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Synthesis of nanostructured materials in inverse

miniemulsions and their applications
Cite this: DOI: 10.1039/c3nr03190j
Published on 15 August 2013. Downloaded by Boston College on 19/09/2013 21:46:00.

Zhihai Cao*a and Ulrich Zienerb

Received 21st June 2013
Accepted 13th August 2013
DOI: 10.1039/c3nr03190j
www.rsc.org/nanoscale
Polymeric nanogels, inorganic nanoparticles, and organic–inorganic hybrid nanoparticles can be prepared
via the inverse miniemulsion technique. Hydrophilic functional cargos, such as proteins, DNA, and
macromolecular fluoresceins, may be conveniently encapsulated in these nanostructured materials. In
this review, the progress of inverse miniemulsions since 2000 is summarized on the basis of the types of
reactions carried out in inverse miniemulsions, including conventional free radical polymerization,
controlled/living radical polymerization, polycondensation, polyaddition, anionic polymerization,
catalytic oxidation reaction, sol–gel process, and precipitation reaction of inorganic precursors. In
addition, the applications of the nanostructured materials synthesized in inverse miniemulsions are also
reviewed.

1 Introduction compounds, e.g., hexadecane); polymer particles are subse-

Miniemulsion systems belong to systems consisting of a
continuous phase and a dispersed phase with a particle/droplet
size of 50–500 nm (Fig. 1).1,2 In the early stage of the develop-
ment of a miniemulsion, the dispersed phase is mainly
composed of hydrophobic vinyl monomers (e.g., styrene and
methyl methacrylate) and a costabilizer (superhydrophobic
a
College of Materials, Chemistry and Chemical Engineering, Hangzhou Normal
University, Xuelin Street 16, Hangzhou, 310036, China. E-mail: caozhihai@hznu.
edu.cn
b
Institute of Organic Chemistry III – Macromolecular Chemistry and Organic
Materials, University of Ulm, Albert-Einstein-Allee 11, Ulm 89081, Germany
quently formed via free radical polymerization. In a typical
miniemulsion system, the dispersed phase is only composed of
surfactant-stabilized monomer droplets. Moreover, the surface
area of monomer droplets in miniemulsions is large enough to
adsorb radicals produced in the continuous phase; thus,
particles are mainly formed via a droplet nucleation mechanism
independent of the loci of polymerization initiation. Addition-
ally, the molecular net diffusion between droplets is effectively
suppressed by the added costabilizer, which can establish an
osmotic pressure in the droplets to counteract the Laplace
pressure. At the end of the last century, miniemulsion
systems were included in various emerging applications in the
preparation of versatile functional nanocomposites, such as

Zhihai Cao received his PhD Ulrich Ziener received his

degree from Zhejiang University
in 2009. He worked as a post-
doctoral fellow at the Institute of
Organic Chemistry III – Macro-
molecular Chemistry and
Organic Materials, University of
Ulm, from 2009 to 2010.
Currently, he is an associate
professor at the College of
Materials, Chemistry and
Chemical Engineering, Hang-
zhou Normal University. His
research interests include the design, synthesis, characterization,
and applications of novel polymeric, organic–inorganic hybrid,
and inorganic nano- and micro-structured materials.
doctoral degree from the
University of Tuebingen, Ger-
many, in 1995. Aer post-
doctoral stays at the Max-Planck
Institute for Polymer Research in
Mainz, Germany, at the Uni-
versité Louis Pasteur, Stras-
bourg, France, and at the
Institute for New Materials,
Saarbrücken, Germany, he
received a permanent scientic
position at the University of
Ulm, Germany, in 2001. There, he nished his habilitation in 2008
and was appointed professor in 2012. His interests lie in the elds
of supramolecular, macromolecular, and colloidal chemistry for
the synthesis of organic materials.

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Fig. 1 Schematic representation of the preparation and reaction mechanism of
direct (a) and inverse (b) miniemulsions.
organic–inorganic hybrid nanoparticles and nanocapsules.
These developments have led to rapid progress in this area. In
addition to free radical polymerization, an increasing number
of types of reactions have been successfully carried out in
miniemulsion systems, a development that has enriched the
types of nanoparticles and their applications. These reactions
include hydrolysis and condensation reactions of inorganic
precursors, polycondensation, polyaddition, ionic polymeriza-
tion, and controlled/living radical polymerization (CLRP).
The invention and development of inverse miniemulsions
have contributed signicantly to the development of the eld of
miniemulsions in recent years. In particular, nano- or micro-gels
are commonly prepared in inverse systems such as inverse (micro)
emulsions or inverse suspensions.3 Landfester et al. showed that
the criteria for miniemulsions established in direct oil-in-water
systems could also be extended to inverse miniemulsions in
which hydrophilic nanogels, inorganic particles, or hydrophilic
nanocomposites may be prepared.4 In general, inverse mini-
emulsions are composed of a polar dispersed phase and a
hydrophobic continuous phase, such as water-in-oil (W/O)
systems (Fig. 1b). In this review, we use the criteria proposed by
Landfester et al. to dene inverse miniemulsions, in which the
dispersed phase is more polar than the continuous phase, for
example, hydrophilic monomer droplets as the dispersed phase
and a hydrocarbon solution of surfactant as the continuous
phase. Such miniemulsions are not solely limited to W/O systems.
To establish a stable inverse miniemulsion system, a
surfactant with a low hydrophilic–lipophilic balance (HLB)
value is required to prevent droplets or particles from
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coalescing. Analogous to direct systems, a costabilizer (normally
hydrophilic salts in inverse miniemulsions) is needed for the
dispersed phase to suppress the molecular net diffusion.
Sometimes, a cosolvent such as water, dimethylsulfoxide
(DMSO), or dimethylformamide (DMF) may be introduced into
the dispersed phase to enhance solubility of the monomers
(precursors) or to promote the dissociation of salts to improve
the droplet stability. Thus, aer polymerization, the dispersed
phase in such dispersions oen comprises not plain polymer
particles but a concentrated solution of polymers. In addition,
both cross-linked and uncross-linked dispersed phases have
been reported. Hence, several different terms referring to
nanostructured materials produced in inverse miniemulsion
systems exist, for example, nanoparticles, nanogels, and nano-
hydrogels. In this review, we dene the nano-objects composed
of hydrophilic polymers or a concentrated solution of hydro-
philic polymers as nanogels.
Landfester and Musyanovych presented a review of the
synthesis of polymeric nanogels in miniemulsions and the
applications of these nanogels.5 Capek summarized the prog-
ress of inverse miniemulsion (co)polymerization of conven-
tional water-soluble monomers from the aspects of reaction and
stabilization mechanisms, reaction kinetics, and products.6
Research work in the eld of inverse miniemulsions has also
been partially covered in some general reviews on mini-
emulsions.7–10 In the present review, we give a comprehensive
overview of the reactions (not limited to polymerization6) that
may be carried out in inverse miniemulsions, the functional
nanomaterials synthesized in inverse miniemulsions (not
limited to polymeric nanogels,5 e.g., hybrid nanogels and inor-
ganic nanoparticles), as well as the potential and known
applications of these functional nanomaterials.
2 General description of inverse
miniemulsions
As shown in Fig. 1b, an inverse miniemulsion system is
composed of a polar dispersed phase and a low-polarity
continuous phase. Polar dispersed phases are typically sterically
stabilized by a (polymeric) surfactant. The surfactants, which
may effectively provide colloidal stability in inverse mini-
emulsions have low HLB values. So far, the non-commercial
block copolymer poly(ethylene-co-butylene)-b-poly(ethylene
oxide) (P(E/B)-PEO)11 may be the most efficient among the
surfactants used in inverse miniemulsions because of its bulky
but exible molecular structure and low HLB value. A promising
characteristic of this surfactant is that the HLB value for P(E/B)-
PEO can be easily tuned by the block length of poly(ethylene
oxide). SPAN 80, a commercially available surfactant, is another
widely used surfactant in inverse miniemulsions. However, the
amount of SPAN 80 required to achieve a good colloidal stability
is much higher than that of P(E/B)-PEO.12 In addition, other
surfactants with low HLB values, such as the SPAN series,
sodium bis(2-ethylhexyl) sulfosuccinate, and amphiphilic poly-
saccharides,13 may also be used in inverse miniemulsions.
Costabilizers in inverse miniemulsions, which are lip-
ophobes, have an importance equivalent to surfactants in terms
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of their ability to build a stable inverse miniemulsion system by
suppressing Ostwald ripening. The lipophobes which must be
insoluble in the continuous phase are typically hydrophilic
salts, for example, sodium chloride, sodium sulfate, and
hydrophilic transition-metal salts.
Hydrophilic vinyl monomers may be the most frequently used
reagents in the preparation of polymer nanoparticles or nanogels
in inverse miniemulsions. However, with the development of
inverse miniemulsions in recent years, precursors for the sol–gel
process, polycondensation, and polyaddition have also been
incorporated into inverse miniemulsions to prepare versatile
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nanomaterials. In addition, the precursors may be introduced
into the dispersed or continuous phase of inverse miniemulsion
systems; therefore, both hydrophilic and hydrophobic precursors
for the preparation of nanomaterials have been reported.
In direct systems, the dispersed phase in most cases consists of
monomer droplets containing a small amount of hydrophobes.
However, in inverse miniemulsions, a specic amount of polar
cosolvents such as water is oen added to the dispersed phase.
Considering the low solubility of water in the continuous phase,
the introduction of water may partially contribute to suppression
of the molecular net diffusion between droplets. In addition, the
effectiveness of hydrophilic salts in suppressing Ostwald ripening
may be enhanced by promoting the dissociation of salts by the use
of a cosolvent. In some cases, cosolvents are required to dissolve
solid monomers or precursors. A promising characteristic of
cosolvents is that they may be used as liquid templates to form a
capsule morphology in specic systems.
Considering the easy removal of solvents to obtain dried
nanomaterials, cyclohexane may be the most frequently used low-
polarity solvent as the continuous phase. In fact, the low-polarity
solvent used as the continuous phase does not have a strict
limitation. Other versatile low-polarity solvents such as iso-
paraffinic uid (for example Isopar M), toluene, and hexadecane
have already been used to build inverse miniemulsion systems.
Analogous to those in direct miniemulsion systems, reac-
tions in inverse miniemulsions could be initiated from the
continuous phase, interface, or dispersed phase. For example,
initiators for free radical polymerization may be pre-added to
the polar solution before sonication or post-added directly to
the prepared inverse miniemulsions.
In principle, the preparation of inverse miniemulsions is the
same as that of direct miniemulsion systems, including pre-
emulsication and homogenization, as shown in Fig. 1b. The
nano-objects can form through a succeeding reaction. The
similarity of inverse and direct miniemulsions leads to their
common applications such as the preparation of nanoparticles in
the size range of 50 nm to 500 nm and preparation of nano-
composites by incorporating a second functional material.
However, there are some specic properties of the inverse mini-
emulsions which are complementary to the direct systems. These
properties are as follows: (1) hydrophilic nanostructured mate-
rials can be conveniently prepared via versatile types of reactions
in inverse miniemulsions; (2) hydrophilic substances, such as
hydrophilic salts, hydrophilic inorganic particles, hydrophilic
drugs, hydrophilic dyes, and hydrophilic magnetic contrast
agents, etc., can be easily incorporated into the matrix to prepare
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hydrophilic nanocomposites; (3) the size effect on the specic
physical properties of a polar solution can be investigated in
inverse miniemulsions; (4) nanocapsules with hydrophilic cores
can be made via an interfacial reaction or an internal phase
separation in inverse miniemulsions. The details related to these
properties will be given in the following sections.
3 Nanostructured materials synthesized in
inverse miniemulsions
3.1 Polymeric nanomaterials
3.1.1 Conventional free radical polymerization. Conven-
tional free radical polymerization may be the earliest and most
widely used reaction type in inverse miniemulsions. In principle,
all hydrophilic vinyl monomers that can undergo free radical
polymerization may be applied to prepare nanogels in inverse
miniemulsions, such as 2-hydroxyethyl methacrylate (HEMA),
acrylamide (AAm),14 acrylic acid (AA), N-isopropyl acrylamide
(NIPAM), N-vinylcaprolactam (NVCL),12 and 1-vinyl-2-pyrroli-
done.15 In comparison with the hydrophobic monomers used in
direct miniemulsion systems, hydrophilic monomers used in
inverse miniemulsions have relatively high solubility in the
continuous phase. In order to minimize partitioning of mono-
mers in the continuous phase, specic treatments are oen
required. For example, a certain amount of sodium hydroxide is
added to the dispersed phase to reduce the solubility of depro-
tonated AA in the continuous phase, and in turn improve the
droplet stability in systems for inverse miniemulsion polymeri-
zation of AA.4 Similarly, Luo et al.16 carried out inverse mini-
emulsion copolymerization of AA and sodium acrylate at a
relatively low temperature (0–5
C) by using a redox initiator
system to minimize the partitioning of monomers in the
continuous phase. Medeiros et al.12 used the strongly hydro-
phobic solvent hexadecane as the continuous phase to minimize
the partitioning of NVCL in the continuous phase.
Nanogels are promising nanocarriers for bio-
macromolecules. As highly efficient loading and controlled
release of payloads are equally important to the role of carriers,
stimuli-responsive nanogels, in particular, are among the
nanocarriers that are the most wildly investigated for tuning the
release behavior of incorporated cargos.17 The physical or
chemical properties of stimuli responsive nanogels may be
tuned by temperature, pH, ionic strength, light, redox condi-
tions, and so forth. These smart properties offer a variety of
applications of the nanogels, such as in controlled drug delivery
systems, chemical sensors, and smart catalysts.18
Enzymatic- and UV light-degradable nanogels have been
prepared via inverse miniemulsion copolymerization of AAm and
a dextran-based cross-linker with a photolabile linker (Fig. 2a).19
The nanogels could be degraded in a continuous or stepwise
manner by controlling the ultraviolet (UV) light source (Fig. 2b).
Klinger and Landfester reported that dual-stimuli-respon-
sive nanogels could be prepared via inverse miniemulsion
copolymerization of HEMA, methacrylic acid (MAA), and two
kinds of newly synthesized photodegradable cross-linkers.20
The schematic representation of the interaction between the
polymeric matrix and the loaded cargos, as well as the
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Fig. 2 Molecular structure of the dextran-based cross-linker (a) and turbidity measurements (b) for the irradiation of an aqueous nanogel dispersion prepared by
copolymerization of AAm and the cross-linker (0.0625%) with UV light (wavelength (l) ¼ 365 nm, intensity (I) ¼ 30 mW cm2) (reprinted with permission from ref. 19.
Copyright 2012 John Wiley and Sons).19

Fig. 3 Schematic representation of the loading and release strategy for poly(2-hydroxyethyl methacrylate-co-methacrylic acid) nanogels. (i) Loading of large cationic
functional compounds into the anionic gel via entrapment due to pH-induced deswelling. (ii) Diffusion-controlled release via reswelling in phosphate buffer saline (PBS).
(iii) Degradation controlled release via irradiation in PBS (reprinted with permission from ref. 20. Copyright 2011 American Chemical Society).20

encapsulation and release processes is shown in Fig. 3. The pH
sensitivity of the nanogels is induced by protonation and
deprotonation of the MAA units. The degradation of the nano-
gels may be triggered by rupturing the cross-links with UV light
(Fig. 3(iii)). They used a model protein, myoglobin, to test the
loading and releasing capabilities of the synthesized nanogels.
Poly(N-isopropyl acrylamide) (PNIPAM), a thermoresponsive
polymer, can undergo a volume phase transition when the
temperature crosses the lower critical solution temperature
(about 32
C). PNIPAM nanocapsules with narrow size distri-
bution have been prepared via inverse miniemulsion polymer-
ization of NIPAM by using aqueous salt-containing droplets as
templates (Fig. 4a and b).21 The formation of the capsule
morphology follows the polymer phase separation in the
droplets. The resulting PNIPAM capsules showed reversible
thermosensitivity (Fig. 4c). Furthermore, pH- and thermo-
sensitive capsules have been prepared via inverse miniemulsion
copolymerization of NIPAM and 4-vinyl pyridine.22
Wu et al. carried out interfacial alternating free radical
polymerization to generate nanocapsules in inverse
miniemulsions.23 They copolymerized a hydrophilic monomer,
poly(hydroxy vinyl ether), with hydrophobic maleates to form
capsules with an aqueous core. Because these two specic
monomers cannot undergo homopolymerization and display
low solubility in the other phase, the alternating polymerization
is strictly conned at the oil/water interface.
In the presence of a preformed hydrophilic polymer
(gelatin), semi-interpenetrating polymer network nanogels have
been prepared via inverse miniemulsion copolymerization of
AA and N,N-methylene bisacrylamide.24 Nanogels could be
formed from interpenetrating polymer networks by further
cross-linking gelatin with glutaraldehyde. These nanogels show
good biocompatibility and have potential applications as drug
delivery carriers for cancer targeting.
The complete removal of surfactants from the synthesized
nanoparticles by (mini)emulsion polymerization is a notori-
ously difficult problem, which sometimes limits the utilization
of nanoparticles in some special elds, such as biological or
optical applications. In addition, obtaining well-separated
nanoparticles aer drying is another unsolved problem in the

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Fig. 4 Atomic force microscopy images of PNIPAM nanocapsules synthesized in
inverse miniemulsions (a, height image; b, phase image) and temperature
dependence of the size of PNIPAM nanocapsules in water (c) (reprinted with
permission from ref. 21. Copyright 2011 American Chemical Society).21
heterophase systems, such as emulsions. Hemingway et al.
solved these two problems by using a drying technique with
supercritical CO2.25 Well-separated polyacrylamide nanogels
synthesized via inverse miniemulsion polymerization were
obtained by injection of an inverse miniemulsion into super-
critical CO2. The efficient removal of solvents and surfactants
from the inverse miniemulsion depends on highly powerful
extraction by supercritical CO2.
3.1.2 Controlled/living radical polymerization
(a) Atom transfer radical polymerization (ATRP). CLRP may be
used to prepare polymers with well-dened molecular structure,
controlled molecular weight, narrow molecular weight distri-
bution, and versatile functionalities. To our knowledge, the
application of CLRP in the synthesis of hydrophilic or water-
soluble polymers in inverse miniemulsions was rst reported by
Oh et al.26 In their report, inverse miniemulsion systems with
good colloidal stability were established for ATRP of oligo-
(ethylene glycol) monomethyl ether methacrylate (OEOMA) by
carefully selecting the appropriate surfactant, initiator, and
ligand. The inverse miniemulsion polymerization of OEOMA
proceeded in a well-controlled manner, indicated by the rela-
tively low ratio of the weight-average molecular weight to the
number-average molecular weight. Degradable nanogels have
also been prepared via ATRP by using a cross-linker containing
a disulde group. These nanogels displayed swellability that is
higher than that of the nanogels prepared through a conven-
tional radical polymerization process; this difference may be
due to the more uniform distribution of cross-links in the
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nanogels formed through ATRP. The preserved halogen end
groups in the polymers could further initiate the polymerization
of styrene to extend the polymer chains, and the resulting
amphiphilic copolymers could self-assemble to form micelles.
More detailed investigations on the inverse miniemulsion
activators generated by electron transfer (AGET) ATRP of
OEOMA are reported elsewhere.27 The inuence of synthetic
parameters on the polymerization and colloidal stability of
OEOMA has been studied in terms of the variation of initiators,
addition of poly(ethylene glycol) monomethyl ether as a cos-
tabilizer, variation of the amounts of ascorbic acid and water,
and use of a bipyridine ligand. A block copolymer, poly(oligo-
(ethylene glycol) monomethyl ether methacrylate 300-b-oligo-
(ethylene glycol) monomethyl ether methacrylate 475), was
synthesized by using poly(oligo(ethylene glycol) monomethyl
ether methacrylate 300)-Br as a macroinitiator for the poly-
merization of OEOMA475 in inverse miniemulsions.
Poly(2-hydroxyethyl methacrylate) (poly(HEMA)) nanogels
have been prepared by inverse miniemulsion ATRP of HEMA.28
Because of the different nature of HEMA and OEOMA, colloi-
dally stable inverse miniemulsion systems with HEMA could
not be achieved by using small organic surfactants with a low
HLB value, such as SPAN 80 and Brij 52. Instead, P(E/B)-PEO,
the block copolymer surfactant, has been used in this case.
Furthermore, a block copolymer, poly(HEMA)88-b-PEO77-b-
poly(HEMA)80, has been synthesized by using a poly(ethylene
glycol)-based macro-initiator.
Inverse miniemulsions show high exibility in incorporating
versatile water-soluble biomacromolecules such as proteins,
DNA, and macromolecular uoresceins. The incorporation of
biomacromolecules in the nanogels may improve their in vivo
stability, minimize immunorecognition, enhance in vivo circu-
lation and therapeutic effects, and even increase the activity of
the biomacromolecules. Recently, a green uorescent protein
(GFP) containing a site-specic initiator has been covalently
encapsulated in nanogels in inverse miniemulsions via AGET
ATRP.29 The results of UV-visible uorescence spectroscopy and
confocal microscopy clearly show that the native tertiary struc-
ture of the incorporated GFP was preserved.
Bencherif et al. prepared degradable nanogels with a
uniform network by AGET ATRP in the presence of a hydrolyt-
ically labile cross-linker.30 Rhodamine B isothiocyanate-dextran
(RITC-Dx) as a model compound was directly incorporated into
the nanogels in inverse miniemulsions. The model compound
was released by breaking the cross-links of the nanogels
(Fig. 5a). Aer modication with acryloyl chloride, the acrylated
nanogels can react with thiol-derivatized hyaluronic acid (HA)
via Michael-type addition reaction to form nanocomposite HA
hydrogels (Fig. 5b). The fast, selective, and in situ polymeriza-
tion properties of this reaction offer its potential application as
an injectable biocompatible matrix, which may be employed in
tissue engineering and drug delivery systems.
The delivery behavior of biodegradable nanogels synthesized
by inverse miniemulsion AGET ATRP has been investigated by
using RITC-Dx as a model compound.31 The incorporation
efficiency of RITC-Dx via inverse miniemulsion is more than
80 wt%, decreasing slightly with the increase in the amount of
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Fig. 5 (a) Digital images of RITC-Dx loaded poly(oligo(ethylene glycol) monomethyl ether methacrylate 300)-co-poly(HEMA) nanogels in water before (i) and after (ii)
acid-catalyzed degradation; (b) gel formation via Michael-type addition reaction under physiological conditions (reprinted with permission from ref. 30. Copyright 2009
American Chemical Society).30
RITC-Dx. The incorporated RITC-Dx could be released aer the
degradation of the disulde-containing nanogels in reducing
media. The released RITC-Dx is attached to concanavalin A, a
well-known protein that can bind to glucose at neutral pH.
These behaviors manifest the potential of this kind of nanogels
for use as carriers for carbohydrate drugs.
Degradable nanogels prepared via inverse miniemulsion
AGET ATRP of OEOMA in the presence of a disulde-function-
alized cross-linker show good biocompatibility.32 These nano-
gels could be degraded in a biocompatible solution of
glutathione. A uorescent dye and doxorubicin loaded in the
nanogels could be released aer degradation of the nanogels.
Furthermore, the OH-functionalized nanogels synthesized by
using 2-hydroxyethyl acrylate as a comonomer could be used to
react with biotin via a carbodiimide coupling reaction. The
biotin-functionalized nanogels could form bioconjugates with
avidin, and display high bioavailability.
Cationic nanogels synthesized by AGET ATRP of quaternized
2-(dimethylamino)-ethyl methacrylate and a disulde cross-
linker in inverse miniemulsions may effectively form polyplexes
with plasmid DNA or short interfering RNA (siRNA) and show
high capabilities in the delivery of nucleic acids.33
Bencherif et al. used nanogels synthesized via inverse mini-
emulsion AGET ATRP to prepare nanostructured hybrid
hydrogels.34 The nanogels functionalized with methacrylated
groups were successfully incorporated covalently into hyalur-
onic acid–glycidyl methacrylate hydrogels via photoinitiated
free radical polymerization. The nanogels bearing versatile
functionalities could endow new properties to the nano-
structured hydrogels. For example, the cell adhesiveness of
nanostructured hydrogels could be promoted by incorporating
nanogels containing Gly-Arg-Gly-Asp-Ser peptides.
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(b) Reversible addition and fragmentation transfer (RAFT)
polymerization. RAFT polymerization is another widely investi-
gated CLRP that can also be used to prepare well-dened
polymers in inverse miniemulsions. Qi et al. carried out RAFT
polymerization of AAm in inverse miniemulsions.35 The
colloidal stability of RAFT inverse miniemulsion polymerization
could be strictly controlled by using MgSO4 (lipophobe) and a
commercial surfactant (B246SF (Uniqema)). The nature of the
initiator showed a signicant inuence on the distribution of
the molecular weight. Compared with the oil-soluble initiator,
2,20 -azobis(2-methyl-propionitrile), the water soluble initiator,
4,40 -azobis(4-cyanovaleric acid), displayed much better control
over the molecular weight and its distribution. The living
property of RAFT polymerization in inverse miniemulsions is
comparable to that of AGET ATRP in inverse miniemulsions at
low conversions (<50 wt%); however, RAFT polymerization
affords less control over polymer properties at high conversions.
Well-dened hydrophilic copolymers, such as statistical and
diblock copolymers of AAm and AA,36 as well as those of AA and
sodium acrylate,37 could also be prepared via RAFT copolymer-
ization in inverse miniemulsions. The kinetics and particle
nucleation mechanism of inverse miniemulsion RAFT poly-
merization were systematically investigated by Qi et al.38 They
found that the majority of radicals that initiate controlled
polymerization came from the continuous phase of the inverse
miniemulsions. In contrast, radicals from both the continuous
and dispersed phases contribute to particle nucleation in
conventional free radical inverse miniemulsion polymerization.
Lu et al.39 used an amphiphilic PEO-RAFT agent to conne the
polymerization of NIPAM to the water/oil interface aiming at the
preparation of thermosensitive capsules in inverse mini-
emulsions. The core–shell morphology of PNIPAM nanoparticles
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was conrmed by transmission electron microscopy (TEM).
Although the molecular weight of the resulting polymer was
higher than the theoretical value, the narrow distribution of the
molecular weight (polydispersity index of 1.3) indicates that the
polymerization was controlled by the PEO-RAFT agent. Wang
et al.40 prepared redox-sensitive and shell cross-linked capsules
via RAFT polymerization in inverse miniemulsions. The cross-
links in the shell formed by introduction of bis(acryloyloxyethyl)
disulde could be cleaved via addition of dithiothreitol.
2-(Dimethylamino)ethyl methacrylate (DMAEMA) can be
used to prepare thermo- and pH-dually sensitive poly(2-(dime-
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thylamino)ethyl methacrylate) (PDMAEMA). Positively charged
PDMAEMA in water may be utilized to interact with DNA or
siRNA. Therefore, the PDMAEMA nanogels can be applied as
nanocarriers for delivering DNA or siRNA. However, biocom-
patibility and biodegradability are also critical to biological
applications of these nanogels. Oliveira et al. synthesized
biodegradable PDMAEMA nanogels via RAFT polymerization in
inverse miniemulsions by utilizing a disulde cross-linker.41
Hydrochloric acid was added to the aqueous solution to mini-
mize the partitioning of DMAEMA in the continuous phase.
RAFT polymerization offers good control over the molecular
weight and its distribution of the primary chains, allowing
fabrication of nanogels with a well-dened network structure.
3.1.3 Polyaddition and polycondensation of organic
precursors
(a) Polyurethane. Polyurethane nanoparticles or nano-
capsules can be conveniently prepared via polyaddition in
inverse miniemulsions. Hydrophilic high-molecular-weight
polyurethane nanoparticles have been synthesized through
nonaqueous inverse miniemulsion polyaddition of oligo-
(ethylene glycol) and toluene-2,4-diisocyanate (TDI) or iso-
phorone diisocyanate.42 The molecular weight of polyurethane
strongly depends on the nature of the hydrophobic continuous
phase. Isopar M as the continuous phase yielded polyurethane
with a molecular weight higher than cyclohexane.
Miniemulsions offer the possibility of conducting interfacial
reactions between one hydrophobic and one hydrophilic
compound to prepare nanocapsules. Crespy et al.43 systemati-
cally investigated the preparation of polymeric particles and
capsules including polyurethane, polyurea, and polythiourea
via interfacial polycondensation or polyaddition in inverse
miniemulsions. The particle morphology strongly depended on
the nature of the precursors and core materials. The size of the
capsules could be tuned by varying the surfactant, whereas the
shell thickness could be controlled by varying the amount of
precursor. Both polyurethane and polyurea capsules could be
easily re-dispersed in water, thus potentially opening doors to
biomedical applications. In addition, the voids of capsules
could be used as nanoreactors for certain reactions, such as the
reduction of silver salts and polymerization of vinyl monomers.
The hydrophilic contrast agents, Magnevist and Gadovist,
have been incorporated into polyurethane capsules via interfacial
polyaddition in inverse miniemulsions.44,45 Compared with that
of the capsules dispersed in cyclohexane, the size of capsules
containing contrast agents in water is larger because of the
diffusion of water into the capsules driven by the osmotic
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pressure. This result suggests that the pore size of the polymeric
shell is large enough to allow the water molecules to permeate.
The encapsulated contrast agents mainly distribute near the
inner surface of the polymeric shell, and no obvious leakage of
the contrast agents appear to occur. Compared with that of the
free contrast agents, the relaxivity of the encapsulated contrast
agents are even slightly increased. The capsules containing the
contrast agents might be employed as new magnetic resonance
imaging contrast agents for targeted imaging.
Hydrophilic uorescent dyes could also be efficiently
encapsulated via interfacial polyaddition of diol and TDI.46
Paiphansiri et al. carried out surface functionalization in order
to improve the capability of capsules to attach covalently to
specic targets such as biointerfaces.46 Carboxy groups or
amino groups were introduced onto the outer surface of poly-
urethane capsules via carboxymethylation or via adsorption of
poly(aminoethyl methacrylate hydrochloride) or poly(ethylene
imine), respectively. The amino-functionalized polyurethane
capsules show higher uptake by HeLa cells than the carboxy-
functionalized and non-functionalized polyurethane capsules.
Thus, the capsules with a specic surface characteristic may be
potential candidates for target biocarriers.
Controlled release of cargos from the capsules is an attrac-
tive approach for applications, such as drug delivery systems
and self-healing materials. Such an approach has been applied
to polyurethane nanocapsules, the shell of which, in principle,
is impermeable. Rosenbauer et al. introduced azo bonds in the
polymeric shell via interfacial polyaddition of TDI and an azo-
containing diol in inverse miniemulsions.47 As a result, the
release of the loaded cargos could be controlled by breaking the
azo bonds via external stimuli such as temperature, UV light, or
pH change.
Siebert et al.48 prepared a new class of polyurethanes that
could be degraded by thermal and acid treatment by using di-
tert-butyldiol as one precursor. The formation of tertiary
carbamate groups in the main chain of the polymer allows the
degradation of the polymer triggered by the aforementioned
treatments. Thermally and acid labile capsules were prepared
from these polymers via interfacial polyaddition in inverse
miniemulsions.
(b) Polyurea. Polyurea capsules with an aqueous core were
synthesized via interfacial polyaddition of hydrophilic 1,6-dia-
minohexane and hydrophobic TDI in inverse miniemulsions.49
Fluorescein and magnetite could be efficiently incorporated
into the capsules by pre-dispersing them in the aqueous
dispersed phase. The polyurea capsules showed no toxicity to
cells, and could be successfully taken up by HeLa cells.
Enzymatically degradable polyurea nanocapsules were
prepared by using peptide and diisocyanate as precursors in
inverse miniemulsions (Fig. 6).50 Live monitoring of the
cleavage of polyurea capsules by enzymes was realized by
measuring the extent of the recovery uorescence from the
quenched uorophore/quencher system based on uorescence
resonance energy transfer in the peptide sequences. In addi-
tion, the release of cargo from the cleaved capsules was also
investigated by using a uorescent dye as a model compound.
All results point out that the polyurea capsules containing a
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Fig. 6 Schematic representation of the interfacial polyaddition of peptide and
TDI in inverse miniemulsions (reprinted with permission from ref. 50. Copyright
2012 John Wiley and Sons).50
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peptide chain could be cleaved by enzymes. Maier et al.51
prepared cross-linked hydrophobic peptide–polymer nano-
particles in inverse miniemulsions by using DMF as a cosolvent
and isooctane as a nonpolar solvent. The resulting peptide–
polymer nanoparticles could be degraded by a protease.
(c) Other reactions. The interfacial polyaddition of polyol
and TDI was also employed to prepare cross-linked starch
capsules in inverse miniemulsions.52 The capsule morphology
was obvious, as shown by TEM observations, but the size
distribution of the capsules was relatively broad. The resulting
polymers consisted of urethane and urea groups showing low
permeability, as veried by the slight leakage of the incorpo-
rated uorescent dye. The cross-linked capsules could be used
as nanoreactors for polymerase chain reactions (PCR) by
incorporating double-stranded DNA (dsDNA) with various
numbers of base pairs.
Because of its high efficiency and mild reaction conditions,
the click reaction may be one of the most widely used reactions
for modifying materials or chemicals with different function-
alities.53,54 Polyurethane and polycyanoacrylate nanocapsules
could be easily prepared via interfacial polyaddition or anionic
polymerization in inverse miniemulsions. By incorporating
propargyl groups in poly(butyl cyanoacrylate-co-propargyl
cyanoacrylate) (poly(BCA/PCA)) capsules and azide groups in
polyurethane capsules, the nanocapsules have been further
functionalized by uorescent dyes via click reactions between
the alkyne and azide groups (Fig. 7).55
Fig. 7 Schematic representation of the fluorescent functionalization of alkyne-
functionalized poly(BCA-co-PCA) and azide-functionalized polyurethane nano-
capsules via click reaction (reprinted with permission from ref. 55. Copyright 2012
American Chemical Society).55
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Polyglycerol nanogels containing disulde groups have
been prepared via acid-catalyzed ring-opening polyaddition of
disulde-containing polyols and polyepoxides in inverse
miniemulsions.56 The size of the nanogels could be conve-
niently tuned in the range of 25 nm to 350 nm by varying the
amount of cosolvent (DMSO) and by the combination of
comonomers with various hydrophilicities. The polyglycerol
nanogels containing disulde groups could be degraded by
dithiothreitol or glutathione. Nanogels with a particle size of
about 23 nm could be rapidly taken up by cells. Compared
with the un-degradable polyglycerol nanogels, the degradable
counterparts showed very similar biocompatibility. The
degradable polyglycerol nanogels have the potential for use as
sophisticated nanovehicles.
3.1.4 Anionic polymerization. Water-sensitive reactions
could be carried out in nonaqueous inverse miniemulsions to
prepare the corresponding polymer particles. Polyamide-6
nanoparticles have been synthesized via anionic polymerization
of 3-caprolactam in nonaqueous inverse miniemulsion cata-
lyzed by NaH.57 Although the molten 3-caprolactam could also
be dispersed in a nonpolar solvent, the colloidal stability could
not be preserved during the reaction under such conditions.
Therefore, a solution of 3-caprolactam in a polar solvent, DMSO,
has been used as the dispersed phase. The resulting polyamide-
6 in a nonaqueous inverse miniemulsion displays a relatively
high molecular weight, and more importantly, the irregularities
of the polymer prepared in inverse miniemulsions are much
less expressed than that synthesized in the bulk because of
fewer side reactions.
Poly(n-butyl cyanoacrylate) capsules have been synthesized
via interfacial anionic polymerization of n-butyl cyanoacrylate
in inverse miniemulsions. A dsDNA with 790 base pairs could
be incorporated into the capsules with 100% encapsulation
efficiency.58 The size and polydispersity of the capsules were
mainly determined by the type and concentration of the
surfactant and the viscosity of the continuous phase. Recently,
Baier et al.59 conducted PCR in inverse miniemulsion droplets.
Next, a poly(n-butyl cyanoacrylate) shell was produced via
anionic polymerization on the droplets to encapsulate the PCR
products. The formation of the polymeric shell could protect the
biological materials from the inuence of the environment.
Living cells are able to take up the resulting polymeric capsules
and subsequently release the biomolecules without inducing
any toxic effect.
3.1.5 Other reactions or processes. Inverse nonaqueous
miniemulsions can be used to carry out water-sensitive reac-
tions. Recently, a catalyst-free process to build up melamine-
based Schiff base networks has been successfully carried out in
an inverse nonaqueous miniemulsion.60 Microporous mela-
mine-based nanoparticles with a quasi-spherical structure have
been prepared. However, compared with bulk melamine-based
materials, the specic surface area of nanoparticles is smaller.
Finally, nitrogenated carbon spheres with 4.2 wt% of nitrogen
content have been obtained by high temperature treatment.
Microscopic observations have shown that the original
morphology of the melamine-based nanoparticles could be
conserved aer heat treatment.
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Conducting polymers have drawn much attention in recent
years because of their unique electronic properties. Among
them, polyaniline may be the most widely investigated on
account of its high stability and controllable electronic prop-
erties. Formation of dispersions of polyaniline nanoparticles
may improve the processability and applicability of polyaniline.
Marie et al.61 prepared highly crystalline polyaniline nano-
particles both in inverse and direct miniemulsions. The inverse
miniemulsion afforded better control over the colloidal stability
in the process of oxidation than the direct miniemulsion.
However, the drawback of the preparation of polyaniline in
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miniemulsions is the relatively low molecular weight of the
polymers prepared.
Nanoparticles designed for bioapplications demand high
biocompatibility, low cytotoxicity, and biodegradability. There-
fore, nanoparticles made of naturally occurring polymers are
attractive candidates for such applications. Ethirajan et al.
prepared cross-linked gelatin nanoparticles via a multiple mini-
emulsion process.62 They rst prepared two inverse
miniemulsions containing aqueous gelatin and aqueous glutar-
aldehyde droplets and then combined the miniemulsions by
sonication. The cross-linking reaction could take place during
the fusion and ssion of the droplets. When the reaction was
performed in the swollen state of the particles, complete cross-
linking of the whole particles was observed. The cross-linked
gelatin particles showed reversible thermosensitivity, but the
extent of size variation was not signicant, probably because of
the high degree of cross-linking. The amount of free gelatin
chains remaining aer cross-linking was measured by the
bicinchoninic acid protein assay. The results indicate that more
efficient cross-linking could be achieved in inverse mini-
emulsions, compared with other techniques like desolvation and
coacervation. Furthermore, the cross-linked gelatin particles
were used as nanoreactors for the crystallization of hydroxyapa-
tite to prepare organic–inorganic hybrid nanoparticles.63
In addition to the in situ polymerization of hydrophilic
monomers, cross-linking of the hydrophilic polymers carrying
reactive groups may be an alternative for fabricating nanogels.
By making use of the oxidation of thiol groups to disulde
bonds, Groll et al. prepared biocompatible, noncytotoxic, and
degradable nanogels by cross-linking biocompatible thiol-
functionalized polymers in inverse miniemulsions.64 The
disulde cross-linked nanogels could be degraded under
reductive conditions, such as in a solution of glutathione.
By using aqueous droplets containing an antiseptic agent as
templates, Paiphansiri et al. prepared capsules composed of
hydrophobic polymers. Poly(methyl methacrylate), poly(3-cap-
rolactone), or poly(methyl acrylate) formed a shell via nano-
precipitation of the polymers from the hydrophobic continuous
phase by selective evaporation of the good solvent for the
polymers.65 The capsules loaded with the antiseptic agent were
incorporated into lms of natural rubber to prepare antiseptic
gloves.
3.1.6 Summary. Polymeric nanogels can be prepared in
inverse miniemulsions via conventional free radical polymeri-
zation, CLRP, polyaddition, polycondensation, anionic poly-
merization, cross-linking of the pre-formed polymers
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containing reactive groups, etc. Both hydrophilic and hydro-
phobic nanocapsules may be prepared in inverse mini-
emulsions. It is of high interest to incorporate functional cargos
to prepare functional nanocomposites. The inverse mini-
emulsion technique provides high exibility and convenience to
achieve this aim. Considering the low leakage of loaded cargos,
macromolecular functional compounds are more popular to be
incorporated into the polymer matrix than compounds with a
low molecular weight. Correspondingly, the change of the mesh
size of the polymer matrix or even breakage of the polymer
matrix is required for controlled release of functional cargos.
Therefore, specic bonds which may respond to the tempera-
ture, light, pH, redox conditions, enzymes, etc. should be
incorporated into the polymer matrix. The high biocompati-
bility or specic interaction with cells or tissues may be ach-
ieved by surface modication through versatile reactions, for
example click reactions.
3.2 Inorganic nanoparticles
3.2.1 Sol–gel process of inorganic precursors. Depending
on its crystal structure, TiO2 shows versatile properties,
including photocatalytic activity, high refractive index, and
good ultraviolet absorptivity, allowing a variety of applications
in technologies such as photocatalysis, solar cells, and lithium
batteries.66 In order to form crystal structures, high-temperature
reactions or annealing at elevated temperatures are frequently
employed, but this oen leads to the reduction of the surface
area because of the collapse of the pores.66 Rossmanith et al.
prepared porous anatase nanoparticles with a high specic
surface area at a relatively low temperature in inverse mini-
emulsions by using a water-soluble precursor, bis(2-hydroxy-
ethyl)titanate (EGMT).67 The relatively low hydrolysis and
condensation rates of EGMT were believed to promote the
formation of anatase. The crystal structure of TiO2 was inu-
enced by the ratio between EGMT and hydrochloric acid,
synthesis temperature, and amount of block copolymer
surfactant. It is believed that in addition to stabilizing the
dispersion, the surfactant inuences the formation of the TiO2
crystals and the pore structure of TiO2 particles as well. With the
increase in the amount of surfactant, the size of crystals
decreased and the surface area increased.
Mesoporous anatase-type TiO2 nanoparticles doped with
zirconium have been prepared through a sol–gel process
involving titanium glycolate and zirconium isopropoxide in
inverse miniemulsions.68 Zr-doped TiO2 nanoparticles with a
size in the range of 100 to 300 nm display specic surface areas
higher than that of pure TiO2. The phase stability of the anatase
is improved because of the presence of Zr, which may increase
the temperature of phase transformation from the anatase to a
rutile structure by suppressing the crystal growth of the anatase.
Promisingly, the presence of Zr in the TiO2 led to a higher
photocatalytic activity compared with that of pure TiO2.
Because of the high rates of hydrolysis and condensation
reactions of normal titanium precursors, the particle morphology
could not be controlled well in the presence of large amounts of
water as in direct aqueous or inverse aqueous miniemulsions.
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Collins et al. established an inverse miniemulsion system con-
sisting of a formamide dispersed phase and a hexadecane
continuous phase.69 Hollow titania nanocapsules were synthe-
sized via the interfacial sol–gel process of titanium(IV) ethoxide. It
should be pointed out that a small amount of water was still
required in the dispersed phase for the hydrolysis and conden-
sation reactions of the titanium precursor.
Schiller et al.70 prepared mesoporous silica particles and
capsules via a sol–gel process of a hydrophilic silica precursor in
inverse miniemulsions. Recently, Cao et al.71 reported the
fabrication of mesoporous silica capsules via an interfacial sol–
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gel process triggered by a cationic surfactant, cetyl-
trimethylammonium bromide (CTAB), on droplet templates in
inverse miniemulsions (Fig. 8). The specic surface area could
be tuned by varying the amount of tetraethylorthosilicate
(TEOS) and CTAB; similarly, the pore size could be modied by
varying the amount of CTAB. Interfacial deposition of silica
species may be triggered by the presence of transition-metal
salts. More recently, Cao et al. prepared silica nanocapsules by
promoted interfacial deposition of silica species in inverse
miniemulsions by introducing transition-metal salts such as
Co(BF4)2 and Fe(BF4)2.72 The magnetic hollow silica particles
were subsequently prepared by converting iron salts to
magnetic iron oxides by heat treatment.
Mesoporous CeO2 nanoparticles have been prepared
through a sol–gel process of the salt precursor, cerium nitrate
hexahydrate, in inverse miniemulsions.73 In this case, the
mesoporous structures have been formed in the system with or
without templates, but the specic surface area of the CeO2
nanoparticles has been increased by the addition of a second
surfactant, CTAB, poly((ethylene oxide)20-b-(propylene oxide)70-
b-(ethylene oxide)20) or poly((ethylene oxide)73-b-(propylene
oxide)28-b-(ethylene oxide)73). The CeO2 nanoparticles synthe-
sized in inverse miniemulsions show a catalytic activity for the
Fig. 8 Schematic representation of the formation of submicrometer silica capsules via an interfacial sol–gel process in inverse miniemulsions (reprinted with
permission from ref. 71. Copyright 2012 American Chemical Society).71
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oxidation of methane. In addition, the performance of these
nanoparticles is better than that of the reference samples
prepared through a bulk precipitation process; this difference is
probably due to the higher specic surface area and homoge-
nous small pores of CeO2 nanoparticles.
Superparamagnetic Fe3O4/SiO2 nanocomposites have also
been synthesized via a sol–gel process in inverse mini-
emulsions.74 The magnetic uid is dispersed in inverse mini-
emulsions by homogenization and TEOS is added through the
continuous phase, which hydrolyzes and condenses in the
droplets to form nanocomposites. The magnetic properties of
Fe3O4 are well preserved aer coating with silica.
3.2.2 Precipitation reaction of metal salts. Willert et al.
prepared a series of inorganic particles in inverse mini-
emulsions with a dispersed phase composed of aqueous salt
solutions or molten salts.75 The formation of inorganic parti-
cles, for example, Fe2O3, Fe3O4, and CaCO3, was induced by
addition of other reactive species such as methoxyethylamine
and CO2 to the continuous phase. They also prepared mini-
emulsions with droplets of molten metals, from which solid
metal nanoparticles were simply obtained by reducing the
external temperature below the melting point of the metal.
Dolcet et al. prepared ZnO colloids in inverse miniemulsions
at room temperature.76 Two inverse miniemulsions containing
a Zn salt and base were rst prepared, and then the reaction was
carried out in a conned space by mixing two inverse mini-
emulsions to obtain the ZnO colloids. Inorganic particles
synthesized through this technique were composed of the
highly crystallized wurtzite ZnO, and showed a strong UV
emission band.
Nanoparticles composed of the precursors of complex
lanthanide phosphors with binary and ternary composition
(red phosphor ((Y0.94Eu0.06)2O3), green phosphor
(La0.5Ce0.3Tb0.2PO4), and blue phosphor (Ba0.90Eu0.1MgAl10O17))
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have been prepared via evaporation of water from droplets in
inverse miniemulsions.77 The inverse miniemulsion shows
sufficiently high exibility and stability to fabricate inorganic
precursor nanoparticles. The dispersion of precursor nano-
particles has been successfully employed to fabricate lms of
red, green, or blue phosphor.
3.2.3 Summary. Inorganic nanoparticles can be prepared
via either a sol–gel process of inorganic precursors or a simple
precipitation of inorganic salts under specic conditions in
inverse miniemulsions. It is promising to obtain crystallized
TiO2 nanoparticles with a high surface area via the sol–gel
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process at relatively high temperatures in inverse mini-
emulsions. The doping of different elements to TiO2 is a
common method to improve the properties of plain TiO2, for
example the catalytic activity. The doping of other elements to
TiO2 nanoparticles may be conveniently realized by addition of
the corresponding compounds to the disperse phase of inverse
miniemulsions. The preparation of inorganic nanocapsules has
drawn intense attention in recent years, because they have high
thermal, mechanical, chemical stabilities, porous structures,
and good biocompatibility. Silica nanocapsules with aqueous
cores can be conveniently fabricated by using aqueous droplets
as templates in inverse miniemulsions. The formation of silica
capsules is triggered by the interaction between CTAB and silica
species or the interaction between transition-metal salts and
silica species. In addition, the aqueous droplets used in the
inverse miniemulsion technique can work as nanoreactors for
the precipitation of versatile inorganic salts to prepare inor-
ganic nanoparticles. In conclusion, the inverse miniemulsion
technique shows high versatility to prepare inorganic
nanoparticles.
3.3 Organic–inorganic hybrid nanoparticles
3.3.1 Metal salt/polymer hybrid nanocomposites. Hydro-
philic salts are inherently required for improving droplet
stability as they suppress Ostwald ripening in inverse mini-
emulsions. Therefore, soluble metal salts can be conveniently
incorporated into a hydrophilic polymeric nanogel via the
inverse miniemulsion technique. Cao et al. synthesized
narrowly size distributed cobalt salts containing poly(HEMA)
nanogels in inverse miniemulsions.78 They found that the
introduction of a cobalt salt has a positive impact on narrowing
the particle size distribution and improving the colloidal
stability. The inverse miniemulsion technique shows a large
versatility in incorporating various transition-metal salts79 into
different polymeric matrices, such as poly(HEMA) and poly-
acrylamide (PAAm).80 The narrowly size distributed nanogels
with transition-metal salts have potential applications in the
eld of nanolithography as etching masks to create nanopillars
or nanoholes.
3.3.2 Inorganic nanoparticles/polymer nanocomposites
(a) Inorganic nanoparticles prepared via in situ reactions in
the dispersed phase. Nanogels containing metal salts may func-
tion as nanoreactors in the preparation of metal/polymer hybrid
nanoparticles. First, silver salts were encapsulated in the
poly(HEMA) matrix via the inverse miniemulsion
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Fig. 9 TEM images of silver salt/poly(HEMA) and silver/poly(HEMA) hybrid
nanogels (reprinted with permission from ref. 81. Copyright 2011 American
Chemical Society).81
polymerization; subsequently, the silver salts inside the nano-
gels were reduced in situ by gaseous hydrazine (Fig. 9).81 The
reduction kinetics of silver ions was followed by UV-visible
spectroscopy. The formation of the silver/polymer hybrid
particles has been conrmed by TEM and X-ray diffraction.
Similarly, silver/poly(2-hydroxyethyl methacrylate-co-2-meth-
acryloxyethyl phosphorylcholine) hybrid nanogels have been
prepared and utilized to fabricate antibacterial and antifouling
multifunctional lms.82 The silver/polymer nanoparticles could
also be obtained via reduction of silver ions by the polyol
process in silver salt/polymer nanoparticles at a high tempera-
ture (150
C).15 Silver salt/polymer nanoparticles containing
ethylene glycol (reducing agent) have been also prepared via the
inverse miniemulsion polymerization technique in Isopar M, a
high-boiling-point low-polarity solvent.
Nabih et al.83 synthesized water-borne organic–inorganic
hybrid particles prepared via a multiple miniemulsion process.
They dispersed two aqueous solutions of inorganic precursors,
such as zinc acetate and phosphoric acid, in two identical
polymerizable continuous phases composed of hydrophobic
vinyl monomers and epoxy resin to form two inverse mini-
emulsions. Mixing of the two inverse miniemulsions by soni-
cation led to the formation of inorganic particles, for example,
zinc phosphate, which was dispersed in the polymerizable
continuous phase. The dispersed inorganic particles were
further dispersed in an aqueous continuous phase to form a
direct miniemulsion. Inorganic particle/polymer hybrid nano-
composites were nally prepared via free radical miniemulsion
polymerization. The major advantage of this technique is that
no organic solvent is required in the entire process.
Cross-linking of aqueous nanodroplets of poly(vinyl alcohol)
(PVA) by glutaraldehyde in inverse miniemulsions has also been
performed.84 The preloaded Fe2+ and Fe3+ ions in the PVA
nanoparticles could further react with triethylamine to form
magnetic Fe3O4 nanoparticles at the polymer/oil interfaces. The
magnetic nanoparticles mainly distribute on the surface of the
hybrid particles.
(b) Incorporating inorganic particles via polymerization.
Organic–inorganic nanocomposites may also be prepared via
free radical polymerization in inverse miniemulsions in the
presence of inorganic materials. Poly(acrylic acid-co-sodium
acrylate) (poly(AA-co-SA))/ZnO nanocomposites have been
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prepared by this technique.85 Oleic acid modied ZnO nano-
particles initially added to the continuous phase are mainly
distributed on the surface of the poly(AA-co-SA) particles. Both
the poly(AA-co-SA) nanoparticles and poly(AA-co-SA)/ZnO nano-
composites display a good capacity for pH buffering.
Poly(methacrylic acid) stabilized iron oxide nanoparticles with
a size of about 10 nm have been successfully encapsulated by
using PAAm via inverse miniemulsion polymerization.86 The
superparamagnetic nanocomposites could be easily separated
from the dispersion by using a bulk magnet; such a property
shows its potential application as a magnetic separation material.
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Magnetic Fe3O4/poly(HEMA) nanocomposites could also be
prepared via the inverse miniemulsion polymerization of HEMA.87
3.3.3 Summary. Nanocomposites may embody multiple
characteristics of the corresponding building blocks. Therefore,
much effort has been made on the preparation of nano-
composites. Metal-containing organic–inorganic nanogels can be
conveniently prepared via incorporation of metal salts or metal-
containing nanoparticles into inverse miniemulsions. The
inverse miniemulsion technique shows an extremely
high exibility to incorporate hydrophilic salts. The types
and amount of salts may be tuned in a wide range. The high
exibility can be ascribed to the inherent requirement of hydro-
philic salts to improve the droplet stability and high solubility of
most hydrophilic salts in polar solvents. Promisingly, the incor-
porated metal salts can be further converted to other functional
compounds to confer additional functionalities to nanogels.
Most of the inorganic particles have hydrophilic surfaces. These
inorganic nanoparticles can be directly incorporated into the
polymer matrix without any surface modication. The conve-
nient preparation of hydrophilic nanocomposites may be one of
the most intriguing properties of inverse miniemulsions.
4 Physical transition in droplets of inverse
miniemulsions
With the reduction of size to the nanometre range, liquids may
display signicantly different physical properties from those in
the bulk state. For example, the crystallization process can be
conveniently changed from heterogeneous nucleation in bulk
systems to homogenous nucleation in nanoobjects, leading to
an obvious change of crystallization temperature and behavior.
The inverse miniemulsion is a powerful model system to
investigate the size effect on the physical properties of hydro-
philic compounds or their aqueous (polar) solutions.
The crystallization behavior of poly(ethylene oxide) (PEO) in a
conned environment was investigated by Taden and Land-
fester.88 An aqueous solution of PEO was dispersed in a hydro-
phobic continuous phase by sonication. PEO nanoparticles in
inverse miniemulsions were obtained by the evaporation of water
from the droplets. Differential scanning calorimetry results
clearly indicate that the crystallization of PEO in the droplets,
rather than the melting process, was more strongly inuenced by
the conned space. The homogeneous crystallization of PEO in
the droplets took place in an obvious supercooling state because
of the absence of active nuclei for heterogeneous nucleation in
the droplets. In addition, the crystallization of PEO exclusively
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occurred in the respective droplet. The authors envisioned that
single-chain single crystals might be obtained by reducing the
size to contain only one polymer chain inside each droplet of the
miniemulsion. In addition, the crystallization of aqueous solu-
tions of NaCl in the conned nanodroplets was also investigated
by Montenegro et al.89 Similarly, undercooling required to obtain
crystallization was observed in this case, and it increased with
decreasing droplet size.
5 Applications of nanostructured materials
synthesized in inverse miniemulsions
The application of nanomaterials synthesized in inverse mini-
emulsions depends strongly on the chemical composition of
the polymer matrix and the incorporated functional cargos.
5.1 Imaging
By incorporating uoresceins or magnetic materials into
biocompatible nanomaterials, the image quality of cells or tissues
may be enhanced by internalization of these functional nano-
materials by cells. Functional cargos, such as uorescent dextrans,
gold nanoparticles, and proteins, have been encapsulated in
biocompatible and uniformly cross-linked nanogels by inverse
miniemulsion ATRP.90 The results of such syntheses indicate that
the functional cargos could be successfully internalized by cells via
clathrin-coated pits (Fig. 10). Modication of the nanogels with a
cell attachment peptide could promote cellular uptake.
5.2 Delivery system
As a drug carrier, (hybrid) nanogels must be re-dispersed in
aqueous media prior to use. Because the nanogels can swell in
aqueous media, the leakage of the incorporated small molecules
cannot be avoided. Therefore, functional macromolecular cargos
are more oen incorporated into the nanogels in inverse mini-
emulsions, such as proteins,20,29,34 DNA,33 dextran-based uores-
ceins,30,31,46,50 and drugs. However, sometimes the incorporated
macromolecular cargos are difficult to release because of the
small mesh size of the nanogels, the entanglement of polymer
chains, and the secondary interactions between the loaded
molecules and the polymeric matrix. Therefore, labile bonds are
introduced into the polymer matrix, such as light-, disulde-, and
enzyme-degradable bonds. As a result, release of the functional
cargos can be controlled by external triggers. Nanocapsules with
impermeable shells such as polyurethane could also be used as
carriers for controlled release of functional cargos through
incorporation of labile bonds such as azo bonds into the poly-
meric shell.47,48 The release of functional cargos could occur by
breaking the labile bonds through using external stimuli.
5.3 Nanoreactors
PCR is a typical method for amplifying the quantity of a specic
DNA sequence by using a few DNA molecules as templates. In
principle, the interaction between DNA molecules can be
completely avoided if a compartment can be created; such a
compartment contains only one DNA molecule, the minimum
amount for a PCR experiment. This requirement could be
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Review
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Fig. 10 Confocal images of nanogels loaded with rhodamine B isothiocyanate-dextran. (a) Differential interference contrast (DIC), (b) fluorescence, and (c) combined
DIC and fluorescence confocal images showing internalization of nanogels after 24 h (reprinted with permission from ref. 90. Copyright 2009 American Chemical
Society).90
conveniently met in inverse miniemulsions. By controlling the
size of the droplets and the concentration of the PCR template
in solution, Musyanovych et al. created an inverse mini-
emulsion in which each droplet contains one PCR template
molecule on average.91 Detection of PCR products in the nal
product indicated that single-molecule PCR could be success-
fully carried out in the aqueous nanodroplets.
Hamberger and coworkers conducted in situ precipitation of
hydrophilic salts inside aqueous nanodroplets in inverse
miniemulsion.92 The resulting inorganic nanoparticles were
subsequently encapsulated in a polyurethane shell via a
subsequent interfacial polyaddition.
5.4 Scaffold for the formation of functional lms
Holtze et al.93 prepared a kind of porous polymeric material by
inclusion of aqueous droplets. They dispersed an aqueous
solution of salts in a hydrophobic mixture of the monomers and
an organogelator by sonication. Because of the presence of the
organogelator, the inverse miniemulsion was frozen through
decreasing the temperature. Gelation could protect the droplets
from coalescence. The composite polymeric materials were
nally formed via photoinitiated polymerization. Fuchs et al.82
prepared antifouling and antibacterial coatings by using silver-
containing colloids of poly(2-methacryloyloxyethyl phosphoryl-
choline-co-2-hydroxyethyl methacrylate).
6 Concluding remarks and perspective
In conclusion, inverse miniemulsions may be used to prepare
nanogels, inorganic nanoparticles, and organic–inorganic
hybrid nanogels via versatile types of reactions. Macromolec-
ular functional cargos may be conveniently incorporated into
the nanogels in inverse miniemulsions. The controlled release
of these incorporated functional compounds may be performed
by breaking labile bonds in the nanogels by external stimuli,
such as light or enzymes. The functional nanogels have poten-
tial applications in imaging, delivery systems, nanoreactors,
and preparation of functional lms.
Versatile hybrid nanocomposites may be prepared via a
combination of various types of reactions in inverse mini-
emulsions. Environmentally responsive nanomaterials may
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nd wide applications in biology, controlled drug delivery,
sensors, and so forth. In principle, the inverse miniemulsion
technique offers a convenient route to synthesize responsive
nanogels. The synthesis of nanogels that respond to multiple
external stimuli in a controlled manner may also be realized in
inverse miniemulsions. Although enzyme- and light-sensitive
nanogels,19 as well as pH- and temperature-sensitive nanogels22
have been synthesized, much effort should be made to optimize
their properties and realize intelligent control. Compared to UV
light, infrared light shows higher penetration depth into
animals' skin and tissues and less damage to the healthy
tissues.94–97 Therefore, it is of high interest to develop systems
that involve infrared light for bio-applications.
Bioapplication of nanogels synthesized via the inverse min-
iemulsion technique is promising but still far from realization.
Numerous issues need to be addressed to meet the require-
ments of bioapplications, including the biocompatibility of
nanogels, purication of nanogels to remove the remaining
monomers and surfactants, control over the size and size
distribution of the nanogels, control of release of the functional
cargos at a specic site, internalization of nanogels by cells in
vitro, and in vivo experiments with nanogels.
A greater number of mechanistic investigations on inverse
miniemulsion polymerization are required. There are relatively
fewer mechanistic investigations on inverse miniemulsions than
are direct studies, perhaps because the reaction mechanism of
inverse systems is more complicated than that of direct mini-
emulsions. For instance, apart from the low aqueous solubility of
hydrophobic monomers, the solubility of most hydrophilic
monomers in the continuous phase of inverse miniemulsions
cannot be neglected. The dissolution of monomers in the
continuous phase may destabilize the miniemulsion and lead to
the formation of nanogels via secondary nucleation, especially in
systems initiated by oil-soluble initiators. This may cause the
deviation of the formation mechanism of nanogels from the
classical droplet nucleation in typical miniemulsion systems.
Acknowledgements
The nancial support from the National Natural Scientic
Foundation of China (NNSFC) project (51003023) and the
Nanoscale

Nanoscale
Hangzhou Normal University high-level talents start-up fund
(2011QDL04) is gratefully acknowledged.
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