Mechanochemical Preparation of Stable Sub-100 nm γ-Cyclodextrin:Buckminsterfullerene (C60) Nanoparticles by Electrostatic or Steric Stabilization

Article abstract of DOI:10.1002/chem.201705647

Buckminster fullerene (C₆₀)′s main hurdle to enter the field of biomedicine is its low bioavailability, which results from its extremely low water solubility. A well-known approach to increase the water solubility of C₆₀ is by comple

Full text of DOI:10.1002/chem.201705647

A Journal of
Accepted Article
Title: Mechanochemical preparation of stable sub-100 nm γ-
cyclodextrin:Buckminsterfullerene (C60) nanoparticles by
electrostatic or steric stabilization
Authors: Joachim Van Guyse, Victor R. De la Rosa, and Richard
Hoogenboom
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To be cited as: Chem. Eur. J. 10.1002/chem.201705647
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Mechanochemical preparation of stable sub-100 nm γ-
cyclodextrin:Buckminsterfullerene (C60) nanoparticles by
electrostatic or steric stabilization
Joachim F.R. Van Guyse, Victor R. de la Rosa and Richard Hoogenboom[a]*
identified as toxic due to the remaining organic solvents.[14]
Abstract: Buckminsterfullerene (C60)'s main hurdle to enter the field
of biomedicine is its low bioavailability, which results from its
extremely low water solubility. A well-known approach to increase the
water solubility of C60 is by complexation with γ-cyclodextrins.
However, the formed complexes are not stable in time as they rapidly
aggregate and eventually precipitate due to attractive intermolecular
forces, a common problem in inclusion complexes of cyclodextrins. In
this study we attempt to overcome the attractive intermolecular forces
between the complexes by designing custom γ-cyclodextrin (γCD)-
based supramolecular hosts for C60 that inhibit the aggregation found
in native γCD-C60 complexes. The approach entails the introduction
of either repulsive electrostatic forces or increased steric hindrance to
prevent aggregation, thus enhancing the biomedical application
potential of C60. These modifications have led to new sub-100 nm
nanostructures that show long-term stability in solution.
Another drawback of this method is the decrease of biological
activity with the increasing size of the C60 clusters.[15,16]
Another approach is the exploitation of host-guest chemistry for
the complexation of a hydrophobic guest with a water-soluble host.
Here, cyclodextrins are popular building blocks for the preparation
of supramolecular assemblies and nanoparticles by exploiting
dynamic host-guest interactions.[17–19] The utilization of these
water-soluble hosts, such as calixarenes and cyclodextrins, has
led to the successful solubilization of C60, forming 2:1 water-
soluble host-guest complexes with C60.[20,21] These complexes
retain the intrinsic properties of
C60 while allowing the
incorporation of additional functionalities through the modification
of the host molecule. Cyclodextrins are especially suited for the
complexation of C60, as demonstrated by multiple research
groups, based on the hydrophilicity of these cyclic
oligosaccharides.[20,22–24] Despite their excellent complexation
abilities with hydrophobic guests, native CDs and their inclusion
complexes with C60 are known to rapidly aggregate and often
precipitate in aqueous solution.[25] This tendency to rapidly
aggregate greatly limits their biological application potential, as
Introduction
C
60, an allotropic form of carbon, was first discovered by Kroto et
al.[1,2] in 1985, and its macroscopic production was first realized
by Krätschmer in 1990.[3,4] Ever since, this molecule has been the
subject of extensive research, ranging from astrochemistry to,
more recently, materials science and biomedicine, fields where
biological relevance drops with increasing size of the aggregates
[26,27]
by limiting cellular uptake.
This unwanted aggregation
behavior can be mainly attributed to attractive forces between
individual complexes, as it is well known that cyclodextrins
establish efficient intermolecular hydrogen bonds (see Figure
1).[
C
60 has an enormous application potential.[5–7] In the biomedical
26,28,29]
context, C60 stands out as a powerful antioxidant, i.e. a scavenger
of cytotoxic reactive oxygen species (ROS). Moussa et al.
demonstrated this by administering a C60-olive oil suspension to
rats, which resulted in a pronounced increase in their life span,
implying their potential use as a powerful anti-ageing agent and a
preventative measure for cancer and neurodegenerative
diseases, such as Alzheimer’s.[8] In addition, C60 could also be
used as a photosensitizer, as it generates ROS upon light
irradiation.[9,10] Therefore, C60 could be used in photodynamic
therapy to treat several pathologies, including cancer and
bacterial infections.
Despite C60's large application potential in biomedicine, the
realization thereof is hampered by its negligible water solubility of
1
0-8 ng L .
-1 [11]
To increase C60's water solubility, several
procedures can be applied, one of which is the covalent
modification of C60. However, this can induce toxicity, the loss of
C
60's beneficial intrinsic properties and it is not straightforward due
to lack of stereoselectivity.[12,13] An alternative procedure is based
on the dispersion of C60 in water through co-solvent evaporation,
creating meta-stable C60 clusters. This method has been used in
the past to determine the toxicity of C60, mistakenly being
Figure 1. Schematic representation of the proposed concept used to prevent
aggregation between individual 2:1 γCD-C60 complexes based on electrostatic
(bottom left) and steric (bottom right) stabilization.
[
a]
Supramolecular Chemistry Group, Department of Organic and
Macromolecular Chemistry, Ghent University Krijgslaan 281-S4,
9000 Ghent, Belgium.
E-mail: richard.hoogenboom@UGent.be
Supporting information for this article can be foun under
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In addition, the complexed C60 units are still partially exposed to
the aqueous environment in the γCD-C60 complexes, potentially
inducing hydrophobic interactions that further induce unwanted
aggregation. In an attempt to enhance the stability of γCD-C60
complexes and suppress their natural tendency to aggregate, we
have designed functional γCD hosts aiming to minimize the
attractive intermolecular forces between individual CDs and their
complexes, by the incorporation of repulsive charges or steric
hindrance by polymer chains (Figure 1). The incorporation of
these Coulombic or steric factors is hypothesized to hinder or slow
down the aggregation of the individual CDs and complexes,
leading to more stable complexes.
Results and Discussion
The Coulombic and steric factors anticipated to stabilize the γCD-
C
60 copmlexes were incorporated in γCD by modification of the
Figure 2. Synthesis scheme of the different modified cyclodextrin hosts, by
incorporation of either one or multiple polymer chains or multiple charges.
primary hydroxyl groups, which are the most straigthforward to
chemically modify due to their higher nucleophilicity and
accessability compared to their secondary counterparts.[30]
Moreover, performing the modifications on the primary hydroxyl
groups –cyclodextrin's narrow rim- will have the least impact on
inclusion complex formation, as this occurs at the cyclodextrin's
wide rim side, where the secondary hydroxyl groups, are
located.[31] Additionally, the secondary hydroxyl groups are
important for the structural integrity of cyclodextrins, as they 'lock'
the structure into its shape through intramolecular hydrogen
Once the new γCD hosts were synthesized, the formation of
supramolecular host-guest complexes with C60 was investigated.
In literature two methods are mainly used to form native-γCD-C60
complexes: the first utilizes a two-phase toluene:water system,
which exploits the lower solubility of C60 at higher temperatures in
toluene to displace it into the γCD-containing aqueous phase,
where it then forms complexes with γCD.[20] The second method
circumvents the use of solvents by applying HSVM, using
mechanical forces in a ball mill to yield the γCD-C60 complexes
bonding, thus having a major influence on the molecule's flexibility,
solubility and complexation ability.[30,31]
[
39–
from the solid reagents, followed by their dispersion in water.
4
1]
For our purposes, the second method allows a better
Starting from native γCD, novel γCD hosts for C60 were
synthesized through either selective tosylation of one of the
primary alcohols or iodination of all the primary alcohols. Next, the
azide was easily and almost quantitatively obtained via an S 2
N
substitution with sodium azide. The polymer-bearing γCDs were
comparison between the native and modified γCDs, disregarding
the difference in solubility of the γCD hosts, which could have an
influence on the complexation with C60. Additionally, the HSVM
method is faster, more effective, and does not involve the use of
organic solvents, which is beneficial when considering biomedical
applications. In fact, this method applies some principles of green
chemistry as it avoids the use of solvents, is more energy efficient
and is overall safer.[42–44]
then obtained by copper(I)-catalyzed-azide-alkyne cycloaddition
(
CuAAC) click chemistry between an alkyne-bearing polymer
chain and mono-(6-azido-6-deoxy)- or octakis(6-azido-6-deoxy)-
γCD, yielding products 1 and 3 respectively (Figure 2).
Following the synthesis of the modified γCD hosts, the stability of
these hosts in aqueous solution was evaluated and compared to
native γCD. As can be seen from Figure 3 (top), the freshly
prepared native γCD solution shows a size distribution of less
than 5 nm in the volume plot, which corresponds to the expected
molecularly dissolved CD. However, 5 hours later, the size
distribution looks significantly different, showing micron sized
aggregates in both the intensity and volume plots. This is in
agreement with previous reports stating that native CDs rapidly
aggregate in solution due to the establishment of intermolecular
hydrogen bonds.[26,28,29] The modified γCDs 1-3 show a different
behavior as the size distributions for both intensity and volume
remain relatively unchanged over the course of 24 hours. The
volume plot shows a size distribution around the expected values
for molecularly dissolved hosts, which is larger for the polymer
bearing γCDs.
In addition, this synthetic approach grants easy access to a
charged γCD through Staudinger reduction of the azide groups,
yielding octakis(6-amino-6-deoxy)-γCD, which can then be
converted to its respective water-soluble salt 2 by addition of
hydrochloric acid.
As a stabilizing polymer we chose poly(2-ethyl-2-oxazoline),
which is a biocompatible and water-soluble polymer, easily
functionalized by initiating the cationic ring opening
polymerization with an alkyne bearing initiator,[32] such as
propargyl benzenesulfonate.[33–36] Additionally, these polymers
where chosen as they exhibit excellent chemical and physical
stability, anticipated to lead to good compatibility with the high
speed vibration milling (HSVM) treatment.[37,38]
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The fact that the size distributions (both volume and intensity)
remain unaltered over 24 hours, already indicates the inhibition of
hydrogen bonding induced aggregation between the γCDs by the
presence of either Coulombic or steric repulsion.
Next, the γCD hosts were complexated to C60 to evaluate their
ability to complexate C60 and assess the stability of the formed
complexes. The complexation of C60 with the newly synthesized
γCD hosts 1-3 was performed by HSVM and compared with γCD
as a control. Subsequently, water was added to extract the
complexes after which the solution was filtered to remove any
excess of uncomplexed C60. Next, the formed complexes were
analyzed to quantify the C60-content and assess their size and
stability in solution. C60-content was determined by UV-Vis
spectroscopy, using the Lambert-Beer law to calculate the
concentration from the characteristic absorption band of C60
,
using the known molar extinction coefficient of ε(335nm)= 51900
-1
-1 [45]
M
cm . From the C60 concentration in a 1 mg/mL solution of
each complex, we were able to calculate the weight percentage
of C60, the yield of C60 incorporation in each of the formulations
and the ratio of CD to C60 in the obtained nanoparticle
formulations (Table 1). All hosts display the ability to complexate
C
60 as the UV-vis spectra showed the presence of absorbance
bands related to C60. Table 1 shows that both the native γCD and
the per-amino-γCD 2 have a similar weight percentage of C60
,
while the polymer-bearing γCDs 1 and 3 show a lower weight
percentage. This is a result of the larger molecular weight of the
polymer-bearing hosts compared to the native and per-amino-
γCDs allowing the addition of more CD host to the milling process.
Importantly, when the yields are compared, it can be seen that the
modified hosts lead to more efficient incorporation of C60 than the
native γCD. An increased host/guest ratio is obtained for all hosts
after milling and filtering, which is expected as the non-water
soluble C60 aggregates were removed from solution by filtration.
At this stage it is not yet clear whether the excess of CD is present
in the nanoparticles or is free in solution, but the observed
increase in molar ratio corresponds well to the observed loss of
C60 from the calculated yields.
Table 1. Weight and mol percentages of C60 in the nanoparticles that are
formed with the different hosts.
Host
Molecular
weight Host
Wt%
Yield in %
Molar ratio
CD/C60 in
(Da)
formulation
γCD
1297
11291
1490
5.4
2.6
5.8
1.4
43
79
50
54
9.75
2.38
7.85
2.85
1
2
3
17804
Figure 3. DLS spectra of γ-CD, mono-P(EtOx)100-γCD 1, octakis(6-amino-6-
deoxy)-γCD 2 and octakis-P(EtOx)20-γCD 3 (1mg/mL) from top to bottom. DLS
spectra show the particle size distributions both by intensity (.-.) and volume
Next, the stability of the C60 complexes with the new γCD hosts
was investigated by measuring the evolution of their particle-size
distribution in time by dynamic light scattering (DLS). The
___
(
).
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Figure 4. DLS spectra showing the particle size distribution for native C60-γCD
complexes (1mg/mL) both by intensity (.-.) and volume (___). Bottom plot shows
the size distribution of the time zero sample, the top plot shows the size
distribution for t = 24 hours.
nanoparticles were filtered prior to the first measurement, and
remeasured over the course of two weeks. The results are shown
in Figures 4 and 5.
Figure 4 shows the fast aggregation of the native γCD-C60
complexes: initially, small nanoparticles were observed with a
size of ca. 3 nm, corresponding to the expected 2:1 γCD-C60
complex together with free CD in solution. However, the spectrum
also shows the presence of larger aggregates in the intensity plot,
but the volume plot shows the majority of the complexes are
molecularly dissolved. However 24 hours later, the particle-size
distribution shows a large shift with the mean particle-size
evolving from 3 nm to ca. 200 nm, indicating aggregation due to
attractive intermolecular forces, as was also seen in the solution
of native γCD, this is in agreement with previous reports.[25,26]
Within three days after sample preparation, the formation of a
macroscopic precipitate was observed. Sonication and refiltration
proved ineffective to break the aggregates and the defined
complexes could not be regenerated.
In contrast to these results with native γCD, the modified γCD
hosts showed an entirely different behavior as observed in the
DLS measurements. Instead of obtaining small sub 10 nm
particles, which would correspond to a molecularly dissolved
bicapped 2:1 complex, rather defined nanoparticles with a size of
ca. 50 nm were observed which was later confirmed by
transmission electron microscopy (TEM).
Figure 5. DLS spectra and TEM pictures of mono-P(EtOx)100-γCD-C60
complexes 1 (top), octakis(6-amino-6-deoxy)-γCD-C60 2 (center) and octakis-
P(EtOx)20-γCD-C60 complexes
3 (bottom) (1mg/mL) with their proposed
structures. DLS spectra show the particle size distributions both by intensity (.-.)
and volume (_ ). Bottom plots show the size distribution of the t
__
sample, while
0
the top plots show the size distribution for t = 2 weeks.
These results together with the UV-vis results indicate the
successful complexation of C60 with the modified hosts. However,
the presence of defined nanoparticles rather than discrete 2:1
complexes indicates that additional intermolecular forces are
present and the the absence of a population with small size in
DLS indicates that the excess of γCD is incorporated in the
nanoparticles. Since self-assembly of the modified γCDs does not
interactions that might play a role are Coulombic interactions
between the cationic per-amino-CD 2 and their respective
counterions, or poly(2-oxazoline)-C60 donor and acceptor
interactions with C60 as reported by Kabanov et al.[21]
This controlled assembly towards this nanoparticle structure
seems to be based on a fine balance of forces during the HSVM
occur in absence of the guest, the hydrophobic
C60 is
process. In the native γCD-C60 complexes,
a bicapped
hypothesized to play a major role in the controlled self-assembly,
which is in agreement with a report from Uekama et al.[46,47] As
hypothetically visualized in Figure 5, the further agglomeration of
the γCD-C60 complexes is ascribed to the establishment of
hydrophobic interactions and Van der Waals forces between the
partially exposed C60 guests within the complexes. Additional
molecularly dissolved complex is initially observed, which is
favoured as the secondary hydroxyl groups ‘lock’ the sandwich-
like structure via intermolecular hydrogen bonding. The further
aggregation in time is then caused by the hydrogen bonding via
CD’s primary hydroxyl groups. In the modified hosts, the
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introduction of a repulsive moiety both sterically or Coulombic, is
hypothesized to partially disrupt or weaken the interlocking
mechanism between the 2:1 complexes, resulting in a more
exposed C60. This could make the formed complexes prone to
assemble into the observed nanoparticle structure mainly through
attractive and repulsive forces. We hypothesize that the
introduction of repulsive forces affects the formation of sandwich-
like complexes, thus leaving C60 more exposed and allowing the
strong hydrophobic character of C60 to steer the supramolecular
assembly. Further aggregation of the obtained supramolecular
assembly seems to be inhibited by these repulsive forces,
therefore successfully counteracting the natural tendency of
native cyclodextrins to aggregate, as was confirmed before. The
enhanced stability could be rationalized by a nanoparticle
conformation where the charges and polymers are directed away
from one another, thus minimizing the electrostatic repulsion or
steric hindrance, i.e. maximizing the volume that the polymer
chain(s) can occupy. Therefore, the combination of
supramolecular interactions led to the synthesis of highly stable
nanoparticle solutions that, unlike their native precursors,
remained unchanged for weeks, while maintaining a relatively
high C60-content.
The proposed concept could lead to the design of modified C60
complexes, which are more suitable for biological applications as
they are more stable in solution. In addition, the larger
hydrodynamic volume of these C60 nanoparticles could possibly
result in a beneficial longer retention time in the body and
enhanced uptake in tumors by the EPR effect. Furthermore,
additional functionalities may be added by varying the side chains
and termini of the polymer(s), allowing the incorporation of
specific targeting groups for selective delivery to aid in the
treatment of cancers or neurodegenerative disorders.
hydrophobic interactions from
60
C . Once assembled, the
assembly remains stable in solution, which is hypothesized to be
caused by Coulombic or steric stabilization. Both these repulsive
factors will be mainly projected onto the surface of the assembly
in order to minimize the overall charge or maximize the free
volume that the polymer chains can occupy. The contribution of
the repulsive factors to the stability of the assembly could already
be observed from the stability of the modified hosts themselves
and will also inhibit further aggregation between the separate
nanoparticle assemblies, as could be evidenced from the
absence of change in the DLS size distribution plots over the
course of 2 weeks. Therefore, the stability and assembly of this
system relies on the subtle balance of attractive host-guest and
hydrophobic interactions and repulsive Coulombic or steric
factors, as was achieved before in other dynamic supramolecular
cyclodextrin assemblies.[46–49]
Even though the modified hosts did not lead to the formation of a
stable molecularly dissolved bicapped C60 complex, they were
successful at complexating C60 into nanoparticles and capable of
inhibiting aggregation of the separate assemblies. Furthermore,
the size of the obtained particles is sub-100 nm, which will
influence their cellular uptake pathways and kinetics. Recent
studies on cell internalization show that particles ≤ 200 nm are
internalized via pinocytosis as opposed to unwanted
phagocytosis and ≤100 nm particles show faster uptake than their Experimental Section
[16,27]
larger counterparts.
Therefore, the developed stable C60
nanoparticles will be interesting candidates for further research
with regard to their activity as an antioxidant or photosensitizer,
especially since a recent study suggests that the photosensitizing
properties of C60 depend on its aggregate structure, where
aggregated C60 has a shorter-lived triplet state, leading to
diminished ROS production.[10]
Materials and methods:
Size-exclusion chromatography (SEC) was performed on an Agilent 1260-
series HPLC system equipped with a 1260 online degasser, a 1260 ISO-
pump, a 1260 automatic liquid sampler (ALS), a thermostatted column
compartment (TCC) at 50°C equipped with two PLgel 5 µm mixed-D
columns and a guard column in series, a 1260 diode array detector (DAD)
and a 1260 refractive index detector (RID). The used eluent was N,N-
dimethylacetamide DMA containing 50 mM of LiCl at a flow rate of 0.593
mL/min. The spectra were analyzed using the Agilent Chemstation
software with the GPC add-on. Molar mass and ᴆ values were calculated
against PMMA standards from PSS. UV-VIS spectra were recorded on a
Varian Cary 100 Bio UV-VIS spectrophotometer equipped with a Cary
temperature and stir control. Samples were measured in either quartz or
disposable cuvettes with a pathlength of 1.0 cm in the wavelength range
of 200 to 700 nm. The concentration of each sample was 1.0 mg/mL in
milliQ water. Dynamic light scattering (DLS) and Zeta potential
measurements were executed on a Zetasizer Nano-ZS Malvern apparatus
(Malvern Instruments Ltd.) using disposable cuvettes. The excitation light
source was a He−Ne laser at 633 nm and the intensity of the scattered
light was measured at an angle of 173°. The concentration of each sample
was 1.0 mg/mL in milliQ water. All samples were filtered with a 0.2 µm pore
sized filter prior to measurement. Matrix assisted laser
desorption/ionization time of flight mass spectroscopy (MALDI-TOF MS)
was performed on an Applied Biosystems Voyager De STR MALDI-TOF
mass spectrometer equipped with 2 m linear and 3 m reflector flight tubes,
and a 355 nm Blue Lion Biotech Marathon solid state laser (3.5 ns pulse).
All mass spectra were obtained with an accelerating potential of 20 kV in
positive ion mode and in either reflectron or linear mode. The
Conclusions
In summary, we have explored the inhibition of intermolecular
hydrogen bond driven association/aggregation between
cyclodextrins via the incorporation of charges or steric hindrance.
Both strategies proved to be successful in improving the stability
of γCDs in aqueous solution, as observed from the DLS data.
Next, we studied the influence of these modifications on the
complexation behavior with C60. Here UV-vis data showed the
ability of the modified hosts to interact and solubilize C60 in water.
However, upon characterization of the complexes via DLS and
TEM, well defined nanoparticles were observed rather than
molecularly dissolved 2:1 CD-C60 complexes. Surprisingly, both
the steric and Coulombic systems displayed a similar behavior,
indicating a common driving force in the formation of the
supramolecular assemblies, viz. C60, during HSVM. The formation
towards the observed kinetically trapped supramolecular
assemblies was rationalized and attributed to a balance of
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polymerizations were performed in capped vials in a single mode
microwave Biotage initiator sixty (IR temperature sensor) (Biotage,
Uppsala, Sweden) following a previously reported protocol.[34] Infrared
spectra were measured on a Perkin-Elmer 1600 series FTIR spectrometer
4.5 eq.) was added in small portions over the course of 5 minutes under
vigorous stirring. The mixture was stirred for half an hour at -5°C. Next, the
mixture was filtered and the filtrate was neutralized with hydrochloric acid
(pH range from 5-6). Following the neutralization, the solution was
precipitated in 1L of acetone. This resulted in the co-precipitation of the
starting material and the product. The presence of the starting material did
not entail any issues for the following steps and the product was used as
-
1
and are reported in wavenumber (cm ). ESI-MS spectra were acquired on
a quadrupole ion trap LC mass spectrometer (Thermo Finnigan MAT LCQ
mass spectrometer) equipped with electrospray ionization. Lyophilisation
was performed on a Martin Christ freeze-dryer, model Alpha 2-4 LSC plus.
High Speed Vibration Milling (HSVM) was performed in a Fritsch Mini-Mill
Pulverisette 23 in a 10 mL stainless steel grinding bowl with 15 mm
diameter grinding ball(s). Preparative size exclusion chromatography was
performed with Disposable PD-10 Desalting Columns from GE Healthcare.
Nuclear magnetic resonance spectra ( H and 13C NMR) were recorded on
a Bruker Avance 300 or 400 MHz spectrometer at room temperature. The
chemical shifts are given in parts per million (δ) relative to TMS. The
1
such, correcting for its purity. Yield= 54%, purity= 28% (calculated from H
1
NMR). H NMR (300 MHz, D
2
O): δ 7.61 (0.54H, d, SO
2
Cl-C-CH-CH), 7.29
(0.58H, d, R-C-CH-CH) ), 5.03 (8H, d, 2(O)-CH-CH), 3.90-3.70 (32H, m,
16H ( CH-OH)), 8H (CH-CH-OCH),8H (CH-CH-CH-OH ), 3.60-3.45 (16H,
CH-CH
2
-OH).;13C NMR (75 MHz, D
2
O): δ 129.27 (CH), 125.33 (CH),
1
101.63 (CH), 80.37 (CH), 72.82(CH), 72.16 (CH), 71.65 (CH), 60.02 (CH
LC-MS: Mass Theoretical =1451.31 Da, Found= 725.55 Da = [M ]
2
);
2-
compounds were dissolved in either CDCl
Eurisotop.
3 2
, D O or DMSO-d6 from
Synthesis of Mono(6-azido-6-deoxy)-γ-cyclodextrin
Following the procedure of Stadermann et al.[50]
toluenesulfonyl))-γ-cyclodextrin was weighed (3.57 g, 700 µmol, 1 eq.,
8% pure) and dissolved in 20 mL of water, which was then heated to 80°C.
Subsequently, sodium azide (225 mg, 3.5 mmol, 5 eq.) was added to the
solution. The reaction was left overnight, followed by the precipitation of
the solution in 500 mL of acetone. The resulting precipitate (co-precipitated
,
mono(6-O-p-
Unless otherwise stated, all chemicals were used as received. All HPLC
grade solvents were purchased from Sigma-Aldrich (acetone, diethylether,
DMA, dichloromethane, methanol, acetonitrile), from Fischer Scientific
2
(Toluene) or from Acros (dry DMF, DMSO). All reagents were purchased
from Sigma-Aldrich, with the exception of triphenyl phosphine and sodium-
L-ascorbate, which were bought from Acros. γ-Cyclodextrin was kindly
provided by Wacker Chemie. 2-Ethyl-2-oxazoline was kindly provided by
with γ-cyclodextrin) was filtered off, washed with milliQ water and dried.
Yield= 77% purity = 21%. 1H NMR (300 MHz, DMSO-d6): δ 6.9-6.7 (16
PCI, and
was
further
purified
by distilling over BaO.
OH, m, CH-OH), 4.88 ( 8 H, d, 2(O)-CH-CH ), 4.52 ( 8 OH, t, CH
.70-3.50 ( 32 H, m,16H ( CH-OH), 8H (CH-CH-O-CH),8H (CH-CH-CH-
O); 13C NMR (75 MHz, DMSO-
OH)), 3.40-3.25 ( 8H, m, CH-CH -OH + H
d6): δ 101.40 (CH), 80.37 (CH), 72.91 (CH), 72.17 (CH),71.69 (CH), 60.20
2
-OH),
Propargylbenzenesulfonate was purchased from Sigma-Aldrich and was
further purified by vacuum distillation. Acetonitrille was dried through a
custom-built solvent purification system whereby the solvents pass an
Alumina oxide column for drying. Further characterization details (NMR
spectra, MALDI-TOF-MS spectra, etc.) on the synthesis of the described
compounds can be found in the supporting information.
3
2
2
(
CH
2
); LC-MS:Mass Theoretical =1322.14 Da, Found= 659.7 Da = [(M-
+
2H )/2]
Synthesis of Octakis-6-iodo-6-deoxy-γ-cyclodextrin
Synthesis of propargyl-poly(2-ethyl-2-oxazoline)s
The synthesis of Octakis-6-iodo-6-deoxy-γ-cyclodextrin was adjusted from
the procedure reported by Ashton et al.[51] γ -Cyclodextrin (13 g, 10.2 mmol,
The polymerization mixture was prepared in accordance with the method
of Hoogenboom et al.[34] 10 mL microwave vials were dried in a high
temperature oven (180°C) for at least 2 hours, after which they were
allowed to cool under vacuum, in the vacuum chamber of a glovebox.
Inside the glovebox two mixtures were prepared, with a monomer:initiator
1
eq.) was dried overnight in a vacuum oven at 50°C. A 1L round bottom
flask was filled with 250 mL of dry dimethylformamide (DMF). Next,
triphenylphosphine (40 g, 153 mmol, 15 eq.) was added to the dry DMF
under an argon flow. The following step required the addition of iodine
(
2-ethyl-2-oxazoline:propargyl benzenesulfonate) ratio of 20 and 100. An
(40.5 g, 160 mmol, 15.7 eq.) over the course of 15 minutes under vigorous
appropriate amount of dry acetonitrile was added, to obtain a 4M monomer
solution. Subsequently, the vials were capped and polymerized in a
microwave synthesizer at 140°C until a conversion of roughly 100% was
reached (3.2 min for DP20 and 16 minutes for DP100). The reaction was
terminated with a methanolic solution of tetramethylammonium hydroxide.
Afterwards, the polymers were isolated by precipitation in cold diethyl ether
from dichloromethane. This precipitation cycle was repeated three times,
stirring and an argon flow. Lastly, γ- cyclodextrin was added under an
argon flow and the mixture was stirred for 24 hours at a temperature of
70°C. Afterwards, the reaction was left to cool to room temperature and
then concentrated under reduced pressure until it reached one third of its
original volume. The next day, a 3 M sodium methoxide solution in
methanol was added and left to stir for one hour, after which the solution
was precipitated in 1L of methanol, resulting in a white precipitate. The
suspension was then filtered and the yellow solid obtained was extracted
after which the solvent traces were removed by placing the obtained solid
1
in a vacuum oven at 50°C. H NMR(300 MHz, CDCl
3
): δ 4.4-4.15 (2H,m ,
-N),2.50-2.14 (40H, m, OC-CH
); SEC: PEtOx20: Mn:6140 Da Ð: 1.15,
PEtOx100: Mn=16400 Ð= 1.03; MALDI-TOF-MS: PEtOx20: 2061.84Da =
M+Na]+ PEtOx83: 8310.9 Da = [M+Na]+
with methanol for 5 days with a Soxhlet apparatus. The white solid was
then dried in a vacuum oven at 50°C. Yield= 48% purity= 95%. 1H NMR
C-CH
2
-N), 3.65-3.00 (80H, m, N-CH
CH ), 1.18-0.89 (60H, m, CH
2
-CH
2
2
-
3
3
(
300 MHz, DMSO-d6): δ 6.2-5.9 (16 OH, m, CH-OH), 5.03 (8H, d, 2(O)-
CH-CH), 3.82 (8 H, d, O-CH-(CH) ), 3.70-3.50 (16 H, m, CH-OH), 3.45-
O); 13C NMR (75 MHz, DMSO-d6):
.2 (24 H, m, (16CH2,8 CH-CH2 + H
101.92 (CH), 85.16 (CH), 72.32 (CH),71.74 (CH), 71.00(CH),
5.74(CH ,DMF), 30.77(CH ,DMF), 9.22(CH ); LC-MS: Mass Theoretical
2176.31 Da Found= 2174.85 Da = [M-1H ]
2
[
3
δ
3
=
2
3
3
2
+
-
Synthesis of Mono(6-O-p-toluenesulfonyl))-γ-cyclodextrin
Synthesis of Octakis-6-azido-6-deoxy-γ-cyclodextrin
This procedure was adapted from Stadermann et al.[50] γ -Cyclodextrin (20
g, 15 mmol, 1 eq.) was dried overnight in a vacuum oven at 50°C, after
which it was weighed and dissolved in 200 mL of a 0.4M NaOH aqueous
solution at 0°C. Once dissolved, p- toluenesulfonyl chloride (13 g, 67 mmol,
The synthesis of Octakis-6-iodo-6-deoxy-γ-cyclodextrin was adjusted from
the procedure reported by Ashton et al.[51] Octakis-6-iodo-6-deoxy-γ-
cyclodextrin (5 g, 2.3 mmol, 1 eq.) was added under a nitrogen flow to a
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Chemistry - A European Journal
10.1002/chem.201705647
FULL PAPER
250 mL flask filled with 100 mL of dry DMF. Subsequently, NaN
3
(1.67 g,
Synthesis of per-PEtOx-γ-cyclodextrin (Host 3)
26 mmol, 11 eq.) was added. Next, the solution was heated to 60°C and
left to react for 24 hours, after which the solution was concentrated with a
rotary evaporator. The remaining liquid was precipitated in a large excess
The protocol for this reaction is similar to the protocol used for the
synthesis of mono-PEtOx100-γ-cyclodextrin. Propargyl-PEtOx (188 mg,
(
(
1L) of H
300 MHz, DMSO-d6): δ 6.1-5.6 (16 OH, m), 4.94 ( 8 H, d,2(O)-CH-
), 3.65-3.50 ( 16 H, m, CH-OH),
O); 13C NMR (75 MHz, DMSO-d6): δ 101.95 (CH),
2.56 (CH), 72.39 (CH), 72.15 (CH),51.07 (CH ); IR: 3300 (OH-str), 2979
-str), 2200 (N≡C-str); LC-MS: Mass Theoretical =1496.47 Da, Found=
O to obtain a white powder. Yield= 88% Purity > 95%. 1H NMR
2
140 µmol, 10.5 eq.), 20 repeating units, was weighed in a microwave vial.
Next Octakis-6-azido-6-deoxy-γ- -cyclodextrin (20 mg, 13 µmol, 1 eq.) was
added to the microwave vial, followed by the addition of CuBr (3 mg, 22
µmol, 1.6 eq.), PMDETA (3.7 mg, 22 µmol, 1.6 eq.) and Sodium-L-
ascorbate (0.26 mg, 1.3 µmol, 0.1 eq.). The microwave vial was then filled
with argon and capped. Subsequently, 4 mL of dry DMF were added, the
reaction mixture became slightly blue and the reaction mixture reacted for
CH),3.8-3.67 ( 16 H, m, O-CH-CH, CH-CH
3
8
2
2 2
.45-3.2 (16H,m, CH +H
2
(CH
2
+
-
+ -
1495.9 Da = [M-H ] , 747.2 Da = [M-2H ]
15 minutes at 100°C in the microwave, after which it turned yellow. The
Synthesis of Octakis-6-amino-6-deoxy-γ-cyclodextrin (Host 2)
isolation of the star polymer is identical to the method described for mono-
PEtOx100-γ-cyclodextrin. To separate the excess of polymer from the
product, a PD-10 column was used, after which the obtained fractions were
The synthesis of Octakis-6-amino-6-deoxy-γ-cyclodextrin was adjusted
from the procedure reported by Ashton et al.[51] Octakis-6-azido-6-deoxy-
1
freeze-dried. Yield= 56 %. H NMR (300 MHz, CDCl3): δ 6.00-3.96 ( 72 H,
m, CD), 3.90-3.00 ( 738 H, m, N-CH2-CH2-N), 2.62-1.85 ( 416 H, m, OC-
CH2-CH3), 1.24-0.60 ( 607 H, m, CH3); SEC:per-PEtOx20-γ-cyclodextrin:
Mw= 29420 Da, Ð= 2.02; MALDI-TOF-MS (linear mode): per-PEtOx20-γ-
cyclodextrin: ±17000 Da
γ-cyclodextrin (0.4 g, 267 µmol, 1 eq.) was dissolved in 8 mL of DMF and
triphenylphosphine (1.261 g, 4.81 mmol, 18 eq.) was added. The
development of nitrogen gas was observed by the formation of bubbles in
the reaction vessel. When the development of nitrogen gas ceased,
3
concentrated aqueous NH (1.35 mL, approximately 35%) was added in a
drop-wise manner to the solution. After the addition was complete, the
reaction mixture turned into an off-white suspension. This suspension was
stirred for 18 hours before it was concentrated under reduced pressure to
approximately 10 mL. The product was precipitated by the addition of 100
mL EtOH. The precipitate was washed with EtOH and dried under high
vacuum to yield a white solid. This solid was then converted into the HCl
salt by suspending the product in a small volume of water followed by the
addition of a dilute solution of HCl until a pH of 6 was reached. At this pH,
a clear solution formed which became yellowish when evaporated under
Complexation of CDs with C60 via HSVM
The complexation of the CDs with C60 was carried out in a Fritsch Mini-Mill
Pulverisette 23 in a 10 mL stainless steel grinding bowl equipped with one
15 mm diameter grinding ball. The solid reagents were added and the
mixture was agitated for 10 min at 50 Hz. Next 1 mL of milliQ water was
added and the mixture was agitated again for 2 min at 50 Hz, in order to
solubilize the solids. The resulting solution was then filtered over a 0.2µm
PTFE pore filter. The following molar equivalents of the respective γCDs
to C60 were used: 3.88; 1.87; 3.44 and 1.53 for γCD, host 1, host 2 and
host 3, respectively. The total mass of the powders was kept constant at
reduced pressure. The obtained product was then dialyzed and freeze-
1
dried. H NMR (300 MHz, D
2
O): δ 5.15 (8H, d,2(O)-CH-CH), 4.25-4.15(8H,
m, O-CH-CH),3.98 (8H, m, CH-CH
2
), 3.66 (8H, m, CH-OH), 3,57 (8H, m,
50 mg.
CH-OH), 3.44 (8H ,m,CH
2
), 3.26 (8H,m,CH
2
); LC-MS: Mass Theoretical
+
2+
=
1490 Da, Found= 645 Da [M + 2H - 8 HCl]
Acknowledgements
Synthesis of mono-PEtOx100-γ-cyclodextrin (Host 1)
The authors would like to thank Wacker Chemie for kindly
donating the native γCD used in this paper. Furthermore we would
like to thank Riet De Rycke for providing the TEM-images taken
at the VIB-UGent Transmission Electron Microscopy-Core facility.
The protocol for this reaction was adjusted from the protocol reported by
Hoogenboom et al.[33] Propargyl-PEtOx (1 g, 0.1 mmol, 1 eq.), 100
repeating units, was weighed in a microwave vial. Next mono(6-azido-6-
deoxy)-γ-cyclodextrin (1.260 g, 0.2 mmol, 2 eq., 21 % pure) was added to
the microwave vial, followed by the addition of a 10 mL DMF solution of
copper(I)
bromide
(22
mg,
0.15
mmol,
1.5
eq.),
Keywords: Cyclodextrins • Fullerenes • C60 • Aggregation •
pentamethyldiethylenetriamine (PMDTA) (26 mg, 0.15 mmol, 1.5 eq.) and
sodium-L-ascorbate (2 mg, 0.01 mmol, 0.1 eq.). The microwave vial was
then filled with argon and capped. 10 mL of dry DMF was added, the
reaction mixture became slightly blue and the reaction mixture reacted for
poly(2-oxazoline)s
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Chemistry - A European Journal
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FULL PAPER
FULL PAPER
Overcoming attraction: A well-
known problem of cyclodextrin
inclusion complexes is their
aggregation. In this study we
attempt to overcome the attractive
intermolecular forces between the
complexes, by designing custom γ-
cyclodextrin(γCD)-based
Joachim F.R. Van Guyse, Victor R. de
la Rosa, Richard Hoogenboom*
Page No. – Page No.
Mechanochemical preparation of
stable sub-100 nm γ-
cyclodextrin:Buckminsterfullerene
(
C60) nanoparticles by electrostatic
or steric stabilization
supramolecular hosts for C60 to
inhibit the aggregation found in
native-γCD:C60 complexes, via
Coulombic repulsion or steric
hindrance. This led to partial
inhibition of the aggregation,
yielding stable sub-100 nm
nanostructures.
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