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Tailor-Made Ligands for Biocompatible Nanoparticles.

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DOI: 10.1002/anie.200602209
Tailor-Made Ligands for Biocompatible
Marija S. Nikolic, Maren Krack, Vesna Aleksandrovic,
Andreas Kornowski, Stephan Frster, and Horst Weller*
Nanobiotechnology is one of the most exciting fields of
nanotechnology.[1, 2] A few years ago semiconductor nanocrystals were recognized as materials perfectly suited to
replace organic dyes currently used in experiments involving
fluorescent labeling. In addition to their better photostability,
nanoparticles are superior to organic dyes in other aspects,
such as broader excitation and narrower emission spectra,
which can be easily tuned. As far as magnetic materials used
in biomedicine are concerned the use of nanoparticles of high
monodispersity with sizes in the range of those of the
biological entities under investigation offers attractive possibilities.[3] Magnetic materials currently used in magnetic
resonance imaging (MRI) techniques are obtained in a
water-based synthesis and suffer from poor size distribution
resulting in only a low enhancement of the magnetic
resonance signal.
The drawback concerning further biological applications
of nanoparticles with superior properties is that synthetic
approaches used yield nanoparticles that are insoluble in
aqueous media. However, the first step in making the
nanoparticles useful for any bioapplication is efficient phase
transfer to water. A great deal of effort has been put into this
task and all the developed methods belong to one of two
strategies:[4] ligand exchange,[5, 6] or encapsulation of the
original nanocrystals into a thick and cross-linked polymer
Herein, a ligand-exchange method for the transfer of
nanoparticles into an aqueous solution using amino-modified
poly(ethylene oxide)s (PEOs) is presented. Poly(ethylene
oxide) is a water-soluble polymer suitable for biological
application since surfaces covered with PEO have proven to
be non-immunogenic, non-antigenic, and protein resistant.[10]
Recently, it was also shown that the use of PEO in the hitherto
developed nanoparticle bioconjugates reduced nonspecific
[*] M. S. Nikolic, Dr. M. Krack, V. Aleksandrovic, Dipl.-Ing. A. Kornowski,
Prof. Dr. S. F)rster, Prof. Dr. H. Weller
Institute of Physical Chemistry
University of Hamburg
Grindelallee 117, 20146 Hamburg (Germany)
Fax: (+ 49) 40-42838-3452
[**] This work was funded by the German Research Foundation
(SFB508, GK611)and FCI.
Supporting information for this article is available on the WWW
under or from the author.
Angew. Chem. Int. Ed. 2006, 45, 6577 –6580
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
The end groups of PEOs were modified to obtain amino
functionalities at one end of the polymer chain. Amino
functionalities are anchor groups which can bind to the metal
sites of nanoparticles and, in some cases, improve the
luminescent properties of semiconductor nanocrystals.[12]
The diisocyanate coupling reaction was used to obtain
amino-functionalized PEOs. This reaction has already shown
itself to be suitable for coupling PEOs to high-molecularweight poly(ethylene imine)s (PEI).[13] In the first step, PEOs
terminated with OH groups were treated with hexamethylene
diisocyanate to obtain PEOs with NCO end groups. In the
second step, the NCO end groups were treated with a large
excess of diethylenetriamine (DETA) to obtain PEOs with
two amino groups at one end of the polymer chains
(Scheme 1). The NCO-activated PEOs were also treated
with a branched PEI of low molecular weight (Scheme 1). The
ratio of the reactants was chosen to produce molecules
carrying two PEO chains of the desired molecular weight.
Direct extraction, a very frequently used method for
phase transfer of nanoparticles, did not yield nanoparticles
soluble in water. An alternative approach consisting of the
precipitation of the nanoparticles using a nonsolvent for the
new capping ligands (hexane or cyclohexane) was applied.
The precipitate obtained was readily soluble in water as well
as in other protic solvents, such as methanol. A control test
carried out with unmodified PEOs of different molecular
weights resulted in precipitation of the polymer only, while
the nanoparticles remained well dispersed in the hexane/
chloroform mixture. This result indicated a successful binding
of the amino groups of the modified PEO to the metal sites of
nanoparticles and excluded any possible agglomeration of the
nanoparticles by poly(ethylene oxide) itself.
Amino-functionalized PEOs are excellent universal
ligands because various nanoparticles can be easily transferred into water using a similar simple procedure (Figure 1).
Figure 1. Different nanoparticles dispersed in the aqueous phase
below a hexane phase. The quantum dots retain their fluorescence
properties in water (right).
After transfer into a protic solvent, luminescent nanoparticles
retained their original optical properties; although the emitting efficiency was lower (quantum yield (QY) 20 %) as has
been observed before for nanoparticles which were brought
into the aqueous environment.[14–17]
The best quantum efficiencies for CdSe/CdS nanoparticles
were observed when PEO of Mw = 2000 g mol 1 (PEO2000)
modified with linear DETA was used (Figure 2). This result
could indicate a higher grafting density than when PEO
modified with branched PEI was used, which is expected from
steric considerations (Scheme 2). Because of the steric
disadvantages, lower grafting density is also to be expected
for higher-molecular-weight PEOs. The lower grafting densities in all these cases might result in an incomplete
passivation of the surface states and the formation of looser
barriers to water penetration, all these factors give rise to the
lower quantum efficiencies
(Figure 2).
The advantage of PEO–
PEI-branched polymers is
that this structure enables an
easier approach to the inner
binding NH2-rich shell for any
molecule of interest. Currently, the possibility of this
inner shell to be used in crosslinking reactions, which should
further stabilize the organic
coating of nanoparticles, is
under investigation.
The results obtained in
(Figure 3.) show the expected
trends for both the PEO–PEIand the PEO–DETA-based
series. With the increase of
the polymer-chain length the
hydrodynamic radii increase.
However, in the PEO–DETA
series the values obtained in
DLS measurements are conScheme 1. Synthesis of amino-functionalized PEOs; n = 45 or 144, m 4 (Mw(PEI) = 423 g mol 1).
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 6577 –6580
Figure 2. a) Absorption and b) luminescence spectra of CdSe/CdS
nanoparticles in chloroform (c) and in water with PEO2000–PEIbranched (a), PEO2000–DETA (g), PEO5000–PEI-branched (d), and PEO5000–DETA (l).
Figure 3. Diameter of the CdSe/CdS nanoparticles in chloroform (c), and in water with different polymer shells: a) PEO–PEI
series, b) PEO–DETA series (a PEO2000, g PEO5000).
Scheme 2. Ligand exchange with two different types of amino-functionalized PEOs.
siderably higher than the corresponding values in PEO–PEI
This unexpected behavior is clarified after investigation of
the water-soluble nanoparticle/polymer conjugates with
TEM. Figure 4 shows that in PEO–PEI series only single,
well separated particles are present, whereas in the PEO–
DETA series wormlike agglomerates are observed (Figure 4 c, d), which give rise to the larger hydrodynamic radii in
Angew. Chem. Int. Ed. 2006, 45, 6577 –6580
the DLS measurements. This type of organization only
appears in water, in the TEM images obtained from chloroform solutions after ligand exchange only single particles
were observed without any wormlike agglomerates present.
The packing density and the distance between individual
nanoparticles are also influenced by the sizes of nanoparticles/polymer conjugates. TEM images obtained after evaporation of a chloroform solution of CoPt3 nanoparticles before
and after ligand exchange with two polymers of different
molecular weight are presented in Figure 5. In a control
experiment (Figure 5 b), TEM images were taken after
evaporation of the chloroform from the solution of nanoparticles and unmodified poly(ethylene oxide).
The arrangement of nanoparticles was the same as that of
nanoparticles without the addition of polymer (Figure 5 a).
However, after ligand exchange, not only was the arrangement, but also the distance between the nanoparticles
changed. The separation increases with the increasing size
of the polymer chain, that is, the hydrodynamic radius. This
feature can be also seen in the TEM images of CdSe/CdS
nanoparticles obtained from water solution (Figure 4 a and b).
In conclusion, a series of polymeric ligands which enable
the phase transfer of nanoparticles has been designed. The
method used to change solubility properties is simple and can
be applied to a variety of nanoparticles that were originally
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ligands can be tailored, leaving sufficient space for further
functionalization of the nanoparticle/polymer conjugates.
Received: June 2, 2006
Revised: July 3, 2006
Published online: September 12, 2006
Keywords: bioapplications · colloids · ligand design ·
nanotechnology · poly(ethylene oxide)
Figure 4. TEM image of water soluble CdSe/CdS nanoparticles modified with a) PEO2000–PEI-branched, b) PEO5000–PEI-branched,
c) PEO2000–DETA, and d) PEO5000-DETA. Insets show enlargements.
40-nm and 4-nm scale bars apply to all main images and insets,
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Figure 5. TEM images of CoPt3 nanoparticles with a) ligand shell from
the synthesis, b) after mixing with unmodified PEO5000, and after
ligand exchange with c) PEO2000–PEI-branched and d) PEO5000–PEIbranched. 50-nm scale bar applies to all images.
only soluble in organic solvents. As a result, modified PEOcoated nanoparticles suitable for biological applications were
obtained. The number of functional-anchor groups in the new
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 6577 –6580
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