Multiple-interaction ligands inspired by mussel adhesive protein: Synthesis of highly stable and biocompatible nanoparticles

Article abstract of DOI:10.1002/anie.201101521

All bound up: A poly(L-3,4-dihydroxyphenylalanine)-based ligand converts hydrophobic nanoparticles into hydrophilic and biocompatible species through several binding modes. Nanoparticles functionalized with this ligand (see picture) are highly stable in v

Full text of DOI:10.1002/anie.201101521

Communications
DOI: 10.1002/anie.201101521
Nanoparticles
Multiple-Interaction Ligands Inspired by Mussel
Adhesive Protein: Synthesis of Highly Stable and
Biocompatible Nanoparticles**
Daishun Ling, Wooram Park, Yong Il Park, Nohyun Lee, Fangyuan Li,
Changyeong Song, Su-Geun Yang, Seung Hong Choi, Kun Na,* and
Taeghwan Hyeon*
Angewandte
Chemie
11360
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 11360 –11365

Water-dispersible and biocompatible nanoparticles have
attracted much interest for their various biomedical applica-
tions, which include biological sensing, labeling, imaging, cell
separation, and disease treatment.[1] For example, superpar-
amagnetic iron oxide (SPIO) nanoparticles have already been
used in clinical applications for magnetic resonance imaging
(MRI).[2] The prerequisite for the successful biomedical use of
nanoparticles is their colloidal stability in harsh biological
environments. One main approach to render nanoparticles
water-dispersible is replacing the hydrophobic capping
ligands with hydrophilic ones that harbor anchoring groups
such as carboxylic acids, thiols, phosphines, and amines;[3] in
this case, the coordinating ability of ligands is most important
for stable dispersion in water. Ligands that harbor multiple
anchoring groups would provide notably improved colloidal
stability.[3j–m,4] Another approach employs hydrophobic inter-
actions, through which amphiphilic polymers encapsulate the
nanoparticles in a micelle form.[5] Furthermore, the two
approaches mentioned above can be combined to signifi-
cantly enhance the stability of the resulting nanoparticles
under very harsh biological conditions.[6] Mussels have an
adhesive protein that is rich in catechol and amine groups, and
has interesting properties as it can attach to almost all kinds of
surface.[7] Inspired by mussels, catechol-derived dopamine-
based ligands have also been utilized as high-affinity anchors
for nanoparticle stabilization.[3e–i,n] However, most of these
ligands, which have single catechol binding units, impart poor
stabilities to nanoparticles because of dopamine degradation
and metal-ion leaching.[3n,8] Herein, we report the design and
synthesis of a poly(l-3,4-dihydroxyphenylalanine) (poly-
DOPA) based versatile multiple-interaction ligand (MIL)
for ultrastable and biocompatible nanoparticles. To the best
of our knowledge, this is the first report on the polyDOPA-
based ligand for water-dispersible nanoparticles. Scheme 1a
shows the design of MIL, which consists of methoxy
poly(ethylene glycol) (mPEG) grafted cationic hyper-
branched polyethylenimine (bPEI) and the multi-initiated
peptide domain of polyDOPA. This mussel adhesive protein
(MAP) mimicking structure has several binding modes.
Firstly, MIL, which contains the polyDOPA domain and
primary amine end groups, enables simultaneous multiple
catechol binding and amine binding[9] onto the surface of
hydrophobic nanoparticles. Secondly, the amphiphilic hyper-
branched block copolymer structure with both hydrophobic
polyDOPA groups and hydrophilic PEG groups generates
micelles encapsulated with nanoparticles. Finally, the posi-
tively charged bPEI moiety can interact electrostatically with
negatively charged nanoparticles of many metals and metal
oxides.[3m,10] All these binding modes can work cooperatively
to generate highly stable nanoparticles in harsh biological
environments.
MIL was synthesized by the ring-opening polymerization
reaction of di-O,O’-acetyl-l-DOPA-N-carboxylanhydride
(DOPA-NCA), initiated from a macroinitiator of mPEG-
grafted bPEI (Scheme 1b; synthesis and characterization of
MIL are shown in detail in Scheme S1 and Figure S1 in the
Supporting Information). The overall synthetic procedure is
easy to scale up, and 5 g of the ligand can be produced by
using a 1 L reactor. We varied the DOPA content of MIL and
to result in MIL0, MIL1, and MIL2 (Table S1). To demon-
strate the versatility of MIL for the stabilization of various
nanoparticles, oleic acid capped nanoparticles of Fe3O4 and
MnO, and 1-dodecanthiol capped Au nanoparticles were
ligand-exchanged with MIL2 in chloroform at room temper-
ature. After the chloroform was removed by evaporation, the
resulting hydrophilic nanoparticles were highly dispersible in
water, even at extremely high concentrations, with a water
transfer yield of nearly 100% and without any noticeable
aggregation. The excess ligands were removed by ultracen-
trifugation or washing 3–5 times through a spin filter. This
procedure resulted in nanoparticles that were well-dispersed
in water, as confirmed by transmission electron microscopy
(TEM; Figure 1). Dynamic light scattering (DLS) measure-
ments showed that the approximate hydrodynamic diameters
(HD) of these nanoparticles are 31 nm for the MIL2-
functionalized Fe3O4 nanoparticles (core diameter of
11 nm), 34 nm for the MIL2-functionalized MnO nanoparti-
cles (core diameter of 13 nm), and 25 nm for the MIL2-
functionalized gold nanoparticles (core diameter of 5 nm).
Although MIL has a high molecular weight (Mw ꢀ 40 kDa),
the MIL shell thickness deff is smaller than free linear PEG
with Mw = 40 kDa, which is calculated to be 14 nm in aqueous
solution [calculated from Eq. (1)[12]]. On the other hand, the
HD of MIL should be larger than that of free PEG with Mw =
5 kDa [4.47 nm from Eq. (1)]. Consequently, the MIL shell
thickness of between 4.47 nm and 14 nm is reasonable. This
small shell thickness of MIL seems to be derived from the
[*] D. Ling,[+] Y. I. Park, N. Lee, C. Song, Prof. T. Hyeon
World Class University (WCU) program of Chemical Convergence
for Energy & Environment (C2E2) and
School of Chemical and Biological Engineering
Seoul National University, Seoul 151-744 (Korea)
E-mail: thyeon@snu.ac.kr
W. Park,[+] F. Li, Prof. K. Na
Department of Biotechnology, The Catholic University of Korea
Bucheon-si, Gyeonggi-do 420-743 (Korea)
E-mail: kna6997@catholic.ac.kr
Prof. S. H. Choi
Diagnostic Radiology, Seoul National University Hospital, and
Institute of Radiation Medicine, Medical Research Center
Seoul National University, Seoul 110-744 (Korea)
Prof. S.-G. Yang
Department of Applied Bioscience, CHA University
Seoul 135-081 (Korea)
[+] These authors contributed equally to this work.
[**] We thank Prof. Jeffery Pyun, Dr. Jeong Hyun Kim, Dr. Soongu Kwon,
and Dr. Youngjin Jang for valuable discussions. T.H. acknowledges
financial support by the Korean Ministry of Education, Science and
Technology through Strategic Research (2010-0029138), and World
Class University (R31-10013) Programs of National Research
Foundation (NRF) of Korea, and the financial support by Hanwha
Chemical Co. K.N. acknowledges financial support from the
Fundamental R&D Program for Core Technology of Materials of the
Ministry of Knowledge Economy of Korea. Y.I.P and W.P acknowl-
edge the Hi Seoul Science Fellowship from the Seoul Scholarship
Foundation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101521.
Angew. Chem. Int. Ed. 2011, 50, 11360 –11365
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Communications
value (r2) of 151.55 mmꢂ1 sꢂ1
(Figure S3), while the MIL2-
functionalizatized
MnO
nanoparticles with a core
diameter of 13 nm showed a
specific relaxivity value (r1)
of 1.80 mmꢂ1 sꢂ1 at 3 T (Fig-
ure S4). These results indi-
cate that MIL promoted
water dispersion without
affecting the integrity or
properties of the nanoparti-
cles. Analysis of the FTIR
spectra (Figure S5) showed
that the absorption band at
1710 cmꢂ1 in the oleic acid
capped Fe3O4 nanoparti-
cles[4] disappeared after the
ligand exchange with MIL2,
and that a new band related
to the amide group appeared
around 1660 cmꢂ1, thus indi-
cating that oleic acid ligand
was substituted with MIL2.
Thermogravimetric analysis
was performed to quantify
the amount of MIL2 bound
to the nanoparticles. The
weight loss curve showed
that the oleic acid capped
Fe3O4 nanoparticles con-
tained approximately 18%
hydrophobic
surfactant
layer, whereas MIL2-func-
tionalized Fe3O4 nanoparti-
cles contained approxi-
mately 37% by weight of
this layer (Figure S6). This
dense polymer shell is nec-
essary to provide high colloi-
dal stability and presumably
to extend the blood circula-
tion time. The capacity of
facile and successful ligand
Scheme 1. a) Formation of water-dispersible nanoparticles though multiple-interaction ligand (MIL) stabiliza-
exchange with all these
tion. b) Synthetic route to MIL.
nanoparticles should arise
from the multiple-interac-
branched structure of MIL, rather than the linear polymeric
structure.[11]
tion properties of the MILs. All the above MIL2-functional-
ized nanoparticles are stable for more than 1 month at room
temperature or more than 3 h in boiling water without any
noticeable HD change (Figure S7). This excellent stability of
the MIL2-functionalized metal oxide (Fe3O4 and MnO)
nanoparticles seems to be predominantly because of the 1,2-
benzenediol functional groups on MIL2, while the compara-
ble stability of the MIL2-functionalized noble metal (Au)
nanoparticles seems to result from a synergistic kinetic
capping effect of the primary amine end groups in MIL.[13]
To further explore the binding effect of the polyDOPA
domain, we studied the stability of the resulting Fe3O4
deff,PEG ¼ 2 rh ¼ 0:03824 Mw 0:559
ðrh ¼ hydrodynamic radius,
ð1Þ
½12ꢁ
Mw ¼ molecular weight of PEGÞ
The absorption spectra of the Au nanoparticles before and
after ligand exchange with MIL2 were nearly identical
(Figure S2). The MIL2-functionalized Fe3O4 nanoparticles
with a core diameter of 11 nm showed a specific relaxivity
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Angew. Chem. Int. Ed. 2011, 50, 11360 –11365

Figure 1. TEM images of hydrophobic nanoparticles (upper panels)
and hydrophilic counterparts that are functionalized with MIL2 (center
panels): a,d) 11 nm Fe3O4, b,e) 13 nm MnO, and c,f) 5 nm Au nano-
particles. DLS data for the MIL2-functionalized nanoparticles (lower
panels): g) Fe3O4, h) MnO, and i) Au nanoparticles.
~
^
*
)
Figure 2. In vitro stability tests of MIL0 ( ), MIL1( ), and MIL2 (
functionalized Fe3O4 nanoparticles as a function of a) NaCl concen-
tration and b) pH. c) In vivo stability tests: blood circulation data
(plasma iron concentration versus time relationships) of MIL0, MIL1,
and MIL2-functionalized Fe3O4 nanoparticles injected into 8 weeks
BALB/c mice (see inset; n=3 for each group, 3 mg [Fe] per kg of mice
body weight).
nanoparticles as a function of different DOPA ratio in various
acidic, basic, and salt solutions. We found that MIL0 (0 DOPA
unit) functionalized Fe3O4 nanoparticles are unstable in
strong acidic, basic, or concentrated NaCl solutions
(Figure 2), and even precipitated in distilled water within a
few weeks, whereas the MIL1- and MIL2-functionalized
Fe3O4 nanoparticles are very stable (Figure S8). The MIL1 (5
DOPA units) functionalized Fe3O4 nanoparticles were shown
to be stable at pH 1–13 and at a high NaCl salt concentration
(up to ca. 3m), whereas the MIL2 (15 DOPA units) function-
alized Fe3O4 nanoparticles exhibited an amazing stability in
an almost-saturated NaCl solution of up to 5m and a very
broad pH range of 1–14 (Figure 2). The MIL2-functionalized
Fe3O4 nanoparticles can maintain their shape and size under
the extremely acidic conditions of pH 1 for up to one day
before they slowly decompose through the etching process,
according to TEM measurements (Figures S9 and S10). This
effect may be attributable to the existence of a hydrophobic
polyDOPA layer that prevents hydrophilic species such as H+
ions from reacting with the nanoparticles.[14] Furthermore, the
metal catecholate complex formed in the polyDOPA layer[15]
might inhibit metal-ion leaching and consequently maintain
the stability of the whole matrix. The DOPA-content-related
stability suggested that more DOPA units make more
bonding points on nanoparticle surfaces, and consequently
induce increased hydrophobic interaction with the nano-
particles. The increased hydrophobicity of MIL2 with
increased DOPA content was confirmed by a critical micelle
concentration (CMC) test (Figure S1–7).
that the RITC (rhodamine B isothiocyanate) labeled MIL2-
functionalized Fe3O4 nanoparticles can be easily transfected
to MDA-MB-231 cancer cells, but showed no appreciable
cytotoxicity, thus indicating their excellent biocompatibility.
The cytotoxicity of MIL2-functionalized Fe3O4 nanoparticles
was further evaluated by MTT assay, trypan blue exclusion
assay, and live and dead assay of Hela cells (Figures S12 and
S13). The MTT assay showed that cell viability was not
hindered following culture with a concentration of 600 mg
Fe mLꢂ1 for both 24 h and 72 h after the incubation. Trypan
blue exclusion assays also showed that cell proliferation was
not reduced in the presence of the MIL2-functionalizatized
Fe3O4 nanoparticles even after 72 h. Furthermore, for the live
and dead assay, no toxicity was found by fluorescence
microscopy in the cells treated with various concentrations
of the MIL2-functionalized Fe3O4 nanoparticles. These results
demonstrated that the MIL2-functionalized Fe3O4 nanopar-
ticles are highly biocompatible. The in vivo mice pharmaco-
kinetic studies showed that the MIL2-functionalized Fe3O4
nanoparticles (T1/2,MIL2 = 3.45 h) had a longer blood circula-
tion time than that of MIL1- and MIL0-functionalized Fe3O4
nanoparticles (T1/2,MIL1 = 1.30 h, T1/2,MIL0 = 0.56 h). We attri-
bute this variation to the different DOPA content of MIL.
The blood half-lives of both the MIL1- and MIL2-function-
alized Fe3O4 nanoparticles are much longer than that of
previously reported iron oxide based nanoparticles.[16] Bio-
distribution studies showed a relatively high accumulation of
the MIL-functionalized Fe3O4 nanoparticles in the spleen and
The confocal laser scanning microscopy (CLSM) study
(Figure S11) and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide) assay (Figure S12) showed
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Communications
liver (Figure S14), as has been commonly observed for
nanoparticles in vivo.[16] As a representative biomedical
application, MRI was performed using the MIL2-functional-
ized Fe3O4 nanoparticles as a T2 MRI contrast agent. The
in vivo mouse MRI results (Figure 3 and Table S2) obtained
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Figure 3. Time-dependent T2-weighted MR images of a nude mouse
a) before, b) immediately after, c) 2 h after, d) 24 h after intravenous
administration of the MIL2-functionalized Fe3O4 nanoparticles (2.5 mg
[Fe] per kg of mouse body weight).
by using the MIL2-functionalized Fe3O4 nanoparticles
showed that the nanoparticles exhibited a long blood
circulation time and accumulated in lymph nodes, as shown
in the MR image obtained 24 h after injection (Figures S15
and S16).[17] These data indicated that the MIL2-functional-
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nanoparticles are highly stable in various harsh biological
media for diverse biomedical applications such as MRI and
cell labeling.
In summary, a mussel-inspired multiple-interaction ligand
(MIL) was developed by combining poly(ethylene glycol),
polyethylenimine, and polyDOPA. The MIL can stabilize
various nanoparticles of metals and metal oxides by various
cooperative binding modes, including direct binding with
catechol and amine groups, micelle formation, and electro-
static interaction between positively charged ligands and the
negatively charged nanoparticle surface. The MIL2-stabilized
nanoparticles of Fe3O4, MnO, and Au exhibited extremely
high stability in various harsh aqueous environments, includ-
ing highly acidic and basic media, highly concentrated NaCl
solutions, and even boiling water. The synthetic procedure is
easy to scale up, and the ligand-exchange process is very
simple and short. The successful in vivo MRI application
using the MIL2-functionalized Fe3O4 nanoparticles confirmed
the suitability of these species for various biomedical
applications.
Received: March 2, 2011
Revised: August 22, 2011
Published online: September 16, 2011
Keywords: biocompatibility · contrast agents ·
.
coordination modes · nanoparticles · polymers
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