A Supramolecular Crosslinker To Give Salt-Resistant Polyion Complex Micelles and Improved MRI Contrast Agents

Article abstract of DOI:10.1002/anie.201805707

Three-component mixtures (diblock copolymer/metal ion/oligoligand) can assemble into micellar particles owing to a combination of supramolecular polymerization and electrostatic complex formation. Such particles cover a large range of compositions, but the electrostatic forces keeping them together make them rather susceptible to disintegration by added salt. Now it is shown how the salt stability can be tuned continuously by employing both a bis-ligand and a tris-ligand, and varying the ratio of these in the mixture. For magnetic ions such as Mn^II and Fe^III, the choice of the multiligand also affects the ion/water interaction and, hence, the magnetic relaxivity. As an example, Mn^II-based nanoparticles with a very high longitudinal relaxivity (10.8 mm^?1 s^?1) were investigated that are not only biocompatible but also feature strong contrast enhancement in target organs (liver, kidney), as shown by T₁-weighted in vivo magnetic resonance imaging (MRI).

Full text of DOI:10.1002/anie.201805707

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
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Accepted Article
Title: Beating Brine. Supramolecular Crosslinker gives Salt Resistant
PIC Micelles and Improved MRI Contrast Agents.
Authors: Martien A. Cohen Stuart, Jiahua Wang, Wenjuan Zhou, Peng
Ding, Yuehua Li, Marcus Drechsler, Xohong Guo, and Junyou
Wang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201805707
Angew. Chem. 10.1002/ange.201805707
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10.1002/anie.201805707
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Beating Brine. Supramolecular Crosslinker gives Salt Resistant
PIC Micelles and Improved MRI Contrast Agents.
Jiahua Wang,[a] Junyou Wang,*[a] Peng Ding,[a] Wenjuan Zhou,[a] Yuehua Li,[b] Markus Drechsler,[c]
Xuhong Guo,*[a] and Martien A. Cohen Stuart*[a]
Abstract: A versatile way to prepare nanoparticles in a wide
range of compositions is by spontaneous multi-component
assembly. Any chosen composition can be realized by simply
mixing ingredients, and the available choices for each component
determine the accessible variations. We explore here three-
component mixtures (diblock copolymer/metal ion/oligoligand)
which assemble into micellar particles due to a combination of
supramolecular polymerization and electrostatic complex
formation. Such particles indeed allow covering a large range of
compositions, but it turns out that the electrostatic forces keeping
them together make them rather susceptible to disintegration by
added salt. In this report we show how we can tune the salt
stability in a continuous way by employing both a bis-ligand and a
tris-ligand, and varying the ratio of these in the mixture. Moreover,
we find that for magnetic ions like Mn(II) and Fe(III) the choice of
the multiligand also affects the ion/water interaction and, hence,
the magnetic relaxivity, so that we can also tune that property.
The approach presented here is generally applicable. As an
example, we discuss Mn(II)-based nanoparticles with a very high
longitudinal relaxivity (10.8 mM-1s-1) that are not only
biocompatible, but also feature strong contrast enhancement in
target organs (liver, kidney) as shown by T1-weighted in vivo
magnetic resonance imaging (MRI).
phase separation can be exploited in the colloidal domain: by
attaching a neutral block to one or both of the charged polymers,
two-component, nanosized core-shell polymer micelles are
formed, known either as complex coacervate core micelles
(C3Ms), as polyion complex micelles (PIC micelles), or as block
ionomer complex micelles (BICs).[4] This type of micelles has
attracted increasing attention in recent years because of their
perceived potential as carriers for drugs, enzymes, or DNA.[5]
However, the fact that charge provides the driving force makes
polyelectrolyte micelles very sensitive to ionic strength: salt
screens the electrostatic interaction between charged blocks and
significantly weakens the coacervation and the stability of the
coacervate complexes that constitute the micellar core.[6]
Typically, PIC micelles hardly tolerate physiological salt
concentration, which seriously limits their application in
biomedical contexts. To address this problem, various strategies
have been developed, such as covalent cross-linking and
introduction of more hydrophobic or dendritic components.[7]
These approaches indeed solve stability problems, but in order to
meet various requirements associated with application, what one
really looks for is a kind of coacervate micelles with a tunable
response to salt (stability) and tunable functional properties,
rather than just enhanced salt stability. This is still a challenge to
date.
It is well known that upon mixing oppositely charged polymers
in aqueous solution, complex coacervation takes place, leading to
macroscopic phase separation with a polyelectrolyte-rich bottom
phase (coacervate) and a dilute top phase.[1] Obviously, this
charge-driven coacervation is tunable by means of many
parameters, such as type of chemical groups, pH, ionic strength
and charge mixing ratio.[2] Among these, the ionic strength is a
crucial factor that generally controls the phase separation,
structure, dynamics and mechanical properties of coacervate
complexes.[3] As is the case with all amphiphiles, the macroscopic
[a]
J. H. Wang, Dr. J. Y. Wang, P. Ding, W. J. Zhou, Prof. X. H. Guo,
Prof. M. A. Cohen Stuart
State Key Laboratory of Chemical Engineering and Shanghai Key
Laboratory of Multiphase Materials Chemical Engineering
East China University of science and Technology
130 Meilong Road, Shanghai 200237, P. R. China
E-mail: junyouwang@ecust.edu.cn, guoxuhong@ecust.edu.cn,
martien.cohenstuart@wur.nl
[b]
[c]
Dr. Y. H. Li
Scheme 1. a) Structure of P2MVP41-b-PEO205. b) Structure of bis-ligand L2. c)
Illustration of the formation of M-L2-L3 micelles. d) Structure of tris-ligand L3.
Institute of Diagnostic and Interventional Radiology
The Sixth Affiliated People’s Hospital, Shanghai Jiao Tong
University, 600 Yi Shan Road, Shanghai 200233, P. R. China
Dr. Markus Drechsler
Bavarian Polymerinstitute (BPI), Keylab of Electron and Optical
Microscopy, University BayreuthInstitute, Universitaetsstr. 30
D-95440 Bayreuth
Some time ago, we have reported a novel type of three-
component PIC micelles prepared from a polycationic-neutral
diblock copolymer and an anionic supramolecular, reversible
coordination polyelectrolyte.[8] The latter had been obtained by
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201805707
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coordination between various metal ions and a bis-ligand (L2)
containing two dipicolinic acid (DPA) groups connected by a tetra-
ethylene oxide spacer (4EO). Unlike micelles formed by common
synthetic polyelectrolytes only, such coordination polyelectrolytes
bring hundreds of metal ions in the micellar core, resulting in novel
functional properties, e.g., magnetic and fluorescent properties.[9]
Moreover, control of the coordination structures allows to
manipulate the strength of the magnetic response or the
fluorescence of the micelles, which gives them great potential as
imaging probes.[10] Regrettably, it was the poor stability against
salt that hampered their practical application, particularly for first-
row transition metals.[11] The reason for this may be that the
combination of bis-ligand (L2) with these ions can only form linear
coordination polymers, producing highly mobile, liquid-like
coacervates.
L3 (corresponding to 100% L3, Fig. 1d) micelles. Note that the
images here highlight the micellar core part due to the enhanced
electron density from Mn2+. The core radius is about 9 nm, which
implies that the shell (corona) thickness is around 15 nm (using
hydrodynamic radius from light scattering as the total radius).
In the present study, we therefore introduce, as an alternative
for L2, a triple ligand with three DPA groups grafted on a benzene
ring (L3). When L3 is added, it creates cross-links between the
linear metal-L2 coordination structures, and then produces
reversible network coordination polymers that, as we demonstrate,
lead to coacervates that are less easily destroyed by salt. The
cross-link density can be simply controlled by varying the L3/L2
ratio, so that we have a method to prepare micelles with
adjustable composition, tunable and enhanced salt stability, and
hopefully other improved properties. The presented strategy is
generally applicable with different metal ions. In particular, we find
that Mn-L3 micelles feature both high stability and high magnetic
relaxivity, and exhibit good biocompatibility and strong contrast in
T1-weighted in vivo magnetic resonance imaging, thereby
showing excellent performance as MRI contrast agent.
Figure 1. Effect of L3 on Mn-based micelles (metal concentration equals 0.3
mM in all cases). a) Hydrodynamic radius and size distribution of Mn-L2-L3
micelles as
a function of L3 ligand percentage; b) Scattering intensity
(normalized by the original value I0, where no salt is added yet) for Mn-L2-L3
micelles at different L3% with increasing salt concentration; c, d) cyro-TEM
images of Mn-L2 (c) and Mn-L3 micelles (d).
The chemical structures of the bis-ligand 1,11-bis(2,6-
dicarboxypyridin-4-yloxy)-3,6,9-trioxaundecane (L2), and the
newly designed tris-ligand 1,3,5-tris(2,6-dicarboxypyridin-4-
yloxymethyl) benzene (L3, see Supporting Information, SI) are
shown in Scheme 1. The diblock copolymer poly(N-methyl-2-
vinyl-pyridinium iodide)-b-poly(ethylene oxide) (P2MVP41-b-
PEO205) has a linear structure and a fixed number of charges
independent of the pH, due to the quaternized pyridinium groups.
As noticed above, many C3Ms are very sensitive to ionic
strength and dissociate completely above
a critical salt
concentration. Figure 1b shows such a typical salt response of
Mn-L2 micelles (for 0% L3): the samples’ light scattering intensity
goes down with increasing salt concentration and levels off
around 180 mM NaNO3, where the micelles fall apart completely,
as evidenced by the low intensity and the disappearance of a
reliable correlation function. (Figure SI 4) Equivalently, one can
say that the CMC of the micelles increases due to added salt so
that, at fixed total concentration, the concentration of
unassociated components increases at the expense of the
micelles. Introducing no more than 20% of L3 already appears to
strongly suppress the salt response, thereby considerably
lowering the CMC, and shifting the appearance of the intensity
plateau to significantly higher salt concentration. The absolute
intensity at the plateau is also higher for mixed L2-L3 micelles than
for pure L2 micelles. This may come from two contributions: 1) The
CMC has been lowered so much that micelles largely survive.
Indeed, for all mixed systems, the intensity correlation curve
appears clearly, even at very high salt concentration, and
CONTIN analysis confirms that there is a well-defined size peak
which must be assigned to (micellar) nanoparticles (Figure SI 5-
SI 8). 2) In addition, some metal-L2-L3 complex released during
micellar dissociation presumably forms ‘naked’ coordination
aggregates, which are insensitive to added salt, and have a size
different from that of the micelles, as indicated by the new peaks
corresponding to a bigger size and a broad size distribution. With
To discuss the effect of the tris-ligand we select manganese,
[12]
Mn(II) which has potential as contrast agent in MRI.
Other
metals (e.g., Zn, Ni) form very similar structures (seeI) so that the
method is generic. The metal/DPA (from both L2 and L3) ratio is
fixed at 1/2, in order to keep the metal ion fully coordinated; under
these conditions one creates
a supramolecular, anionic
coordination polymer with two negative charges on each
coordination unit (4COO- + Mn2+). These polymers reversibly
assemble with the cationic/neutral P2MVP41-b-PEO205 block
copolymers into micellar particles. In the following, we vary the
L3/L2 ratio and measure response in terms of micellar size, salt
stability, and magnetic properties.
Figure 1a shows size and size distribution of Mn-L2-L3
micelles as a function of the percentage of L3 in the ligand (defined
as DPA groups from L3 divided by the total DPA amount). The
hydrodynamic radius is around 24 nm with a narrow distribution
independent of L3 fraction. Angular dependent light scattering
results indicate that both Mn-L2 and Mn-L3 micelles are spherical
nanoparticles. (Figure S3) This is confirmed by cryo-TEM images
(Figure 1c, 1d) which feature small and fairly uniform spherical
particles for both Mn-L2 (corresponding to 0% L3, Fig. 1c) and Mn-
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increasing L3 fraction, the dissociation of the Mn-L2-L3 micelles is
increasingly suppressed, finally leading to very minor decrease of
light scattering intensity. Pure L3 micelles hardly dissociate at all
and the CONTIN size distribution remains narrow with increasing
salt concentration, in contrast to micelles formed from mixed L2-
L3 ligands (Figure S9). Hence, we may conclude that replacing
bis-ligand by tris-ligand strongly and tunably enhances the salt
stability of the micelles, up to salt concentrations well beyond
physiological conditions.
between the typical spectrum of pure L2 systems (identical to that
of fully coordinated Fe-(DPA)2) and that of mixed systems: the
absorption at 350 nm decreases with increasing L3/L2 ratio and
levels off at around 60% of L3. The relaxivity of Fe-L2-L3 micelles
was measured as well, (Figure SI 12) and we find that, as for Mn,
it again increases with increasing percentage L3, reaching a
plateau around 60% of L3, just like what we found with UV-vis.
Apparently, rigid L3 causes distortion with respect to the ideal M-
(DPA)2 coordination, leading to a better access for water (inner
sphere H2O) to the metal ion, which is favorable for magnetic
relaxation.[17] In other words, the increased number of inner
sphere water molecules in the distorted M-(DPA)2 coordination
sphere enhances the magnetic relaxivity. We also note that the
non-linear dependence on L2/L3 implies that the ligands really mix
inside the micelles rather than forming a mixture of pure L2 and L3
micelles.
As the free Mn2+ is neurotoxic [18], it cannot be used in vivo.
Therefore, the high stability and relaxivity of the Mn-L3 micelles
make them very interesting candidates as in vivo MRI contrast
agent. We first investigated their cytotoxic effect, by means of the
Figure 2. a) The relaxivity r1 of Mn-L2-L3 micelles at different L3 fractions. r1 is
the longitudinal relaxivity of water protons in the presence of Mn-L2-L3 micelles.
b) UV-vis spectra of Fe-L2-L3 micelles at different L3%.
standard
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide (MTT) assay (Figure 3a). Our results indicate that Mn-L3
micelles do not show any obvious toxic effects to cells after
incubation for 24h, up to the largest concentration of 60 μM,
demonstrating good biocompatibility. Finally, in vivo MRI is
performed on 6-week-old male mice through tail vein injection at
a dose of 30 μmol/kg. The first diagrams (0 seconds) serve here
as control. As shown in figure 3b, the contrast enhancement
develops gradually over time, and reaches a maximum about 2h
after injection. The brightening effects are found mainly in liver
and kidney, which is consistent with literature reports that particles
are mainly taken up and accumulated by these two organs.[19]
From light scattering and cyro-TEM, we conclude that by
varying L3/L2 ratios we can get mixed Mn-L2-L3 micelles with
constant size but tunable cross-link density and salt response. We
now consider the magnetic properties and detailed coordination
structures. The paramagnetic manganese(II) ion carries five
unpaired 3d electrons and is one of the metal ions that can
effectively enhance positive contrast in magnetic resonance
imaging (MRI).[13] However, free Mn2+ is neurotoxic [18] and cannot
be used as such; some sort of sequestering inside inert particles
is needed. Mn-based MRI contrast agents have recently been
receiving more attention as an alternative for gadolinium-based
contrast agents, which are associated with a nephrogenic
systemic fibrosis (NSF) problem and increased safety
concerns.[14] As a measure of contrast strength, we use the
longitudinal relaxivity, defined as r1=[(1/T1)-(1/T1,0)]/CMn, (here,
CMn is the manganese concentration, and T1 and T1,0 are the
longitudinal relaxation times of the micellar solution and pure
water, respectively). For our Mn-containing micelles, the
longitudinal relaxivity is shown in Figure 2. We found that it is
around 5.6 mM-1s-1 for Mn-L2, and increases with increasing L3
fraction, initially in a linear fashion but eventually levelling off
around 60% of L3. Pure Mn-L3 micelles display the highest
relaxivity of 10.8 mM-1s-1, which is higher than any of the Mn-
based contrast agents reported so far, including free Mn2+.[15] The
non-linear dependence of relaxivity on L2/L3 implies that in these
mixed micelles the environment of the manganese ion varies with
L3 fraction. Even though the coordinating DPA moieties are the
same, L3 is clearly less flexible than L2 which may lead to strain
and distortion of the local coordination structure. [16] In order to
further investigate detailed coordination structures, we also
investigated Fe-L2-L3 micelles which show similar size and salt
response behavior as Mn-L2-L3 micelles (Figure SI 11). Fully
coordinated Fe-(DPA)2 features a typical UV-vis absorption
around 370 nm.[9a] As shown in Figure 2b, Fe-based micelles
show differences in UV absorption in the range 320-370 nm,
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Acknowledgements
This work was financially supported by the Shanghai Municipal
Natural Science Foundation (17ZR1440500, 17PJ1401800).
Keywords: polyelectrolytes micelles, coordination polymer,
tunable stability and properties, MRI contrast agent
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Figure 3. a) Relative viabilities of SMCC-7721 cells incubated with Mn-L3
micelles at different Mn2+ concentration for 24h. b) In vivo T1-weighted MR
images (0.47T) and color-mapped images of a mouse at different time post-
injection of a Mn-L3 micelles solution at a dose of 30 μmol /kg based on Mn2+
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Arrows indicate the kidney and liver.
In conclusion, we have synthesized and employed a new tris-
ligand with three DPA groups grafted on a benzene ring, to create
branched coordination polymers. Combining mixtures of this tris-
ligand (L3) and a DPA-based bis-ligand (L2) with a polycationic-
neutral diblock copolymer we obtain mixed PIC micelles with a
number of cross-links in the micellar core regulated simply by
varying the L3/L2 ratio. These mixed Mn-L2-L3 micelles feature
enhanced, tunable salt stability and magnetic relaxivity.
The presented strategy is generally applicable to other metal
ions. For example, both Zn-L2-L3 and Ni-L2-L3 micelles show
tunable response and enhanced stability against salt (Figures
S12, S13). Hence, by simple variation of composition (in terms of
metals and ligands) we can make many kinds of polyelectrolyte
complex micelles (PIC micelles) with adjusted properties which
will most likely see more applications in different fields. As an
example of a biomedical application, we prepared Mn-L3 micelles
and find that these micelles feature high stability against salt, high
relaxivity, good biocompatibility and strong contrast enhancement
in a T1-weighted in vivo MRI test, demonstrating their excellent
performance as MRI contrast agent.
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COMMUNICATION
Using two different DPA-based
Jiahua wang, Junyou wang,* Peng Ding,
Wenjuan Zhou, Yuehua Li, Markus
Drechsler, Xuhong Guo,* and Martien A.
Cohen Stuart*
oligo-ligands, namely
a bis-
ligand (L2) and tris-ligand (L3),
and metal ions we produce a
supramolecular polyelectrolyte
system with cross-links, the
number of which can be varied
by varying the L3/L2 ratio.
Combining this with a charged-
neutral diblock copolymer we
obtain M-L2-L3 micelles with
tuneable and enhanced salt
Page No. – Page No.
Beating
Brine.
Supramolecular
Crosslinker Gives Salt Resistant PIC
Micelles and Improved MRI Contrast
Agents.
stability
and
magnetic
relaxivity, that perform very well
as MRI contrast agent.
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