Dissolved white aggregates (MA)n·(ConA)p, collected
from the mixed solution of (MA)n and ConA in buffer,[20]
displayed visible blue emission (lmax = 433 nm) in water
(Figure 5c). Taking advantage of the easy preparation and
high stability of the multimannose-coated host–guest com-
plexes, in the same way, orange emission (lmax = 557 nm) was
detected from pale red aggregates, obtained from host–guest
complex (MA)n·(Rub)m with ConA, in water (Figure 5d).
In conclusion, we have developed a new type of a synthetic
saccharide cluster with changeable fluorescent colors, on the
basis of an aromatic micelle. In water, bent polyaromatic
amphiphiles bearing three mannose groups quantitatively
assembled into a spherical cluster with a 2 nm-sized polyar-
omatic core surrounded by ca. 18 saccharide pendants, as
confirmed by NMR, DLS, and AFM analyses. The relatively
stable cluster could alter its emissivity from moderate blue to
strong red, orange, and green (FF up to 67%) upon simple
encapsulation of fluorescent dyes, without additional multi-
step and time-consuming synthetic procedures as well as
typical aggregation-caused quenching. Furthermore, the
studies on cluster-protein interactions revealed that the
multimannose cluster can selectively bind to mannose-bind-
ing proteins, which was detected by turbidity and fluorescence
(two emission colors) analyses. As a future perspective, the
present “aromatic micelle”-based system would facilitate the
straightforward construction of a new library of multisacchar-
ide clusters by variation of the (i) saccharide pendants, (ii)
polyaromatic core frameworks,[21] and (iii) fluorescent/phos-
phorescent guests, for made-to-order bioapplications (e.g., in
vitro biosensors and bioimaging tags).
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[13] See the Supporting Information. (SDS)n is a typical aliphatic
micelle composed of sodium dodecyl sulfate (SDS) amphiphiles.
[14] We also synthesized an analogue of MA bearing two mannose
groups, which shows poor solubility in water (Figure S13–15).[13]
[15] The DOSY NMR spectrum of (MA)n (1.0 mM based on MA) in
D2O at 608C showed a single band at a diffusion coefficient (D)
of 3.8 ꢄ 10À10 m2 sÀ1 (Figure S17 and S18), which indicates the
thermal stability of the self-assembled structure (2.3 nm in
average diameter).
Acknowledgements
This work was supported by JSPS KAKENHI (Grant No.
JP18H01990 and JP19H04566) and “Support for Tokyo Tech
Advanced Researchers (STAR)”. L.C. thanks the JSPS and
Humboldt Postdoctoral Fellowship.
Conflict of interest
The authors declare no conflict of interest.
[16] The emission lifetime analysis of MA in CH3OH and (MA)n in
H2O suggested the presence of shorter (6.5 ns) and longer
lifetime species (5.1, 17.3, and 46.5 ns), respectively (Fig-
ure S22b).
Keywords: aromatic micelle · encapsulation · fluorescent color ·
host–guest complex · saccharide cluster
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high kinetic barrier of hydrophobic guest incorporation into the
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tightly self-assembled host framework surrounded by multiple
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[20] a) No interaction of ConA with monomeric MA (0.1 mM) was
detected under similar conditions (Figure S35f); b) The self-
assembled structure of (AA)n is stable at low concentration
(0.1 mM based on AA) in the present buffer solution, as
confirmed by the NMR and fluorescence analyses (Figure S37);
c) According to UV/Vis analysis, 54% of initial MA is consumed
for the formation of precipitated aggregate (MA)n·(ConA)p after
standing at room temperature for 4.5 h (Figure S36c).
Manuscript received: February 19, 2021
Revised manuscript received: March 11, 2021
Accepted manuscript online: March 13, 2021
Version of record online: && &&, &&&&
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Communications
Saccharide Clusters
A multisaccharide-coated aromatic
micelle forms in water through quantita-
tive assembly of bent polyaromatic
amphiphiles bearing three mannose
groups. The emission intensity and color
of the saccharide cluster can be altered
from blue to strong red, orange, and
green (FF up to 67%) upon encapsula-
tion of hydrophobic fluorescent dyes.
Moreover, the present fluorescent clus-
ters display selective interactions with
mannose-binding proteins in vitro.
H. Narita, L. Catti,
M. Yoshizawa*
&&&& — &&&&
An Aromatic Micelle-Based Saccharide
Cluster with Changeable Fluorescent
Color and its Protein Interactions
6
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Angew. Chem. Int. Ed. 2021, 60, 1 – 6
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