Click chemistry for the assembly of gold nanorods and silver nanoparticles

Article abstract of DOI:10.1002/chem.201101027

Click chemistry based on a 1,3-dipolar cycloaddition between lipophilic gold nanorods (GNRs) containing an acetylene group with spherical silver nanoparticles containing an azide has been accomplished (see scheme). Phantom experiments show that this organ

Full text of DOI:10.1002/chem.201101027

DOI: 10.1002/chem.201101027
Click Chemistry for the Assembly of Gold Nanorods and Silver Nanoparticles
Erica Locatelli,[a] Guido Ori,[b] Marc Fournelle,[c] Robert Lemor,[c]
Monia Montorsi,[b] and Mauro Comes Franchini*[a]
Dedicated to Professor Giuseppe Bartoli on the occasion of his 70th birthday in recognition of his fruitful career
The synthesis of compact nanostructures with highly inte-
grated functionalities through the controlled assembly of
nanoparticles (NPs) is potentially of broad interest in re-
search fields such as drug delivery, multimodal imaging, and
electronic devices.[1] This concept seems to be particularly
important in view of the emerging concept of theranostic,[2]
according to which both therapeutic and diagnostic capabili-
ties can be present in two nanostructures. A key step, how-
ever, is how to combine individual nanostructures without
loosing the original properties.[3]
Most often a single type of nanoentities have been assem-
bled by using polydentate or bioconjugate ligands[4] whereas
also heterodymer structures[5] composed of quantum dots,
magnetic, and metallic NPs have been deeply investigated.
In the latter case the optical, magnetic, and electronic prop-
erties are often altered or lost,[4d–e] since the different com-
ponents are touching each other. An elegant solution is to
build multifunctional NPs in which the individual compo-
nents are spatially separated by an organic framework ob-
tained after an organic reaction. OꢀBrien[6] recently reported
the covalent assembly of Ag, Au, and CdS spherical NPs
through amido and azo linkages. They have demonstrated
that controlled growth can be achieved by reacting the NPs
at high dilutions showing for the first time, to the best of
our knowledge, the formation of covalently bound NP as-
semblies. Noble metal nanostructures, in particular gold an
silver, play a prominent role in nanotechnology.[7] Gold
nanorods (GNRs) thanks to the two plasmon absorption
bands, tunable from the visible to the near-IR region of the
electromagnetic spectrum, have important advantages for
applications in biological sensing, imaging, and therapy.[8]
The bactericidal and bacteriostatic properties of silver ion
have been well known for some time[7b] but recently Ag NPs
have also attracted a great deal of attention in biomedical
applications due to their toxicity on cell membranes.[9] Ac-
cordingly, it would be important to have a quick, reliable,
and simple organic transformation to link these two metallic
nanostructures to obtain
a theranostic nanostructured
system. Moreover, the possibility to build polyethyleneglycol
(PEG)-based targetable nanostructures containing GNRs
linked to Ag NPs could be particularly useful for nanomedi-
cine applications. This seems to be the case for using a
chemistry tailored to generate a new nanoentity quickly and
reliably by joining small modular units therefore corre-
sponding to the click chemistry philosophy.[10] One of the
most popular reactions within the click chemistry concept is
the azide/alkyne Huisgen cycloaddition.[11] We earlier have
reported[12,13] of lipophilic GNRs entrapped into PEG-based
polymeric NPs and their suitability as optoacoustic contrast
agents.[12] Herein, we have investigated how the chemical as-
sembly of GNRs with silver nanoparticles influences the op-
tical properties.
Therefore, we wish to report the first example of click
chemistry for the covalent assembly of GNRs with spherical
Ag NPs, their entrapment into water-soluble polymeric
PEG-based micelles, and the demonstration that this assem-
bled nanostructure is suitable for optoacustic imaging. The
new disulfides 1–2 proved to be very efficient for the coating
of the two nanostructured surfaces of GNRs and of AgNPs
(Figure 1). Indeed, GNRs-CTAB and its ligand exchange
[a] E. Locatelli, Dr. M. Comes Franchini
Dipartimento di Chimica Organica “A. Mangini”
University of Bologna
Viale Risorgimento 4, 40136 Bologna (Italy)
Fax : (+39)0512093654
E-mail: mauro.comesfranchini@unibo.it
[b] Dr. G. Ori, Dr. M. Montorsi
Department of Materials and Environmental Engineering
University of Modena e Reggio Emilia
Via Vignolese 905A, 41100 Modena (Italy)
[c] Dr. M. Fournelle, Dr. R. Lemor
Fraunhofer IBMT, Group Biomedical Ultrasound Research
Ensheimer Str. 48, 66386 Sankt Ingbert (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101027.
Figure 1. w-Functionalized disulfides 1–3 used for the coating of the sur-
faces and lipophilic GNRs-1/3 and AgNPs-2/3.
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COMMUNICATION
with disulfide 1 to give lipophilic GNRs-1 was achieved
using our reported methods[13] and this procedure was also
used for the coating of commercially available Ag NPs with
disulfide 2 giving AgNPs-2 (see Figures S1–S4 in the Sup-
porting Information). On the other hand, disulfide 3 has
been also already reported by us for the coating of GNRs[13]
As reported by OꢀBrien,[6] the concept of high dilution of
solvent appears to be necessary for the covalent linkage of
the reactive groups that are in the outer shell of NPs but, in
our case, we decided to dilute the functional group onto the
surface making a coating with a mixture of ligands. This pro-
tocol is scarcely reported in the literature.[14]
Therefore, GNRs-CTAB were treated at the same time
with ligands 1 and 3 in DMF in different ratios to optimize
the coating. UV/Vis spectra (lmax at 756 nm) and High Reso-
lution Transmission Electron Microscopy (HRTEM) images
of GNRs-1/3 show that the shape of the GNRs has been re-
tained (Figure 2A and B). The presence of the two ligands 1
stable and not aggregated dispersions showing a uniform
size distribution with average diameter of 12.0 nm (Fig-
ure 2C and D). In the H NMR spectrum no citrate was de-
1
tected while this time a ratio of 1:1 for 2/3 has been calculat-
1
ed in the H NMR spectrum starting with a ratio of ligands
2/3 of 5:1. The differences in the two coating could be as-
cribed to the different solubility of the ligands.
Therefore, following our interest for the 1,3-dipolar cyclo-
addition,[15] we attempted the click 1,3-dipolar cycloaddition
between the acetylenic groups of GNRs-1/3 and the azide
groups of AgNPs-2/3 to covalently link the two nanostruc-
tures. By simply admixing the lipophilic GNRs-1/3 with
AgNPs-2/3 in DMF for 24 h under reflux we obtained
GNRs-1/3-click-AgNPs-2/3, as reported in Scheme 1.
Scheme 1. Synthesis of GNRs-1/3-click-AgNPs-2/3.
The 1H NMR spectrum shows two signals at 8.96 and
9.16 ppm in a 1:1 ratio (Figure 3) corresponding to the heter-
oaromatic CH of the two possible regioisomers of the 1,2,3-
triazole ring. Copper and ruthenium are the commonly used
Figure 2. A–B) Transmission electron microscopy (TEM) and UV/Vis of
GNRs-1/3. C–D)TEM and DLS image of AgNPs-2/3.
and 3 was further confirmed by 1H NMR spectrum of
GNRs-1/3 which shows the signals corresponding to the two
ligands, such as the CH2O of the ethyl ester of 3 and the sp
Figure 3. 1H NMR and TEM of GNRs-1/3-click-AgNPs-2/3.
1
CH triple bond of 1. Moreover, H NMR spectrum shows
catalysts in the reaction, the use of copper as catalyst results
in the formation of 1,4-regioisomer whereas ruthenium re-
sults in the formation of the 1,5-regioisomer. Interestingly,
under copper catalysis[16] (CuI with NEt3) only the signal at
9.16 was present while the signal at 8.96 ppm was the only
detected under ruthenium catalysis with the chloro(penta-
methylcyclo pentadienyl)ruthenium(II) tetramer.[17]
Figure 3 shows TEM images of the assemblies from a
click linkage between GNRs-1/3 and AgNPs-2/3, where
GNRs can be easily identify by their peculiar shape. The
nature of the two different nanostructures (Au and Ag)
were analyzed and confirmed by energy dispersive analysis
the disappearance of CTAB signals indicating a complete
ligand exchange. Using a starting ratio of ligands 1/3 of 1:1,
we obtained a final ratio onto the surface of GNRs 1:1 cal-
culated by the two diagnostic signals above mentioned (see
Figures S5–S10 and in the Supporting Information and the
experimental procedures for more details). Also the AgNPs-
2/3 became lipophilic after contemporaneous ligand ex-
change with 2 and 3, and the same morphology of the start-
ing water soluble Ag NPs was retained as shown in the
TEM microphotograph. Dynamic Light Scattering (DLS)
measurements indicated that the mixture of ligands produce
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M. Comes Franchini et al.
(EDS; Figures S11 and S12 in the Supporting Information).
From TEM images a value of GNR-AgNPs interparticles
distance in the range of 2–3 nm is obtained, calculated be-
tween GNRs and the closest AgNPs respect to the GNRs
surface, which is in quite good accordance with the value ex-
pected (ca. 3 nm, see Figure S13 in the Supporting Informa-
tion), considering that between the metallic surfaces the or-
ganic clicked linkage could be further constrained.
To obtain a further insight on how molecules arrange
when assembled around a particle core, we should also
invoke the concept of molecular-scale phase separation of a
self-assembled monolayer (SAM) formed from a binary
mixture of thiols. It has been reported[18] that hydrogen-
bonding of the buried amides functionality gives formation
of nanometer-scale, phase separated discrete domains or is-
lands. This is the typical case that happens when one ligand
contains an internal amide functional group and the other is
a simple n-alkanethiol. In our case, the two ligands 1/3 for
GNRs and 2/3 for AgNPs both contained internal amide
functional group but the amide functionalities are in a dif-
ferent position of the alkylic chain, and this would confirm
the formation of phase separated discrete domains.
Furthermore, the angular distributions analysis showed
tilted 1- and 3-chains angles of approximately 29.98 and
30.58 (averaged between alkyl and phenyl titled angles, see
the Supporting Information), respectively, in good accord-
ance with literature values (ca. 308).[20] The atomic density
profiles showed averaged interatomic distances of the amide
groups respect to Au surface of approximately 14.9 ꢂnm
and 8.4 ꢂ, respectively for 1 and 3 (Figure 4). Thus, the re-
sulting difference (ca. 6.5 ꢂ) between amide groups heights
is significantly high, suggesting the impossibility to promote
H-bonding (acceptor–donor distance ꢀ3.5 ꢂ)[21] between 1
and 3. This would also suggest the formation of phase sepa-
rated discrete domains in order to promote H-bonding be-
tween ligands of the same type.
Polyethyleneglycol (PEG)-based polymeric nanoparticles
(PNPs), owing to their stealth character,[22] are useful deliv-
ery systems for in vivo applications. Poly(d,l-lactide-co-gly-
colide)-block-poly(ethylene glycol) copolymer (PLGA-b-
PEG-COOH) self-assembles to form targetable PNPs (due
to the COOH) consisting of a hydrophobic PLGA core and
a hydrophilic PEG corona-like shell.
The lipophilic cycloadduct was then entrapped into the
PLGA-b-PEG-COOH using the nanoprecipitation tech-
nique[23] as reported in Scheme 2, thus giving click-PNPs. As
a comparison we have also prepared polymeric nanoparti-
cles inside, whitout the cycloadducts blank-PNPs (see Fig-
ure S14 in the Supporting Information).
Molecular Dynamics (MD) simulations have been used to
obtain a further inside into these aspects: the quantification
of the distance between amide groups of ligands 1- and 3-
SAM respect to an AuACTHNUTRGNEUNG(111) surface and a further analysis of
the H-bonding interactions of the systems. The importance
of obtaining an insight into mixed-SAM morphology of
monolayer-protected nanoparticles have been recently high-
lighted by the possible effect/role of nanoparticle ligand
shell morphology on nanostructuring on a molecular-lengths
scale, that can be manipulated in view of specific biomedical
application.[19] MD simulations of homogenous-like surface
ligands dispositions of 1 and 3 (60 thiols on Au
ACHTUNGTRENNUNG
p
p
porting Information) showed the formation of the typical[20]
oriented thiol-SAMs respect to the surface Au normal
(Figure 4), thus demonstrating the formation of an evident
network of H-bonds between the amide groups for both the
ligands.
Scheme 2. Nanoprecipitation for the entrapment of GNRs-1/3-click-
AgNPs-2/3 into PLGA-b-PEG-COOH NPs (click-PNPs).
ICP analysis shows an Au concentration in the final
sample of 15 ppm and simultaneously an Ag concentration
of 18 ppm. DLS analysis shows that click-PNPs have an uni-
form size distribution with average diameter of 287.0 nm
and a PDI of 0.10. On the contrary, blank-PNPs have also a
PDI of 0.09 but shows an average diameter of 87.3 nm. This
increase of size clearly demonstrates the entrapment of
GNRs-1/3-click-AgNPs-2/3
into
PLGA-b-PEG-COOH
nanoparticles. Furthermore, Zeta potential analysis of click-
PNPs indicated a value of ꢁ37 mV, attesting the stability in
water of these nanoparticles.
For proving the suitability of the click-PNPs nanostructure
as contrast agent for optoacoustic imaging, we performed a
phantom study using particle-loaded alginate structures (see
Figure S17 in the Supporting Information).
Conventional GNRs-PNPs, as already reported by us[13]
without Ag-NPs, were used for as reference. Optoacoustic[24]
signal amplitudes of phantoms containing either GNRs-
PNPs or click-PNPs at the same concentration were investi-
Figure 4. MD snapshots of 1- (A) and 3-SAM (B) on Au 111 surface (Au:
violet, S: yellow, C: grey, H: white, O: red and N: blue). C) Atomic den-
sity profiles along the z-direction of hydrogen and oxygen atoms of 1-
and 3- amide groups, participating in H-bonding (z indicates the distance
respect to surface Au layer).
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Click Chemistry for the Assembly of Gold Nanorods and Silver Nanoparticles
COMMUNICATION
gated using a Nd:YAG laser at its fundamental wavelength
of 1064 nm and an optoacoustic imaging platform (DiPhAS,
Fraunhofer IBMT). A reconstructed optoacoustic cross sec-
tional image of the phantoms is shown in Figure 5.
lipophilic GNRs with organosoluble Ag NPs. The reaction
proceeds cleanly and it is reasonable to expect that the con-
cept of dilution of the functional groups onto nanostruc-
tured surfaces, with mixed SAMs, will open new opportuni-
ties in nanochemistry. Moreover, our GNRs-1/3-click-
AgNPs-2/3 has been entrapped into biodegradable, FDA-ap-
proved and targetable PEG-based polymeric nanoaparticles
(click-PNPs) and phantom experiments have shown quanti-
tatively that they efficiently generate ultrasound signals
after irradiation with laser pulses. Therefore we have shown
that the organic linkage with silver nanoparticles did not
affect the suitability of the GNRs as contrast agents for op-
toacoustic imaging. Since the toxicity of AgNPs against
cancer cells is a new emerging concept,[9] the click-PNPs
herein reported are currently being investigated in our labo-
ratories for theranostic applications in nanomedicine for
cancer treatment.
Figure 5. Cross sectional optoacoustic image through 3 alginate spheres
loaded with click-PNPs and GNRs-PNPs.
The acquired data shows that click-PNPs particles lead to
similar optoacoustic signal amplitudes than conventional
GNRs-PNPs without silver NPs. We therefore can state that
the chemical linkage between the two nanostructures does
not affect the excellent optical and optoacoustical properties
of the GNRs entrapped into the polymeric matrix.
The acquired data shows that both click-PNPs and con-
ventional GNR-PNPs are detectable with optoacoustic
imaging. In the performed experiments, signals of the click-
PNPs were detected with a signal-to-noise ratio of 45 dB
and the GNR-PNPs signals had a SNR of 55 dB (see
Figure 6). Although replacing GNR-PNPs by click-PNPs in
the phantoms has resulted in a loss of SNR of 10 dB, we can
state that both particles are well suitable as optoacoustic
contrast agent due to the high SNR which was observable
for both particle types. The chemical linkage between the
two nanostructures does therefore only slightly affect the ex-
cellent optical and optoacoustical properties of the GNRs
entrapped into the polymeric matrix.
Acknowledgements
We are grateful to Dr. M. Zapparoli of the CIGS for TEM analysis (Uni-
versity of Modena and R.E., Italy).
Keywords: click chemistry · functionalized disulfides · gold
nanorods · nanoparticles · optoacoustic imaging
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Received: April 4, 2011
Revised: May 24, 2011
Published online: July 8, 2011
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