A sugar-functionalized amphiphilic pillar[5]arene: Synthesis, self-assembly in water, and application in bacterial cell agglutination

Article abstract of DOI:10.1021/ja405237q

A novel sugar-functionalized amphiphilic pillar[5]arene containing galactose groups as the hydrophlic part and alkyl chains as the hydrophobic part was designed and synthesized. It self-assembles in water to produce nanotubes as confirmed by TEM, SEM, and fluorescence microscopy. These nanotubes, showing low toxicity to both cancer and normal cells, can be utilized as excellent cell glues to agglutinate E. coli. The existence of galactoses on these nanotubes provides multivalent ligands that have high affinity for carbohydrate receptors on E. coli.

Full text of DOI:10.1021/ja405237q

Communication
pubs.acs.org/JACS
A Sugar-Functionalized Amphiphilic Pillar[5]arene: Synthesis, Self-
Assembly in Water, and Application in Bacterial Cell Agglutination
Guocan Yu,† Yingjie Ma,† Chengyou Han,† Yong Yao,† Guping Tang,§ Zhengwei Mao,‡ Changyou Gao,‡
and Feihe Huang*,†
‡
†Department of Chemistry and Department of Polymer Science and Engineering, MOE Key Laboratory of Macromolecular
Synthesis and Functionalization, Zhejiang University, Hangzhou 310027, P. R. China
§Department of Chemistry, Institute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University, Hangzhou 310027, P.
R. China
S
* Supporting Information
or spacer groups, which play decisive roles in carbohydrate−
protein interactions.6
ABSTRACT: A novel sugar-functionalized amphiphilic
Pillararenes, mainly including pillar[5]arenes7 and pillar[6]-
pillar[5]arene containing galactose groups as the hydro-
arenes,8 are linked by methylene (−CH2−) bridges at para-
phlic part and alkyl chains as the hydrophobic part was
designed and synthesized. It self-assembles in water to
positions of 2,5-dialkoxybenzene rings, forming a unique rigid
produce nanotubes as confirmed by TEM, SEM, and
pillar architecture, which is different from the basket-shaped
fluorescence microscopy. These nanotubes, showing low
structure of meta-bridged calixarenes. The unique symmetrical
toxicity to both cancer and normal cells, can be utilized as
structure and easy functionalization of pillararenes have afforded
excellent cell glues to agglutinate E. coli. The existence of
them outstanding abilities to selectively bind different kinds of
galactoses on these nanotubes provides multivalent ligands
guests and provided a useful platform for the construction of
that have high affinity for carbohydrate receptors on E. coli.
various interesting supramolecular systems, including cyclic
dimers,9 chemosensors,10 supramolecular polymers,11 liquid
crystals,12 and transmembrane channels.13 However, the
onsiderable attention has been devoted to understanding
application of pillararenes in biologically relevant fields has not
C
and mimicking bacterial adhesion-specific interactions for
been reported.
various purposes, such as pathogen detection and the inhibition
of bacterial infections via the chemotactic responses of bacteria
toward the corresponding ligands.1 Generally, pathogens bind to
carbohydrates existing on the host cells they infect. Carbohy-
drate−protein interactions typically exhibit high specificity and
weak affinities toward the corresponding ligands or receptors,
always in the millimolar range.2 In order to produce
glycotherapeutics and diagnostic tools for antimicrobial therapy,
targeted drug delivery and cell imaging, multivalency or cluster-
glycoside effects are particularly well-documented to effectively
enhance the affinity and selectivity in carbohydrate−protein
interactions.3 In most cases, chemists have linked synthetic
oligosaccharides to multivalent scaffolds (ranging from peptides,
polymers, oligonucleotides, fullerenes, and calixarenes to
dendrimers, nanoparticles, and arrays)4 through suitable “spacer”
molecules to overcome the low binding affinities of monovalent
glycosides.
Herein, we report the design and synthesis of a novel sugar-
functionalized amphiphilic pillar[5]arene P1 (Figure 1a) via the
copper(I)-catalyzed alkyne−azide 1,3-dipolar cycloaddition
(CuAAC) reaction (Scheme S2). Biocompatible galactoses
were introduced as the hydrophilic part to endow the amphiphile
excellent biological functions. Nanotubes were obtained by
allowing an aqueous solution of P1 to stand ∼1 week, driven by
van der Waals (vdW) interactions between the alkyl chains on
the hydrophobic side and the intermolecular hydrogen bonds
between the hydroxyls on the galactoses (Figure 1b). These
nanotubes were utilized as excellent cell glues to agglutinate and
inhibit the motility of pathogenic cells E. coli. The agglutination
ability of the nanotubes was much higher than those of model
compounds (MC1 and MC2) and the parent water-soluble
macrocyclic host P2 (Figure 1a).
The critical aggregation concentration (CAC) of P1 in water
was calculated to be ∼2.48 × 10−5 M by plotting the surface
tension (γ) of the solution as a function of the concentration of
P1 (Figure S31). Similarly, the CAC value of the amphiphilic
compound MC1 was also obtained (1.01 × 10−5 M). However,
the γ values of the solutions of P2 and MC2 remained almost
unchanged at different concentrations, indicating that nano-
structures did not form from them due to their excellent
solubility in water (Figure S31).
However, contrary to the synthetic routines of oligonucleo-
tides and peptides, the preparation of such complex
glycomaterials can not be approached by any generalized
protocols, and each target molecule represents an individual
and challenging research project. Supramolecular self-assembly
mediated by noncovalent forces,5 such as hydrogen bonding and
hydrophobic, π−π stacking, electrostatic, and charge-transfer
interactions, is an effective approach to construct desired
architectures containing multivalent ligands, which can greatly
reduce the need for tedious chemical syntheses. More
importantly, the sizes, shapes, and functions of the self-
assemblies can be easily controlled by changing the functional
Received: May 24, 2013
Published: June 24, 2013
© 2013 American Chemical Society
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Communication
2b). Then, DLS, SEM, and TEM were employed to investigate
the self-assembly of the macrocyclic amphiphile P1. As shown in
Figure 2c, when P1 was dissolved in water with a concentration
of 5.0 × 10−5 M, which was higher than its CAC value, vesicles
with the average diameter of ∼150 nm were observed. The
thickness of the vesicles was calculated to be ∼6.7 nm (Figure
2d). Notably, the extended length of the P1 is ∼3.2 nm (Figure
S32), close to half the thickness of the vesicles, indicating P1 self-
assembled into vesicles in a bilayer packing mode. Moreover,
calcein could be wrapped up by the vesicles (Figure S34c),
confirming that the vesicles were hollow. As shown by DLS
investigation, the main diameter distribution of the vesicles was
∼170 nm (Figure S35b), in agreement with the TEM images in
Figure 2c,d. It should be pointed out that the diameter of the
vesicles measured by DLS was a little larger than that obtained
from the TEM images, attributable to swelling of the spherical
structures in water.5i,k
Notably, black floccules were clearly observed in an aqueous
solution of P1 after 1 week (Figure S36b) and became larger as
the standing time increased. The aggregation behavior of P1 in
water as a function of time was investigated by UV−vis
spectroscopy (Figure S36). The peak at ∼285 nm ascribed to
the characteristic absorbance of P1 decreased due to the
formation of floccules. On the contrary, almost no changes
were observed in the UV−vis spectra corresponding to the
absorption of MC1 even after 2 weeks (Figure S37), indicating
that the pillar[5]arene frame plays an important role in the self-
assembly process of P1. The morphology of the floccules
displayed by the TEM images was regular nanotubes 100−200
nm in diameter and several micrometers in length (Figure 2e−g).
The coexistence of vesicles and short nanotubes could also be
observed after standing the solution for 4 days (Figure S34d),
demonstrating the gradual transformation from vesicles to
nanotubes by increasing the standing time. The thickness of
the nanotubes was ∼30 nm (Figures 2g and S34f), indicating a
multiple-layer structure of the nanotubes (Figure 1b). SEM was
also utilized to confirm the tubular structure of the self-
assemblies (Figure 2h), which was consistent with the TEM
results. In order to further demonstrate the successful trans-
formation from the vesicles to the nanotubes, pyrene was used as
a probe to penetrate into the hydrophobic region in the wall of
the nanotubes composed of alkyl chains through hydrophobic
interactions. As shown in Figure 2i, tubular assemblies formed by
P1 could be clearly seen, which certified the existence of
nanotubes.
Figure 1. (a) Synthetic route to the macrocyclic amphiphile (P1) and
chemical structures of the macrocyclic host (P2) and model compounds
(MC1 and MC2). (b) Schematic representation of the self-assembly
process of P1.
For comparison, the self-assembly behavior of amphiphilic
noncyclic monomeric analogue MC1 in water was investigated
first. Vesicles with the average diameter ∼120 nm were observed
in TEM image (Figure 2a), which was confirmed by a dynamic
light scattering (DLS) experiment (Figure S35a). It should be
noted that the vesicles formed by MC1 were quite stable and did
not transform into other structures even after 2 weeks (Figure
Furthermore, FTIR spectroscopy (Figure S38) was utilized to
provide convincing insights into the interactions between the
macrocyclic amphiphile, which were extremely important for the
self-assembly process. Compared with the spectrum correspond-
ing to the powder form of P1, the absorption of the nanotubes
related to the O−H stretching vibration shifted to lower
wavenumber (from 3390 to 3369 cm−1, Figure S38), in
agreement with the participation of hydrogen bonding in the
aggregation process,14 a key factor in the formation of nanotubes.
On the other hand, the FTIR spectra in Figure S33 showed that
the C−H stretching and rocking bands shifted from 2926, 2855,
and 1234 cm−1 to 2920, 2851, and 1209 cm−1, respectively, after
the formation of nanotubes. This result provided reliable
evidence to confirm effective achievement of vdW interactions
between the alkyl chains in the nanotubes,14 which is another
crucial driving force for the transformation of the vesicles to the
nanotubes and the stabilization of the supramolecular structures.
Figure 2. TEM images: Vesicles formed from MC1 (a) 5 min after it was
poured into water and (b) after standing the solution for 2 weeks (both
scale bars = 200 nm) with an inset showing an enlarged vesicle pointed
out by a purple arrow. (c) Vesicles formed from P1 5 min after it was
poured into water (scale bar = 500 nm). (d) Enlarged image of a vesicle
(scale bar = 100 nm). (e) Nanotubes formed from P1 after standing the
solution for 1 week (scale bar = 5 μm). Enlarged images of (e) with scale
bars = (f) 500 nm and (g) 200 nm. (h) SEM image of the nanotubes
(scale bar = 500 nm). (i) Fluorescence microscopic image of the
nanotubes with pyrene loaded (λx = 360 nm, scale bar = 5 μm). Initial
concentrations of P1 and MC1 were 50 μM.
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It is a spontaneous dynamic process for an amphiphilic
molecule to aggregate in water when the concentration reaches
or exceeds its CAC value.5g Moreover, the microassembled
structures of the aggregates formed by the building blocks are
determined by the curvature of the membrane.5i,k Typically, low
membrane curvature favors forming a vesicular structure, while
high membrane curvature tends to form a nanotubular structure.
In our system, the membrane curvature was enhanced by
introducing a rigid segment into the macrocyclic amphiphile P1,
resulting in the formation of nanotubes.7d This phenomenon was
quite different from the self-assembly behavior of MC1 which
tended to form vesicles, proving that the pentagon-like cyclic
pillar[5]arene structure played a crucial role in the fabrication of
multidimensional self-assemblies and the stability of the
aggregates formed by P1.
In order to apply a compound in biologically relevant fields, its
toxicity should be evaluated. From hematoxylin and eosin
(H&E) staining experiments and 3-(4′,5′-dimethylthiazol-2-yl)-
2,5-diphenyl tetrazolium bromide (MTT) assays (see Figure
S39), MC1, MC2, P1, and P2 showed low toxicity to both cancer
cells (A549, a kind of lung cancer cells) and normal cells
(Chinese hamster lung fibroblast cell), demonstrating that these
compounds could be utilized in biorelated fields.
As mentioned above, cell-surface carbohydrates are exploited
by many pathogens for adherence to tissues and entry into host
cells. The interactions taking place at cell−cell interfaces occur
simultaneously due to multiple binding events which can
effectively amplify affinities relative to interactions that involve
only a single ligand. This effect has led to the development of
multivalent antiadhesive therapeutics against bacteria and
viruses. Recent reports have demonstrated that pathogenic
cells can be agglutinated and that their motilities are inhibited
effectively by multivalent carbohydrate-coated nanofibers.15
In our systems, the multivalent carbohydrate-coated nano-
tubes can be used as cell glues to study cell−cell interactions
because they can accommodate multivalent bindings. As shown
in Figure 3, no clusters of fluorescent bacteria were observed
when E. coli was cultured with MC2 (Figure 3b) and P2 (Figure
3e). The reason was that their solubility was so good that
multivalent ligands which are extremely important for the
agglutination of bacterial cells could not form in water. TEM
(Figure 3c,f) and optical microscopic images (Figure 3a,d) were
also utilized to confirm whether E. coli agglutination was induced
by MC2 or P2. We found that only few E. coli cells contacted with
each other when they were incubated with MC2 or P2, indicating
extremely low agglutination ability of these water-soluble
compounds in the monovalent binding mode. Meanwhile,
clusters of fluorescent bacteria with small sizes could be observed
when E. coli were incubated with MC1 (Figure 3h). TEM
investigations provided convincing evidence for the agglutina-
tion of bacterial cells. As shown in Figure 3i, several E. coli cells
contacted each other, because the galactoses on the outside of the
vesicles provide binding sites for the receptors on E. coli.
Furthermore, vesicles (pointed out by green arrows in Figure 3i)
could be observed on the surfaces, strongly confirming our
hypothesis. Interestingly, clusters of fluorescent bacteria with
relatively large sizes were observed when E. coli was incubated
with the P1-based nanotubes (Figure 3k), indicating strong
interactions between the nanotubes and the pathogenic E. coli
cells. Therefore, these P1-based nanotubes (pointed out by
purple arrows in Figure 3l) could act as excellent cell glues to
agglutinate E. coli, resulting in the formation of fluorescent
bacteria clusters.
Figure 3. Microscopic images of E. coli agglutination incubated with P1,
P2, MC1, and MC2, respectively (50.0 μM): (a) optical microscopic
image (OMI) of MC2; (b) fluorescence microscopic image (FMI) of
MC2; (c) TEM image (TEMI) of MC2; (d) OMI of P2; (e) FMI of P2;
(f) TEMI of P2; (g) OMI of MC1; (h) FMI of MC1; (i) TEMI of MC1;
(j) OMI of P1; (k) FMI of P1; (l) TEMI of P1. For OMI images, scale
bar = 40 μm; for FMI images, λx = 360 nm, scale bar = 40 μm; for TEMI
images, scale bar = 2 μm. (m) Growth curves based on the optical
density at 600 nm for E. coli grown in the presence of P1, P2, MC1, and
MC2. (n) Agglutination index obtained from fluorescence microscopy
and TEM images.
In order to further investigate the agglutination ability of the
nanotubes, spectrophotometric analysis based on optical density
was used to estimate the number of bacteria in liquid culture. As
shown in Figure 3p, normal bacterial growth curves were
observed for MC2 and P2, indicating extremely low agglutina-
tion ability. Compared with MC2 and P2, the agglutination
ability of MC1 was slightly stronger due to the formation of
vesicles decorated by galactoses. More interestingly, we did not
observe an increase in the cell population cultured with the P1-
based nanotubes during our experimental time range, indicating
that the bacteria were completely inhibited by the nanotubes.
The length of the self-assemblies played a key role in the
formation of bacterial clusters and was a crucial factor in
controlling agglutination. For the nanotubes, the lengths can
reach several micrometers, much longer than the average size of
the vesicles formed by MC1, so they can interconnect more
bacteria, resulting in the enhancement of the agglutination
ability.
Moreover, we defined the average number of E. coli cells
contacted with each other from 10 random fields of microscopic
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Nat. Rev. Immunol. 2007, 7, 255. (e) Park, S.; Lee, M.-R.; Shin, I. Chem.
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images as the agglutination index (AI) to examine the abilities of
the model compounds (MC1 and MC2) and the macrocyclic
hosts (P1 and P2) to agglutinate bacterial cells (Figure 3n). A
significant difference between the macrocyclic amphiphile P1
and the other three compounds was observed. The AI value of P1
was calculated to be 54, much higher than those of MC1 (13),
MC2 (3), and P2 (5), in good agreement with the results
obtained from the above-mentioned fluorescence microscopy,
TEM, and spectrophotometric analyses. Clearly, these P1-based
nanotubes exhibited excellent agglutination ability for E. coli.
In summary, we designed a novel sugar-functionalized
amphiphilic pillar[5]arene P1 with galactoses as the hydrophilic
part and alkyl chains as the hydrophobic part. Due to the
existence of intermolecular hydrogen bonds between the
galactoses and the vdW interactions between the alkyl chains,
P1 self-assembled into vesicles in water and gradually trans-
formed into nanotubes after standing for 1 week. The
biocompatible galactoses coating the nanotubes endowed them
with interesting biofunctions, which could act as excellent cell
glues to effectively agglutinate E. coli. Compared with those of
MC2 and P2 which have good solubility in water, the
agglutination ability of the P1-based nanotubes was much higher
due to the existence of multivalent ligands on their surfaces. For
the amphiphilic model compound MC1 self-assembling into
vesicles, its ability to agglutinate E. coli decreased dramatically
due to the dimensional reduction of the aggregates. These results
showed that supramolecular self-assemblies composed of rather
simple ligands driven by noncovalent interactions are distinctive
chemical tools for capturing living bacteria in solution. The
structures, stability, and functions of the supramolecular self-
assemblies can be easily controlled by introducing different
functional groups through click chemistry, which have the
potential to address many biocompatibility-related issues,
opening up an even wider range of bioapplication opportunities
in areas, such as drug delivery, bioconjugation, and specific
recognition.
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ASSOCIATED CONTENT
* Supporting Information
Experimental details and characterization data. These material
■
S
are available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
fhuang@zju.edu.cn
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by National Basic Research Program
(2013CB834502), the National Natural Science Foundation of
China (91027006 and 21125417), and the Fundamental
Research Funds for the Central Universities (2012QNA3013).
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