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Multicompartment Micelles Formed by Self-Assembly of Linear ABC Triblock Copolymers in Aqueous Medium.

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Multicomponent Micelles
DOI: 10.1002/anie.200500584
Multicompartment Micelles Formed by SelfAssembly of Linear ABC Triblock Copolymers in
Aqueous Medium**
Stephan Kubowicz, Jean-Franois Baussard,
Jean-Franois Lutz, Andreas F. Thnemann,
Hans von Berlepsch, and Andr" Laschewsky*
Multicompartment micelles composed of a water-soluble
shell and a segregated hydrophobic core are novel, most
interesting morphologies for nanotechnology, in particular for
[*] Dipl.-Phys. S. Kubowicz, J.-F. Baussard, Dr. J.-F. Lutz,
Prof. Dr. A. Laschewsky
Fraunhofer Institute for Applied Polymer Research
Geiselbergstrasse 69, 14476 Potsdam (Germany)
Fax: (+ 49) 331-977-5054
Dipl.-Phys. S. Kubowicz
Max Planck Institute of Colloids and Interfaces
Am M=hlenberg 1, 14476 Potsdam (Germany)
J.-F. Baussard
Department of Chemistry
Universit@ catholique de Louvain
1 Place Louis Pasteur, 1348 Louvain-la-Neuve (Belgium)
Prof. A. F. Th=nemann
Federal Institute for Materials Research and Testing
Richard-WillstEtter-Strasse 11, 12489 Berlin (Germany)
Dr. H. von Berlepsch
Research Center for Electron Microscopy
Free University of Berlin
Fabeckstrasse 36a, 14195 Berlin (Germany)
Prof. Dr. A. Laschewsky
Department of Chemistry
University of Potsdam
Karl-Liebknecht-Strasse 24–25, 14476 Potsdam (Germany)
[**] This research was supported by the Fonds der Chemischen
Industrie, the Fraunhofer Society, the Max-Planck Society, and the
French Community of Belgium (Action de Recherche Concert@e,
convention n8 00/05-2619). The authors thank H. Ringsdorf
(UniversitEt Mainz), A. Jonas, B. Nysten, and A. Pallandre
(Universit@ catholique de Louvain) for stimulating discussions, and
C. BHttcher (FU Berlin) for his help with the cryo-TEM experiments.
Supporting information for this article is available on the WWW
under or from the author.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 5262 –5265
nanobiotechnology.[1, 2] For example, for drug-delivery applications the separated incompatible compartments of the
hydrophobic core could enable the selective entrapment and
release of various hydrophobic drugs, while the hydrophilic
shell stabilizes these nanostructures in physiological media.
Thus, several strategies for preparing multicompartment
micelles have been proposed recently.[1, 3–8] However, so far,
the number of morphological studies concerning such
micelles is rather low and therefore little is known about
their exact internal structure.[2]
The most straightforward pathway for preparing multicompartment micelles is the direct aqueous self-assembly of
synthetic polymeric amphiphiles possessing one hydrophilic
segment and two incompatible hydrophobic segments.
Copolymers made of different segments covalently bonded
together such as block, graft, star-block, and miktoarm star
copolymers can often spontaneously self-assemble into various organized superstructures.[9] Such self-assembly processes are driven by diverse repulsion forces between the
segments. In a bulk material, the thermodynamic incompatibility between various connected results in ordered segregated nanophases.[10] In liquid media, the differences in
affinity of the various segments for the solvent lead to
dispersed organized objects. Either in bulk or in solution, the
morphology of the self-assembled structures depends on the
molecular shape of the polymeric building blocks (number of
segments, segment lengths, block sequence, architecture, and
composition).[9] Naturally, the more complex the starting
copolymers, the more complicated and difficult to analyze the
resulting superstructures are. The latter is particularly true in
solution because of the dynamic behavior of most selfassemblies.
For copolymers composed of only two different segments
(AB), the factors governing self-assembly in solution are now
well-understood, and the main morphologies such as spherical
micelles,[11] wormlike micelles,[12] and vesicles[13] have been
described. However, for more complex macromolecules such
as ABC triblock copolymers, the possibilities of self-assembly
in solution remain quite unexplored, although some morphologies have been characterized in either aqueous or
organic media. In the simplest case, two of the three ABC
segments are soluble in the solvent, resulting in micelles with
an insoluble inner core and a mixed-arm soluble shell.[14–16]
But, if two of the three ABC segments are insoluble in the
solvent, the precise morphology of the self-assemblies is
usually more difficult to describe. Concerning the general
shape of the superstructure: spherical micelles[15–23] and
vesicles[19, 24] have been prepared from ABC copolymers
having two insoluble segments. However, the morphology of
the inner core is usually hard to elucidate.
If the two blocks composing the core are large enough and
thermodynamically incompatible, they should most likely
segregate into different phases, forming two or more separated compartments in the core of the micelle. Nevertheless,
depending on the molecular structure of the segments, diverse
morphologies can be expected for the multicompartment
core, for example, “spheres in spheres” (core–shell model,
onionlike) or “spheres on spheres” (raspberrylike). Up to
now, the core structures were often presumed (in most cases,
Angew. Chem. Int. Ed. 2005, 44, 5262 –5265
core–shell construction was proposed) but were not characterized or observed by microscopy. Most recently, Lodge et al.
reported a first convincing visualization by cryo-transmission
electron microscopy (cryo-TEM) of multicompartment
micelles prepared in aqueous medium by self-assembly of
miktoarm star copolymers;[25] they described the coexistence
of segregated domains in the hydrophobic core of the formed
nanostructures. However, the precise morphology of this
inner core was not assessed.
In the present work, the aqueous self-assembly of an ABC
poly(4-methyl-4-(4vinylbenzyl)morpholin-4-ium chloride)-block-polystyreneblock-poly(pentafluorophenyl 4-vinylbenzyl ether) (PVBMb-PS-b-PVBFP) was studied (Scheme 1). The copolymer
Scheme 1. Molecular structure of the triblock copolymer PVBM-b-PS-bPVBFP and possible morphology of the multicompartment micelles
observed in aqueous medium. Light gray: hydrophilic block with morpholinium units; dark gray: hydrophobic hydrocarbon block; black:
hydrophobic fluorocarbon-rich block.
building blocks consist of a long cationic hydrophilic block,
PVBM, and two short consecutive hydrophobic blocks: a
hydrocarbon one (PS) and a mixed hydrocarbon/fluorocarbon one (PVBFP). Hydrocarbon and fluorocarbon blocks
were selected since such segments tend to be strongly
incompatible and should thus favor the segregation into
distinct domains.[1] Moreover, such a choice should lead to
compartments of markedly differing properties,[1, 3, 5, 6] as
desirable, for example, for drug-delivery applications.
The copolymer PVBM-b-PS-b-PVBFP was obtained by
quaternization of a poly(vinylbenzyl chloride)-b-PS-bPVBFP precursor with N-methylmorpholine. The triblock
precursor was prepared by a three-step reversible addition
fragmentation transfer (RAFT) polymerization process using
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
benzyl dithiobenzoate as a chain-transfer agent. To prepare
the multicompartment micelles, the triblock PVBM-b-PS-bPVBFP was initially dispersed in a dioxane/water mixture and
subsequently dialyzed stepwise against pure water. Indeed,
the choice of the organic solvent and of the mode of its
removal is crucial for the outcome of the self-assembly.[26]
Figure 1 shows typical cryo-TEM images of the aqueous
solution obtained. The images reveal uniformly dispersed
dark gray spherical objects with an average diameter of 12–
15 nm. These correspond to the formed micellesA hydrophobic
core, which is composed of segregated domains: inside the
sphere of the micellar core, dark spheres with an average
diameter of about 3.4 0.2 nm can be distinguished. The
strong contrast in the images can be attributed to the presence
Figure 1. Cryo-TEM images and a schematic representation of the
structure of multicompartment micelles obtained by self-assembly of
the triblock copolymer PVBM-b-PS-b-PVBFP in aqueous medium. The
corona of the micelles is not visible. The scale bars correspond to
50 nm.
of electron-rich fluorine atoms.[25] In average, four to ten
segregated dark domains are observed for each micellar core.
The hydrosoluble PVBM corona of the micelles is not directly
observable but can be estimated from the objects interdistance to be around 20–30 nm in diameter.
The observed core morphology resembles a raspberrylike
morphology, as first described by Stadler et al. for the bulk
self-assembly of polystyrene-b-polybutadiene-b-poly(methyl
methacrylate) (SBM) triblock copolymers.[27] Pascault et al.
demonstrated that the raspberrylike morphology can also be
observed in a micellar structure.[28, 29] In their study, micelles of
SBM were initially dispersed in a reactive epoxy–amine
mixture, which was subsequently polymerized. Their work
indicated that the initial micelle morphology was fixed in the
polymer matrix by polymerization and therefore could be
studied by TEM. Figure 1 shows a first example of a similar
morphology for micelles prepared in aqueous medium.
However, the cryo-TEM images cannot distinguish whether
the dark fluorocarbon domains are covering the surface of a
central hydrocarbon core (spheres-on-spheres, raspberrylike
morphology) as shown in Scheme 1 and as described by
Stadler et al.,[27] or whether the dark domains are embedded
in the hydrocarbon core (spheres-in-spheres morphology).
The latter structure might be expected intuitively since the
fluorinated block is the C block of the ABC sequence.
Another question arises concerning the observed morphology: are the segregated dark domains made of the
complete PVBFP blocks or only of the fluorocarbon moieties
of PVBFP? Only if the latter scenario is true can the size
measured by cryo-TEM be correlated to the molecular
volumes of the copolymers (see the Supporting Information).
For this scenario, the calculations give a global theoretical
diameter of 20.5 nm for the whole micelle (swelling of the
corona with water is not taken into account), and a diameter
of 13.8 nm for the whole hydrophobic core, values in good
agreement with the numbers obtained from the cryo-TEM
images. In contrast, when we assume that the dark regions are
due to the whole PVBFP blocks (hydrocarbon and fluorocarbon parts), the calculated diameters for the whole micelle
and for the hydrophobic core are too small. Therefore, we
conclude that the dark spheres comprise only the fluorocarbon moieties of PVBFP, whereas the dark gray region
contains both the hydrocarbon domains of PS and PVBFP.
The overall dimension of the micelle was also confirmed
by static light scattering (see the Supporting Information).
The scattering curve corresponds to the scattering of spherical
particles with a radius of gyration Rg of 14.5 nm. This number
is in good agreement with theoretical calculations and size
estimated from cryo-TEM. Also in agreement with the
micrographs, the scattering curve indicates that the size
distribution of these objects is relatively broad, as may be
expected from the polydispersity of the polymers (Mw/Mn =
In conclusion, multicompartment micelles having a diameter of 20–30 nm were prepared by the self-assembly in
aqueous medium of the amphiphilic triblock copolymer
PVBM-b-PS-b-PVBFP. As evidenced by cryo-TEM, the
core is segregated into nanometer-sized compartments in
which many small, fluorocarbon-rich domains coexist with a
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 5262 –5265
continuous hydrocarbon-rich region. These novel nanostructured colloids may serve as models as well as mimics for
biological structures such as globular proteins, and may open
up interesting opportunities for nanotechnology applications.
Received: February 16, 2005
Revised: March 29, 2005
Published online: July 20, 2005
Keywords: amphiphiles · block copolymers · colloids · micelles ·
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