Chaotropic-anion-induced supramolecular self-assembly of ionic polymeric micelles

Article abstract of DOI:10.1002/anie.201402525

Traditional micelle self-assembly is driven by the association of hydrophobic segments of amphiphilic molecules forming distinctive core-shell nanostructures in water. Here we report a surprising chaotropic-anion-induced micellization of cationic ammonium-containing block copolymers. The resulting micelle nanoparticle consists of a large number of ion pairs (≈60 000) in each hydrophobic core. Unlike chaotropic anions (e.g. ClO₄ ^-), kosmotropic anions (e.g. SO₄^2-) were not able to induce micelle formation. A positive cooperativity was observed during micellization, for which only a three-fold increase in ClO₄ ^- concentration was necessary for micelle formation, similar to our previously reported ultra-pH-responsive behavior. This unique ion-pair-containing micelle provides a useful model system to study the complex interplay of noncovalent interactions (e.g. electrostatic, van der Waals, and hydrophobic forces) during micelle self-assembly.

Full text of DOI:10.1002/anie.201402525

.
Angewandte
Communications
DOI: 10.1002/anie.201402525
Micellization
Chaotropic-Anion-Induced Supramolecular Self-Assembly of Ionic
Polymeric Micelles**
Yang Li, Yiguang Wang, Gang Huang, Xinpeng Ma, Kejin Zhou, and Jinming Gao*
Dedicated to Professor George M. Whitesides on the occasion of his 75th birthday
Abstract: Traditional micelle self-assembly is driven by the
association of hydrophobic segments of amphiphilic molecules
forming distinctive core–shell nanostructures in water. Here we
report a surprising chaotropic-anion-induced micellization of
cationic ammonium-containing block copolymers. The result-
ing micelle nanoparticle consists of a large number of ion pairs
Recently, our lab has established a series of tunable, ultra-
pH-sensitive micelle nanoparticles from different block
copolymers (PEO-b-PR, where PEO is poly(ethylene oxide)
[
2d,e,8]
and PR is the ionizable tertiary amine block).
At
pH values below the transition pH (pH ), micelles dissociate
t
into unimers with protonated ammonium groups. At pH >
(
(
ꢀ 60000) in each hydrophobic core. Unlike chaotropic anions
pH , the neutralized PR segments become hydrophobic and
self-assemble into the micelle cores (left panel in Figure 1).
t
À
2À
4
[9]
e.g. ClO ), kosmotropic anions (e.g. SO ) were not able to
4
induce micelle formation. A positive cooperativity was
observed during micellization, for which only a three-fold
increase in ClO4 concentration was necessary for micelle
formation, similar to our previously reported ultra-pH-respon-
sive behavior. This unique ion-pair-containing micelle pro-
vides a useful model system to study the complex interplay of
noncovalent interactions (e.g. electrostatic, van der Waals, and
hydrophobic forces) during micelle self-assembly.
Hydrophobic micellization dramatically sharpens the
pH transition, so that the fluorescence activation (on/off
states) is narrowed to less than 0.25 pH units, compared to
2 pH units for small-molecular pH sensors.
À
R
esponsive materials have received considerable attention
for the construction of nanosystems that allow highly selective
recognition, catalysis, and transfer operations in a wide range
[
1]
of photonic, electronic, and biological applications. Various
nanosystems that respond to changes in pH value, enzy-
matic expression, redox potential, temperature, and
[
2]
[3]
[4]
[5]
[
6]
light have been developed successfully. The underlying
science in the development of many of these responsive
systems resides in the supramolecular self-assembly principles
conceptualized over two decades ago by Whitesides and
Lehn. In contrast to covalent chemistry, supramolecular
self-assembly engages a multitude of weak and reversible
noncovalent interactions (e.g. electrostatic and hydrophobic
interactions, hydrogen bonds, etc.) to achieve a thermody-
[7]
Figure 1. Self-assembly of ionizable polymeric micelles by two inde-
pendent mechanisms. The left panel shows the induction of micelliza-
tion by an increase in the pH value, resulting in the PR segments
becoming neutralized and hydrophobic to drive micelle formation.
À
Surprisingly, addition of chaotropic ions (CA, such as ClO4 ) at a low
[
7a,c]
namically stable nanostructure.
This strategy has the
pH value also leads to micellization with ammonium PR segments
(right panel). Structures of a series of PEO-b-PR copolymers (1–5) with
different hydrophobic side chains are shown in the inset. CA=chao-
4
10
advantage of reaching sizes (10 –10 Da) that are not easily
achievable by covalent chemistry, and the resulting system
often displays positive cooperativity over the behavior of
single molecules in solution.
tropic anion, pH =transition pH value.
t
Herein, we report the discovery of chaotropic-anion-
induced micellization of protonated PEO-b-PR copolymers
at pH values below the pHt (right panel in Figure 1).
Surprisingly, an anti-Hofmeister trend was observed, in
which the presence of chaotropic anions but not kosmotropic
[
*] Y. Li, Dr. Y. Wang, Dr. G. Huang, Dr. X. Ma, Dr. K. Zhou, Prof. J. Gao
Department of Pharmacology, Harold C. Simmons Comprehensive
Cancer Center, UT Southwestern Medical Center at Dallas
5
323 Harry Hines Blvd., Dallas, TX 75390 (USA)
E-mail: jinming.gao@utsouthwestern.edu
**] This work was supported by the NIH (R01EB013149 and CPRIT
RP120094). We acknowledge the Simmons Cancer Center for their
[
10]
anions resulted in micellization, in contrast to their effects
in protein aggregation (Figure 2a).
[
(
We first established a fluorescence resonance energy
transfer (FRET) method to investigate the micelle self-
assembly process. FRET is highly sensitive for the detection
of conformational and phase transitions of polymers/proteins
support through an NCI Cancer Center Support Grant (P30
CA142543).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402525.
8074
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 8074 –8078

Angewandte
Chemie
The FRET effects were quantified to compare different
anions in their abilities to induce micellization (Figure 2c).
FRETefficiency was normalized as (F /F )/(F /F )max, where
A
D
A
D
F and F were the fluorescence intensity of TMR and Cy5 at
A
D
different anion concentrations, respectively; (F /F ) was
D max
A
À
the maximum value of F /F (3.3) at high ClO4 concen-
A
D
trations. FRET efficiency was plotted as a function of
concentration for different anions. Results displayed an
anti-Hofmeister trend, in which chaotropic anions were able
to induce unimer association (i.e. micellization), whereas the
kosmotropic anions were unable to do so (Figure 2c). This
result is in contrast to the classical Hofmeister effect in
protein solubilization, in which kosmotropic ions are known
to induce protein aggregation in water but not the chaotropic
[
14]
ions.
Copolymer 3 displayed different detection sensitivity
toward the chaotropic anions. Data show that the FRET
À
À
À
À
3
sensitivity followed the order of ClO4 > SCN > I > NO
.
We define FC as the anion concentration at which the FRET
5
0
efficiency was at 50%. The values of FC were 11, 68, and
5
0
À
À
À
À
3
04 mm for ClO4 , SCN , and I , respectively. For NO , only
3
a weak FRET effect was observed at its saturation concen-
tration ( ꢀ 3m). A more detailed examination showed that
À
only a three-fold increase in ClO4 concentration (i.e. from 6
to 18 mm, Figure 2c) was necessary to increase FRET
efficiency from 10% to 90%. This narrowed concentration
dependence suggests an increased cooperative response
[
2d,e,8]
similar to the ultra-pH response as reported previously.
Figure 2. a) Chaotropic anions induce micelle self-assembly of PEO-b-
PR copolymers with protonated PR segment, which is a reversed effect
To further confirm chaotropic-anion-induced micelliza-
tion, we employed transmission electron microscopy (TEM)
and dynamic light scattering (DLS) to investigate the changes
in morphology and hydrodynamic diameter during micelle
(
salt-out) with respect to their ability to solubilize proteins (salt-in).
b) Illustration of FRET design to investigate CA-induced micelle self-
assembly. Addition of CA results in micelle formation and efficient
energy transfer from donor (TMR) to acceptor (Cy5) dyes. c) Chaotro-
pic anion-induced micelle self-assembly showing the anti-Hofmeister
trend.
À
transition, respectively. We used chloride anions (Cl ) as
À
a negative control. In the presence of 50 mm Cl , copolymer 3
remained as unimers at pH 5.0 (below its pH at 6.1, Fig-
t
ure 3a). In contrast, copolymer 3 self-assembled into spher-
À
À
because the energy-transfer efficiency is inversely propor-
tional to the sixth power of the donor–acceptor distance. In
ical micelles when Cl was replaced with ClO4 (Figure 3b).
[11]
our method, we conjugated block copolymers (1–5 in Figure 1
[12]
inset, see also Table S1 in the Supporting Information) with
either a donor or acceptor dye. We chose PEO-b-poly(di-n-
propylaminoethyl methacrylate) (3, pH = 6.1) as a model
t
copolymer, and tetramethyl rhodamine (TMR, l /l = 545/
ex em
5
80 nm)/Cy5 (l /l = 647/666 nm) as donor/acceptor,
ex em
[
13]
respectively.
At pH 4, the tertiary amines in 3 (pH = 6.1) were
t
protonated and the resulting copolymers were soluble in
water as dispersed cationic unimers. No FRET effect was
observed because of the large distance between the unimers
(
i.e. TMR and Cy5) in solution. The addition of chaotropic
À
À
À
anions (e.g. ClO4 , SCN , or I ) resulted in the decrease of
fluorescence intensity from TMR and increase of emission
intensity of Cy5 (Figure S1), thus indicating the formation of
polymeric micelles. Micelle formation was hypothesized to
bring TMR and Cy5 to close proximity within the micelle
core, thereby dramatically increasing FRET efficiency (Fig-
Figure 3. TEM and DLS analyses of micelle transition of copolymer 3
2
À
À
4
ure 2b). In contrast, kosmotropic anions (e.g. SO4 , H PO )
À
À
2
in the presence of Cl (a) and ClO4 anions (b). Concentrations of
both anions were controlled at 50 mm (pH 5.0). The scale bars are
100 nm in the TEM images.
did not lead to any FRET transfer (Figure S2), even at
concentrations close to their solubility limits (Table S2).
Angew. Chem. Int. Ed. 2014, 53, 8074 –8078
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8075

.
Angewandte
Communications
DLS analyses showed an increase in the hydrodynamic
diameter from 7 Æ 2 to 26 Æ 3 nm when the anions were
À
À
changed from Cl to ClO4 (Figure 3). This increase in size
reflects the transition of copolymer 3 from the unimer state to
the micelle state, consistent with the FRETand TEM data. At
pH 7.4, copolymer 3 was present as spherical micelles with
hydrodynamic diameters of 27 Æ 2 and 28 Æ 3 nm in the
À
À
presence of Cl and ClO4 anions, respectively (Figures S3
and S4). For nonionizable amphiphilic block copolymers such
as PEO-b-poly(d,l-lactic acid) (PEO-b-PLA), neither
À
a change in pH value nor the addition of ClO4 had any
effects on the micelle state (Figure S5).
We then studied the chaotropic-anion-induced self-assem-
bly in the presence of competing kosmotropic or borderline
anions. Copolymer 3 was dissolved at pH 4 with different
2
À
À
initial concentrations of competing SO4 or Cl anions. Then
À
chaotropic anions ClO4 were added to induce micellization
(
Figures S6–S9). Figure 4a shows the representative example
Figure 5. a) The hydrophobic strength of the PR segment affects the
À
ability of ClO4 to induce micellization. The more hydrophobic PR
À
segment (e.g. pentyl groups in 5) increases the ClO4 sensitivity to
induce micelle formation. b) An empirical model depicting two impor-
tant contributing factors (length of hydrophobic alkyl chain and
chaotropic anions) on the self-assembly of ionic polymeric micelles.
À
Figure 4. a) ClO4 -induced self-assembly of copolymer 3 in the pres-
chains (i.e. methyl in 1), no micellization was observed,
even at the highest ClO4 concentrations (1m). In contrast, the
2
À
ence of different concentrations of competing SO4 anions. b) The
FRET efficiency (FC ) from ClO -induced self-assembly as a function
of the ionic strength of the competing Cl and SO4 anions. The
pH value of the solution was controlled at pH 4 in these studies.
À
À
5
0
4
À
2À
most hydrophobic side chains (pentyl in 5) resulted in the
À
most sensitive induction of micellization by ClO4 anions. The
FC50 values were 2, 4, 35, 134 mm when the side chains were
pentyl, butyl, propyl, and ethyl groups, respectively (Fig-
ure 5a).
À
of FRET efficiency as a function of ClO concentration.
4
2
À
Addition of SO4 anions was able to decrease the sensitivity
of ClO4 in micelle induction. We quantified the FC50 values
to evaluate the effect of competing anions (Figure 4b). We
observed an interesting bell curve as a function of the ionic
strength of the competing anions. At low ionic strength
< 0.1m), addition of competing anions decreased the ability
of ClO4 to induce micelle formation, consistent with their
competition with the ammonium groups of the PR segment.
At high ionic strength (> 0.5m) of SO or Cl , however, we
observed an enhancement of ClO -induced self-assembly.
We attribute this effect to the more ordered bulk water
structures at high kosmotropic ion concentrations, which
makes the hydrophobic association during micelle self-
assembly more favorable.
Finally, we investigated the effect of the hydrophobic
strength of the PR segment on the chaotropic-anion-induced
micellization (Figure 5a). We synthesized a series of PEO-b-
PR copolymers (1–5 in Figure 1, inset) that bear alkyl chains
of different lengths from methyl to pentyl groups on the
tertiary amines. Results showed a clear dependence of ClO -
induced self-assembly on the hydrophobicity of the PR
segment (Figure S10). With the least hydrophobic side
The results from this study illustrate a highly unusual
micelle self-assembly process of block copolymers with
tertiary ammonium groups induced by chaotropic anions.
The current nanosystem is characterized by several unique
features: first, chaotropic anions were able to form stable ion
pairs with positively charged ammonium groups in the
hydrophobic micelle core environment. Assuming that the
majority of the ammonium groups are present in the ionized
state, this translates into approximately 60000 ion pairs per
micelle with an estimated core size of 14 nm (calculation
À
(
À
2
À
À
4
À
4
[
8b]
based on 800 polymer chains per micelle, 70–80 repeating
units of monomers containing amino groups per polymer
[15]
chain, and a PEO shell size of 6 nm ). Second, only
chaotropic anions were able to induce micelle formation,
2
À
À
whereas the kosmotropic (SO4 ) and borderline (Cl ) anions
did not pertain this ability. This trend appears to be contrary
to that observed in classical protein solubilization studies.
Third, the ability of chaotropic anions to induce micellization
appears to show positive cooperativity similar to an ultra-pH-
sensitive response. Our previous study showed fluorescence
activation (10% to 90% response) that occurred within
À
4
+
a pH value change of 0.25 units (< 2-fold in [H ]). The current
8076 www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 8074 –8078

Angewandte
Chemie
study shows that the FRET transfer was induced by a three-
Shieh, R. B. Dorshow, K. L. Wooley, J. Am. Chem. Soc. 2011,
33, 8534 – 8543.
3] a) C. Wang, Q. Chen, Z. Wang, X. Zhang, Angew. Chem. 2010,
22, 8794 – 8797; Angew. Chem. Int. Ed. 2010, 49, 8612 – 8615;
À
1
fold increase of [ClO ]. Last, competition experiments with
4
[
kosmotropic and borderline anions illustrated a bell-curve
behavior, which points to the complexity and subtle nature of
the micelle self-assembly process in the current system.
We built an empirical model (Figure 5b) to depict the
factors that contribute to the micelle self-assembly process.
We hypothesize that the hydrophobic interactions from alkyl
chains of increasing lengths provide the dominant driving
force for micelle formation. This is supported by the lack of
micelle formation when the side chain of the tertiary amines is
a methyl group (as indicated by the dashed line on the left side
of Figure 5b). Similarly, neutralized copolymer 1 did not form
1
b) E. S. Olson, T. Jiang, T. A. Aguilera, Q. T. Nguyen, L. G.
Ellies, M. Scadeng, R. Y. Tsien, Proc. Natl. Acad. Sci. USA 2010,
107, 4311 – 4316; c) A. Bernardos, E. Aznar, M. D. Marcos, R.
Martꢀnez-MꢁÇez, F. Sancenꢂn, J. Soto, J. M. Barat, P. Amorꢂs,
Angew. Chem. 2009, 121, 5998 – 6001; Angew. Chem. Int. Ed.
2009, 48, 5884 – 5887; d) T. L. Andresen, J. Davidsen, M.
Begtrup, O. G. Mouritsen, K. Jorgensen, J. Med. Chem. 2004,
47, 1694 – 1703.
[
4] a) Y.-L. Li, L. Zhu, Z. Liu, R. Cheng, F. Meng, J.-H. Cui, S.-J. Ji,
Z. Zhong, Angew. Chem. 2009, 121, 10098 – 10102; Angew.
Chem. Int. Ed. 2009, 48, 9914 – 9918; b) G. Saito, J. A. Swanson,
K.-D. Lee, Adv. Drug Delivery Rev. 2003, 55, 199 – 215; c) M. S.
Shim, S. H. Bhang, K. Yoon, K. Choi, Y. Xia, Angew. Chem.
[
2d]
micelles at pH values above its pHt. Meanwhile, anions also
play a critical role in micellization. Kosmotropic anions, which
are known to have strong hydration shells and weak polar-
2
012, 124, 12069 – 12073; Angew. Chem. Int. Ed. 2012, 51, 11899 –
11903.
[5] a) S.-W. Choi, Y. Zhang, Y. Xia, Angew. Chem. 2010, 122, 8076 –
080; Angew. Chem. Int. Ed. 2010, 49, 7904 – 7908; b) B. Jeong,
[
16]
ization characteristics, are energetically less favorable in
[
17]
the formation of ion pairs and stabilization of ion pairs in
the hydrophobic core. Chaotropic anions, with their strong
polarizability and low energy cost at removing the hydration
8
Y. H. Bae, S. W. Kim, J. Controlled Release 2000, 63, 155 – 163;
c) Q. Zhang, C. G. Clark, M. Wang, E. E. Remsen, K. L. Wooley,
Nano Lett. 2002, 2, 1051 – 1054.
[
18]
sheath, allows formation of stable ion pairs in the hydro-
phobic micelle core. Further studies are necessary to elucidate
the thermodynamic contributions in enthalpy and entropy to
the overall free energy of micelle phase transitions by the
chaotropic anions.
[
6] a) E. Feigenbaum, K. Diest, H. A. Atwater, Nano Lett. 2010, 10,
2111 – 2116; b) D. V. Volodkin, A. G. Skirtach, H. Mçhwald,
Angew. Chem. 2009, 121, 1839 – 1841; Angew. Chem. Int. Ed.
2009, 48, 1807 – 1809; c) A. G. Skirtach, A. MuÇoz Javier, O.
Kreft, K. Kçhler, A. Piera Alberola, H. Mçhwald, W. J. Parak,
G. B. Sukhorukov, Angew. Chem. 2006, 118, 4728 – 4733; Angew.
Chem. Int. Ed. 2006, 45, 4612 – 4617; d) J. L. Sorrells, R.
Shrestha, W. L. Neumann, K. L. Wooley, J. Mater. Chem. 2011,
In conclusion, we report a surprising micelle self-assembly
process enabled by chaotropic anions with block copolymers
containing hydrophobic, cationic ammonium groups. Unlike
conventional micelles with simple hydrophobic cores, the
current ionic micelles contain a large number of ion pairs in
the core environment. The resulting micelles provide a good
model system to study the fundamental process of supra-
molecular self-assembly through the interplay of noncovalent
forces (e.g. electrostatic, van der Waals, and hydrophobic
interactions) in aqueous environments. From the application
standpoint, results from this study may also open up new
opportunities to tailor micelle systems with stabilized ion
pairs for the delivery of charged drug molecules.
2
1, 8983 – 8986.
7] a) G. M. Whitesides, J. P. Mathias, C. T. Seto, Science 1991, 254,
312 – 1319; b) J.-M. Lehn, Angew. Chem. 1988, 100, 91 – 116;
[
1
Angew. Chem. Int. Ed. Engl. 1988, 27, 89 – 112; c) G. M. White-
sides, B. Grzybowski, Science 2002, 295, 2418 – 2421.
[8] a) X. Huang, G. Huang, S. Zhang, K. Sagiyama, O. Togao, X. Ma,
Y. Wang, Y. Li, T. C. Soesbe, B. D. Sumer, M. Takahashi, A. D.
Sherry, J. Gao, Angew. Chem. 2013, 125, 8232 – 8236; Angew.
Chem. Int. Ed. 2013, 52, 8074 – 8078; b) Y. Wang, K. Zhou, G.
Huang, C. Hensley, X. Huang, X. Ma, T. Zhao, B. D. Sumer, R. J.
Deberardinis, J. Gao, Nat. Mater. 2013, 12, 204 – 212.
[
9] a) G. Riess, Prog. Polym. Sci. 2003, 28, 1107 – 1170; b) E. S. Lee,
H. J. Shin, K. Na, Y. H. Bae, J. Controlled Release 2003, 90, 363 –
Received: February 17, 2014
Published online: June 10, 2014
374; c) J. Hu, G. Zhang, Z. Ge, S. Liu, Prog. Polym. Sci. 2014, 39,
1
096 – 1143.
Keywords: anti-Hofmeister effect · block copolymers · ion pairs ·
micelles · self-assembly
[
10] a) Y. Zhang, P. S. Cremer, Curr. Opin. Chem. Biol. 2006, 10, 658 –
663; b) D. F. Parsons, M. Bostrom, P. Lo Nostro, B. W. Ninham,
Phys. Chem. Chem. Phys. 2011, 13, 12352 – 12367; c) W. Kunz, P.
Lo Nostro, B. W. Ninham, Curr. Opin. Colloid Interface Sci.
.
2
004, 9, 1 – 18.
11] a) E. A. Jares-Erijman, T. M. Jovin, Nat. Biotechnol. 2003, 21,
387 – 1395; b) K. E. Sapsford, L. Berti, I. L. Medintz, Angew.
Chem. 2006, 118, 4676 – 4704; Angew. Chem. Int. Ed. 2006, 45,
562 – 4589.
12] a) N. V. Tsarevsky, K. Matyjaszewski, Chem. Rev. 2007, 107,
270 – 2299; b) Y. Ma, Y. Tang, N. C. Billingham, S. P. Armes,
[
1] M. A. Stuart, W. T. Huck, J. Genzer, M. Muller, C. Ober, M.
Stamm, G. B. Sukhorukov, I. Szleifer, V. V. Tsukruk, M. Urban,
F. Winnik, S. Zauscher, I. Luzinov, S. Minko, Nat. Mater. 2010, 9,
[
1
1
01 – 113.
2] a) E. S. Lee, K. Na, Y. H. Bae, J. Controlled Release 2003, 91,
03 – 113; b) Y. Bae, S. Fukushima, A. Harada, K. Kataoka,
Angew. Chem. 2003, 115, 4788 – 4791; Angew. Chem. Int. Ed.
003, 42, 4640 – 4643; c) D. M. Lynn, M. M. Amiji, R. Langer,
Angew. Chem. 2001, 113, 1757 – 1760; Angew. Chem. Int. Ed.
001, 40, 1707 – 1710; d) K. Zhou, Y. Wang, X. Huang, K. Luby-
Phelps, B. D. Sumer, J. Gao, Angew. Chem. 2011, 123, 6233 –
238; Angew. Chem. Int. Ed. 2011, 50, 6109 – 6114; e) K. Zhou,
4
[
[
1
2
2
A. L. Lewis, A. W. Lloyd, J. P. Salvage, Macromolecules 2003, 36,
3475 – 3484.
2
[13] a) T. Ha, A. Y. Ting, J. Liang, W. B. Caldwell, A. A. Deniz, D. S.
Chemla, P. G. Schultz, S. Weiss, Proc. Natl. Acad. Sci. USA 1999,
96, 893 – 898; b) J. R. Grunwell, J. L. Glass, T. D. Lacoste, A. A.
Deniz, D. S. Chemla, P. G. Schultz, J. Am. Chem. Soc. 2001, 123,
4295 – 4303.
6
H. Liu, S. Zhang, X. Huang, Y. Wang, G. Huang, B. D. Sumer, J.
Gao, J. Am. Chem. Soc. 2012, 134, 7803 – 7811; f) G. Sun, H. Cui,
L. Y. Lin, N. S. Lee, C. Yang, W. L. Neumann, J. N. Freskos, J. J.
Angew. Chem. Int. Ed. 2014, 53, 8074 –8078
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 8077

.
Angewandte
Communications
[
14] a) F. Hofmeister, Arch. Exp. Pathol. Pharmakol. 1888, 25, 1 – 30;
b) K. D. Collins, M. W. Washabaugh, Q. Rev. Biophys. 1985, 18,
[16] a) E. Leontidis, Curr. Opin. Colloid Interface Sci. 2002, 7, 81 – 91;
b) V. Merk, C. Rehbock, F. Becker, U. Hagemann, H. Nienhaus,
S. Barcikowski, Langmuir 2014, 30, 4213 – 4222.
323 – 422.
[
15] Y.-Y. Wang, S. K. Lai, J. S. Suk, A. Pace, R. Cone, J. Hanes,
[17] K. D. Collins, Biophys. J. 1997, 72, 65 – 76.
Angew. Chem. 2008, 120, 9872 – 9875; Angew. Chem. Int. Ed.
[18] a) A. L. Underwood, E. W. Anacker, J. Colloid Interface Sci.
1987, 117, 242 – 250; b) Y. Zhang, P. S. Cremer, Proc. Natl. Acad.
Sci. USA 2009, 106, 15249 – 15253.
2008, 47, 9726 – 9729.
8078 www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 8074 –8078