Dual stimuli-responsive dendritic-linear block copolymers

Article abstract of DOI:10.1039/c2cc17205d

Dendritic-linear block copolymers that have pH responsive poly(benzyl ether) dendrons and temperature responsive PiPrOx chains have been designed by copper-mediated click reactions. These copolymers exhibit sharp thermal transitions with a wide range of pH-dependent thermal transition temperatures.

Full text of DOI:10.1039/c2cc17205d

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COMMUNICATION
Dual stimuli-responsive dendritic-linear block copolymersw
Joo-Ho Kim,a Eunyoung Lee,a Jun-Sik Park,b Kazunori Kataoka*b and Woo-Dong Jang*a
Received 19th November 2011, Accepted 16th February 2012
DOI: 10.1039/c2cc17205d
Dendritic-linear block copolymers that have pH responsive
poly(benzyl ether) dendrons and temperature responsive PiPrOx
chains have been designed by copper-mediated click reactions.
These copolymers exhibit sharp thermal transitions with a wide
range of pH-dependent thermal transition temperatures.
Dendritic macromolecules are promising nano-objects for use
in designing bio-inspired functional materials. Unlike common
linear-type polymers, solution properties of dendrimers can be
predominantly controlled by the nature of their peripheral
functionalities.1 Dendrimers with an ionic periphery are soluble
in aqueous medium, regardless of the hydrophobicity of the
dendrimer framework. Poly(benzyl ether) dendrimers, which
have a carboxylate periphery, would be one of the typical
examples.2 Because of the low pKa of benzoic acid (B4.8),
poly(benzyl ether) dendrimers with carboxylate peripheries
show appreciable solubility in aqueous medium under neutral
conditions. As the pH becomes lower, the peripheral carboxylates
are protonated, and the dendrimers eventually precipitate.
Using this property, pH responsive materials can easily be
designed.3 Recently, great attention has been focused on
stimuli-sensitive polymers which changes their propensity
response to external physical and chemical stimuli, such as
temperature, pH, ionic strength, and light irradiation.4 In
particular, thermo-responsive polymers have great potential
for use as sensors,5 catalyst supports,6 carriers for bioactive
materials delivery,7 and in separation processes.8 Poly(2-isopropyl-
2-oxazoline) (PiPrOx) is a typical thermo-responsive polymer
that undergoes a rapid and reversible hydration–dehydration
Scheme 1 Synthesis of dendritic-linear block copolymers.
change through the lower critical solution temperature
(LCST).9,10 The fast responsiveness of PiPrOx is achieved
by precise control of well-defined polymeric structures with
appreciably narrow molecular weight distributions, which can
be achieved by the living cationic polymerization mechanism.10
Furthermore, PiPrOx is biocompatible, biodegradable, and
possesses stealth characteristics in vitro and in vivo comparable
to poly(ethylene glycol). Based on the above information, we
have designed new type dendritic-linear block copolymers that
have pH responsive poly(benzyl ether) dendrons and temperature
responsive PiPrOx chains. The dendritic-linear block copolymer
exhibits a sharp thermal transition with a wide range of
pH-dependent thermal transition temperatures.7,11
Poly(benzyl ether) dendrimers carrying PiPrOx were synthe-
sized by copper-mediated click chemistry at 50 1C in DMF for
24 h. Clickable PiPrOx with a propargyl end-functional group
(Scheme 1; Prop-PiPrOx) was synthesized by the cationic ring
opening polymerization reaction of iPrOx.10
a Department of Chemistry, Yonsei University, Seoul 120-749, Korea.
E-mail: wdjang@yonsei.ac.kr
The reaction was initiated with propargyl tosylate at 40 1C
in acetonitrile for 10 days. The products were then characterized
with 1H NMR, GPC, and MALDI-TOF-MS analyses
(Fig. S1–S3, ESIw). The estimated number average molecular
b Department of Materials Science and Engineering, Graduate School
of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-8656, Japan. E-mail: kataoka@bmw.t.u-tokyo.ac.jp
w Electronic supplementary information (ESI) available: Detailed
synthesis and analytical data. See DOI: 10.1039/c2cc17205d
weight values of Prop-PiPrOx (Mn,GPC = 4800, Mn,TOF-MS
=
4900) were close to the value predicted from the initial
c
3662 Chem. Commun., 2012, 48, 3662–3664
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monomer/initiator ratio [Mn,calc. = 5000], and its polydispersity
index (PDI = Mw/Mn) was determined to be 1.03. Frechet’s
type dendritic bromides (GnBr; n = nth generation dendrimer,
n = 2, 3)2 were reacted with sodium azide to obtain dendritic
azides (GnN3). After conjugating GnN3 to PiPrOx, Gn-PiPrOxs
were obtained and purified using preparative recycled GPC to
remove unreacted Prop-PiPrOx and GnN3. The resulting
Gn-PiPrOxs were confirmed by 1H NMR and MALDI-
TOF-MS analyses. Finally, the peripheral methyl ester groups
of Gn-PiPrOxs were hydrolyzed using a 3 M NaOH solution,
resulting in dual-stimuli-responsive dendritic-linear block
copolymers (Scheme 1; 1 and 2).
Table 1 Result of DLS and z-potential measurement of 1 and 2
Polymer pH Temperature/1C Size/nm (PDI) z-Potential/mV
1
5.1 30
60
6.8 30
60
5.1 30
60
6.2 30
60
51.9 (0.332)
Precipitation
N.A.
587.3 (0.245)
81.4 (0.540)
Precipitation
N.A.
À5.97
N.A.a
À9.94
À22.4
À9.45
N.A.
2
À13.7
796.1 (0.459)
À27.97
a
Not available.
The thermo-responsibilities of 1, 2, and Prop-PiPrOx were
tested in physiological saline (150 mM NaCl) phosphate buffer
solution (PBS). Each polymer (0.05 mM) was dissolved in
20 mM PBS, and the pH values were then adjusted from 5.5 to
7.0. Under room temperature conditions, all polymer samples
were transparent. However, the transparent solution became
turbid when it reached the specific temperature for each
polymer solution. For precise determination of the LCST,
the change in optical transmittance at 500 nm was measured
by a spectrophotometer. The LCST was defined as the temp-
erature corresponding to a 10% decrease in the optical trans-
mittance. All polymer solutions exhibited sharp changes in
optical transmittance at specific temperatures. For example,
the Prop-PiPrOx solution became turbid around 49 1C,
regardless of the solution pH. In sharp contrast, the LCST
values of 1 and 2 were greatly dependent on the solution pH
(Fig. 1). The LCST of 1 increased from 35 to 65 1C when the
pH changed from 5.5 to 6.9. At pH lower than 5.5, the LCST
did not decrease further. Therefore, the protonation of
carboxylates was determined to be complete at this pH value.
Increases in LCST values were also not observed when the pH
was greater than 7.0, indicating that carboxylic acid deproto-
nation was complete under this condition. Compared to 1, 2
exhibited more drastic changes in LCST values. With the pH
change from 5.5 to 6.5, the LCST of 2 changed from 35 to 83 1C.
In addition, the LCST value of 2 was more pH-dependent than
that of 1, possibly because of the large number of carboxylic
acid moieties. Due to instrumental limitations, it was
impossible to determine reliable LCST values for 2 when the
pH was greater than 6.3.
Because solubility was greatly altered by pH and temperature
variation in the solutions, we hypothesize that the dendritic-
linear block copolymers exhibit pH- and temperature-
dependent morphology changes.11,12 For example, both PiPrOx
and the dendritic block become hydrophilic under conditions
of high pH with low temperature. Conversely, both PiPrOx
and the dendritic block become hydrophobic under conditions
of low pH with high temperature. The z potential and dynamic
light scattering (DLS) of each polymer solution under several
selected conditions were measured (Table 1). Due to instru-
mental limitations, the upper limit of the z potential measure-
ment was 60 1C.
As shown in Table 1, both 1 and 2 exhibited very low light
scattering intensity and ca. À10 mV of z potential when the
temperature was lower than the LCST at high pH. This
indicates that the polymers are highly soluble in their mono-
meric state because both PiPrOx and the dendritic block are
hydrophilic. In contrast, both 1 and 2 demonstrated obvious
precipitation when the temperature was higher than the LCST.
The polymers are expected to adopt self-assembled supra-
molecular architectures under conditions of low temperature
with high pH and high temperature with low pH because both
1 and 2 become amphiphilic under these conditions.13 If the
temperature is lower than the LCST under low pH, the
hydrophilic PiPrOx block should be predominantly located
at the surface area, while the hydrophobic dendritic block
should be located interior to the supramolecular architectures.
This is supported by the relatively small z potential values of 1
and 2 under those conditions. The DLS results at 30 1C and
pH 5.1 show a relatively broad distribution with average sizes
of 52.9 and 81.4 nm for 1 and 2, respectively. TEM was used to
confirm the polymer morphology under these conditions. As
expected, both 1 and 2 showed the formation of a fibrous
assembly through hydrophobic interactions of the dendritic
wedges (Fig. 2). Alternatively, the charged dendritic block
should be predominantly located at the surface under conditions
of high pH and high temperature. In fact, the z potential
values of 1 and 2 (z o À22 mV) under these conditions were
much greater than those under conditions of high pH and low
temperature. This indicates that the charged dendritic wedges
were predominantly located in the surface area of this formulation.
Therefore, we have tried to obtain information about the
morphology of self-assembled structures under these conditions.
The DLS results indicate that 1 and 2 form very large particles
Fig. 1 Temperature-dependent transmittance change by temperature
variation for 1 (a) and 2 (b), and pH-dependent LCST changes of 1 (c)
and 2 (d).
c
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Notes and references
1 (a) J. M. J. Frechet, Science, 1994, 263, 1710; (b) M. Fischer and
´
F. Vogtle, Angew. Chem., Int. Ed., 1999, 38, 884; (c) W.-S. Li and
¨
T. Aida, Chem. Rev., 2009, 109, 6047; (d) N. Nishiyama,
Y. Morimoto, W.-D. Jang and K. Kataoka, Adv. Drug Delivery
Rev., 2009, 61, 327; (e) W.-D. Jang, S. K. M. Kamruzzaman,
C.-H. Lee and I.-K. Kang, Prog. Polym. Sci., 2009, 34, 1.
2 (a) W.-D. Jang, N. Nishiyama, G.-D. Zhang, A. Harada,
D.-L. Jiang, S. Kawauchi, Y. Morimoto, M. Kikuchi,
H. Koyama, T. Aida and K. Kataoka, Angew. Chem., Int. Ed.,
2005, 44, 419; (b) R. Ideta, F. Tasaka, W.-D. Jang, N. Nishiyama,
G.-D. Zhang, A. Harada, Y. Yanagi, Y. Tamaki, T. Aida and
K. Kataoka, Nano Lett., 2005, 5, 2426; (c) W.-D. Jang,
Y. Nakagishi, N. Nishiyama, S. Kawauchi, Y. Morimoto,
M. Kikuchi and K. Kataoka, J. Controlled Release, 2006,
113, 73; (d) W.-D. Jang, N. Nishiyama and K. Kataoka, Supramol.
Chem., 2007, 19, 309.
Fig. 2 TEM images of 1 and 2. Samples were prepared from PBS
solution of pH 5.1 at 30 1C for 1 (a) and 2 (b), and pH 6.2 at 80 1C
for 2 (c).
3 (a) T. Tanaka, I. Nishio, S.-T. Sun and S. Ueno-Nishio, Science,
1982, 218, 467; (b) Y. Osada, H. Okuzaki and H. Hori, Nature,
1992, 355, 242.
4 (a) G. Chen and A. S. Hoffman, Nature, 1995, 373, 52; (b) J. Ricka
and T. Tanaka, Macromolecules, 1985, 18, 83; (c) I. C. Kwon,
Y. H. Bae and S. W. Kim, Nature, 1991, 354, 291; (d) C. Kim,
S. C. Lee, I. C. Kwon, H. Chung and S. Y. Jeong, Macromolecules,
2002, 35, 193; (e) K. M. Huh, H. Tomita, T. Ooya, W. Lee,
S. Sasaki and N. Yui, Macromolecules, 2002, 35, 3775.
5 (a) S. Uchiyama, N. Kawai, A. P. de Silva and K. Iwai, J. Am.
Chem. Soc., 2004, 126, 3032; (b) Z. B. Hu, Y. Y. Chen, C. J. Wang,
Y. D. Zheng and Y. Li, Nature, 1998, 393, 149.
6 (a) D. E. Bergbreiter, P. L. Osburn, A. Wilson and E. M. Sink,
J. Am. Chem. Soc., 2000, 122, 9058; (b) H. Hamamoto, Y. Suzuki,
Y. Yamada, H. Tabata, H. Takahashi and S. Ikegami, Angew.
Chem., Int. Ed., 2005, 44, 4536.
Fig. 3 Proposed temperature- and pH-dependent morphology
changes of dendritic-linear block copolymers.
7 (a) R. Yoshida, T. Sakai, T. Okano, Y. Sakurai, Y. H. Bae and
S. W. Kim, J. Biomater. Sci., Polym. Ed., 1991, 3, 155; (b) S. Cammas,
K. Suzuki, Y. Sone, Y. Kakurai, K. Kataoka and T. Okano,
J. Controlled Release, 1997, 48, 157; (c) K. Kono, Adv. Drug Delivery
Rev., 2001, 53, 307; (d) D. Schmaljohann, Adv. Drug Delivery Rev.,
2006, 58, 1655; (e) I. Dimitrova, B. Trzebickab, A. H. E. Muller,
A. Dworak and C. B. Tsvetanov, Prog. Polym. Sci., 2007, 32, 1275.
8 (a) H. Kanazawa, K. Yamamoto, Y. Matsushima, N. Takai,
A. Kikuchi, Y. Sakurai and T. Okano, Anal. Chem., 1996, 68, 100;
(b) A. Kikuchi and T. Okano, Prog. Polym. Sci., 2002, 27, 1165.
9 (a) H. G. Schild, Prog. Polym. Sci., 1992, 17, 163; (b) N. Adams
and U. S. Schubert, Adv. Drug Delivery Rev., 2007, 59, 1504;
(c) C. Diab, Y. Akiyama, K. Kataoka and F. M. Winnik, Macro-
molecules, 2004, 37, 2556; (d) H. Uyama and S. Kobayashi, Chem.
Lett., 1992, 1643.
10 (a) S. Kobayashi, S. Iijima, T. Igarashi and T. Saegusa, Macro-
molecules, 1987, 20, 1729; (b) R. Jordan, K. Martin, H.-J. Rader
and K. K. Unger, Macromolecules, 2001, 34, 8858; (c) J. S. Park
and K. Kataoka, Macromolecules, 2007, 40, 3599; (d) J. S. Park,
Y. Akiyama, Y. Yamasaki and K. Kataoka, Langmuir, 2007,
23, 138; (e) J. S. Park and K. Kataoka, Macromolecules, 2006,
39, 6622; (f) J. S. Park, Y. Akiyama, F. M. Winnik and
K. Kataoka, Macromolecules, 2004, 37, 6786.
that cannot be explained by the formation of a simple micellar
structure. Notably, we did not observe any precipitation under
these conditions, even though the particle size was very large.
When considering the hydrophobic nature of the dendritic
framework except carboxylate periphery, the hydrophobic
portion of the dendritic-linear block copolymers was much
greater than the hydrophilic portions under these conditions.
Therefore, the dendritic-linear block copolymers possibly
form a lamellar structure. To confirm the morphology, a hot
solution of the dendritic-linear block copolymers was freeze-
dried and subjected to TEM measurement. A sheet-like structure
was observed for 2. Dendritic-linear block copolymers success-
fully change their morphologies depending on the pH and
temperature of solution (Fig. 3).
In conclusion, new pH- and temperature-responsive dendritic-
linear block copolymers were designed by copper-mediated
click reactions between PiPrOx and poly(benzyl ether) dendrimers.
The dendritic-linear block copolymers exhibited a very wide
range of LCST variations with changes in solution pH.
Dendritic-linear block copolymers successfully changed their
morphologies with variations in pH and temperature. This
concept may contribute to the design of functional materials.
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government (MEST)
(No. 2009-0073885 and 2011-0001126). J.-H. Kim acknowledges
fellowships from the BK21 Program of MEST, Korea.
11 (a) Z. Guo, Y. Zhang, W. Huang, Y. Zhou and D. Yan, Macromol.
Rapid Commun., 2008, 29, 1746; (b) F. Liu and M. W. Urban,
Macromolecules, 2008, 41, 6531; (c) K. Kono, E. Murakami,
Y. Hiranaka, E. Yuba, C. Kojima, A. Harada and K. Sakurai, Angew.
Chem., Int. Ed., 2011, 50, 6332; (d) C. He, C. Zhao, X. Chen, Z. Guo,
X. Zhuang and X. Jing, Macromol. Rapid Commun., 2008, 29, 490.
12 (a) H.-I. Lee, J. A. Lee, Z. Poon and P. T. Hammond, Chem.
Commun., 2008, 3726–3728; (b) E. R. Gillies, T. B. Jonsson and
J. M. J. Frechet, J. Am. Chem. Soc., 2004, 126, 11936.
´
13 (a) A. Simonyan and I. Gitsov, Langmuir, 2008, 24, 11431;
(b) K. Aoi, A. Motoda and M. Okada, Macromol. Rapid Commun.,
1997, 18, 945.
c
3664 Chem. Commun., 2012, 48, 3662–3664
This journal is The Royal Society of Chemistry 2012