Synthesis of biodegradable pentaarmed star-block copolymers via an asymmetric BIS-TRIS core by combination of ROP and RAFT: From star architectures to double responsive micelles

Article abstract of DOI:10.1016/j.polymer.2010.01.037

Biodegradable star-shaped poly(ε-caprolactone) and poly(ε-caprolactone-b-l-lactide) (5sPCL-b-PLLA) with five arms were synthesized by ring-opening polymerization (ROP) from an asymmetric BIS-TRIS core via core-first strategy. Subsequently, a series of amphiphilic and double responsive star-block copolymers were synthesized by Z-RAFT star polymerization of N,N-dimethylamino-2-ethyl methacrylate (DMAEMA) from the star-shaped macro-RAFT agent, which was prepared by attaching 3-benzylsulfanylthiocarbonylthiocarbonylsufanylpropionic acid (BSPA) to 5sPCL-b-PLLA using a simple two-step reaction sequence. GPC and ¹H NMR data demonstrated the polymerization courses are under control. The molecular weight of 5sPCL-b-PLLA-b-DMAEMA increased with the monomer conversion, and the molecular weight distribution was in the range of 1.19-1.37. The spherical micelles with degradable core and pH/thermo-double sensitive shell had been prepared from the aqueous medium of the amphiphilic star-shaped copolymers by dialysis method. Both pH and thermal-responsive behaviours of copolymer micelles obtained in this study were investigated. The micelle size and morphology were measured by DLS, AFM and TEM.

Full text of DOI:10.1016/j.polymer.2010.01.037

Polymer 51 (2010) 1301–1310
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Polymer
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Synthesis of biodegradable pentaarmed star-block copolymers via an asymmetric
BIS-TRIS core by combination of ROP and RAFT: From star architectures to double
responsive micelles
,
b
,
a
a
Jianbo Li a, Jie Ren a , Yang Cao , Weizhong Yuan
*
a Institute of Nano- and Bio-polymeric Materials, School of Material Science and Engineering, Tongji University, Shanghai 200092, PR China
b Key laboratory Advanced Civil Engineering Materials, Ministry of Education, School of Material Science and Engineering, Tongji University, Shanghai 200092, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Biodegradable star-shaped poly(3-caprolactone) and poly(3-caprolactone-b-L-lactide) (5sPCL-b-PLLA)
Received 9 September 2009
Received in revised form
28 December 2009
Accepted 16 January 2010
Available online 25 January 2010
with five arms were synthesized by ring-opening polymerization (ROP) from an asymmetric BIS-TRIS
core via ‘‘core-first’’ strategy. Subsequently, a series of amphiphilic and double responsive star-block
copolymers were synthesized by Z-RAFT star polymerization of N,N-dimethylamino-2-ethyl methacry-
late (DMAEMA) from the star-shaped macro-RAFT agent, which was prepared by attaching 3-benzyl-
sulfanylthiocarbonylthiocarbonylsufanylpropionic acid (BSPA) to 5sPCL-b-PLLA using a simple two-step
reaction sequence. GPC and 1H NMR data demonstrated the polymerization courses are under control.
The molecular weight of 5sPCL-b-PLLA-b-DMAEMA increased with the monomer conversion, and the
molecular weight distribution was in the range of 1.19–1.37. The spherical micelles with degradable core
and pH/thermo-double sensitive shell had been prepared from the aqueous medium of the amphiphilic
star-shaped copolymers by dialysis method. Both pH and thermal-responsive behaviours of copolymer
micelles obtained in this study were investigated. The micelle size and morphology were measured by
DLS, AFM and TEM.
Keywords:
RAFT
Star-block copolymer
Double responsive micelles
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
overcome the problem of thermodynamic instability associated
with micelles assembled from linear copolymers [10–12].
Recently, considerable interests have been attracted by the
biomedical materials, especially by the intelligent polymeric
micelles due to their unique core–shell structures [1,2]. It is well
known that core–shell type of polymeric micelles can self-assemble
from amphiphilic copolymers by hydrophobic segment self-
aggregation and hydrophilic segment contacting with water
medium [3]. So far, most of the previously reported polymeric
micelles with core–shell structure have been prepared by linear
block copolymers [4], random copolymers [5], or graft copolymers
[6]. However, several star-shaped copolymers were also reported to
prepare core–shell micelles in recent years [7–10]. Amphiphilic
star-shaped copolymers with several or a large number of linear
arms are becoming attractive because it may overcome or partially
Star polymers have being gained great attention over the past
decades due to their unique three-dimensional shape and proper-
ties. This has provoked considerable interest in the preparation of
a variety of star copolymers with varying arm numbers, chemical
composition, and chain topology [13]. Star polymers can be
produced either by ‘‘arm-first’’ or ‘‘core-first’’ methods. The ‘‘arm-
first’’ method means to prepare the arms of linear polymer chains
primarily and subsequently react with appropriate terminators or
coupling agents to form the star polymers. Therefore, the resulting
star polymers generally have a statistical distribution of the
number of arms by the ‘‘arm-first’’ technique [14]. In the ‘‘core-
first’’ method, polymer chains are propagated from a multifunc-
tional initiator. Generally, the latter method is more popular
because of better control. The arm number of a star polymer is
determined by the number of end groups in the core molecule. Till
now, star polymers with several arms (arm number <10) and
a larger number of arms (arm numbers >10) have been reported in
a pack of papers mostly with the ‘‘core-first’’ strategy [13,15–20].
However, the synthesis for well-defined star copolymers, especially
star-block copolymers, have not grown easier until living/
* Corresponding author at: Institute of Nano- and Bio-polymeric Materials,
School of Material Science and Engineering, Siping Road 1239, Tongji University,
Shanghai, PR China, 200092. Tel./fax: þ86 21 65989238.
E-mail address: renjie@tongji.edu.cn (J. Ren).
0032-3861/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.polymer.2010.01.037

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J. Li et al. / Polymer 51 (2010) 1301–1310
controlled free radical polymerization techniques were developed,
such as reversible addition fragmentation chain transfer (RAFT)
polymerization [15], atom transfer radical polymerization (ATRP)
[20,21], and nitroxide mediated radical polymerization (NMP) [22].
Additionally, the combinations of the living/controlled radical
polymerizations and their combinations with living ring-opening
polymerization (ROP) have also been employed for the preparation
of star copolymers [13,23].
opening polymerization. We aimed to synthesize a series of novel
amphiphilic and biocompatible star-block copolymers with pH/
thermo-double sensitiveness by combination of ROP and RAFT
polymerization from an asymmetric multifunctional core. A star-
shaped hydroxyl-terminated PCL with five arms was firstly
synthesized by ROP with BIS-TRIS as multifunctional initiator.
Subsequently, the terminal hydroxyl groups of star-shaped PCL are
used to initiated the ROP of L-lactide and then reacted with 3-
Stimuli-responsive polymers that undergo phase transitions in
response to external stimuli, such astemperature, pH, ionicstrength,
light or photochemical process, have been widely investigated in
various fields [24,25]. In particularly, many studies are focused on
temperature and pH-responsive designed materials able to respond
in a physiological environment. The most thoroughly investigated
thermoresponsive polymers contain polyethylene glycol (PEG), oli-
goethylene glycol (OEG), poly(N-isopropylacrylamide) (PNIPAAm),
or poly(N,N-dimethylamino-2-ethyl methacrylate) (PDMAEMA)
units [26]. Of these polymers, PDMAEMA has been widely investi-
gated and used in drug delivery systems and modification of
biomedical polymer surfaces due to its biocompatibility, pH/
temperature double responsiveness [27–29]. Many polymerization
techniques are described to synthesize PDMAEMA including anionic
polymerization and group transfer polymerization [30,31]. Con-
cerning the controlled radical polymerizations, atom transfer radical
polymerization (ATRP) of DMAEMA has been investigated to afford
well-controlled polymers. For example, Sui et al. reported the
homogeneous grafting of underivatized cellulose with DMAEMAvia
ATRP under mild conditions [28]. Yuan et al. synthesized the well-
defined dendritic star copolymers by ATRP of DMAEMA with star-
shaped macroinitiator [19]. However, the copper catalyst involved in
ATRP of DMAEMA was complexed by amino groups in both mono-
mer and polymer, which may lead to a loss of control over the
polymerization [29,32]. In addition, the complete removal of the
copper residues from the polymer products of ATRP has always been
problematic. Itwasarguedthat itwasimportant toremovethemetal
residue fromthe products particularlyfor biomedical applications as
they may be harmful for human health. Therefore, reversible addi-
tion fragmentation chain transfer (RAFT) polymerizations was also
investigated to synthesize well-controlled PDMAEMA [29,33].
When aiming at star polymer via RAFT polymerization, a star-sha-
ped RAFT agent needs to be used, in which the stabilizing Z-group is
linked to the core. This so-called Z-RAFT star polymerization effec-
tively prevents extensive coupling reactions between star polymers
as well as side-production of linear material, which occur when
attaching the RAFT agent via its leaving R-group to the core [34,35].
The RAFT agent used in this paper for this purpose is 3-benzylsul-
fanylthiocarbonylthiocarbonylsufanylpropionic acid (BSPA), which
is attached to the star core via a simple two-step reaction sequence.
It is clear that the use of the trithiocarbonate BSPA in conjunction
with AIBN allows for the synthesis of PDMAEMA in a controlled
fashion [33]. Such trithiocarbonates have been previously shown to
be effective for the controlled polymerization of a variety of mono-
mers [18,34,36].
benzylsulfanylthiocarbonylsufanylpropionic acid chloride (BSPAC)
to produce the macro-chain transfer agent (macro-CTA, 5sPCL-b-
PLLA-BSPA) for the subsequent RAFT polymerization (Scheme 1). In
the structure of the novel star-block copolymer, biodegradable and
hydrophobic PCL-b-PLLA blocks can self-aggregate in the core
while PDMAEMA blocks serve as stimuli-responsive and hydro-
philic segments that form the outer shell of polymeric micelles.
2. Experimental
2.1. Materials
3
-Caprolactone (
3-CL; Acros Organic, USA) was purified with
CaH2 by vacuum distillation.
L-lactide (L-LA; TJL Biomaterials,
On the other hand, poly(lactide) (PLA) and poly(
3-caprolactone)
(PCL) are biodegradable and biocompatible linear polyesters with
good mechanical properties, low immunogenicity and FDA
approval [37,38]. They have been widely adopted for biomaterials
and biomedical applications. So PLA and PCL usually were selected
as hydrophobic blocks of amphiphilic copolymers to form hydro-
phobic cores of the core–shell type of polymeric micelles, working
as the sustained release reservoir of insoluble or unstable drug
molecules [3,39]. In the present work, we first started to explore the
utilization of bis(2-hydroxyethyl)amino-tris(hydroxymethyl)-
methane (BIS-TRIS), a buffering agent with five hydroxyl groups
usually used in biochemistry, as multifunctional cores for ring-
Scheme 1. Synthesis of the star-block amphiphilic copolymer by ring-opening poly-
merization and RAFT polymerization.

J. Li et al. / Polymer 51 (2010) 1301–1310
1303
Fig. 1. FT-IR spectra of (a) 5sPCL star polymer, (b) 5sPCL-b-PLLA star-diblock copoly-
mer, (c) macro-CTA 5sPCL-b-PLLA-BSPA, and (d) 5sPCL-b-PLLA-b-PDMAEMA star-tri-
block copolymer.
Shanghai) was purified by twice recrystallization from ethyl acetate
and dried in a vacuum at room temperature. Tin 2-ethylhexanoate
(Sn(Oct)2; Aldrich, USA) was distilled under reduced pressure before
use. Bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane (BIS-
TRIS; Aladdin-Reagent, Shanghai) was dried at 60 ꢀC invacuo for 24h
before use. N,N-dimethylamino-2-ethyl methacrylate (DMAEMA;
Acros Organics, USA) was also dried over CaH2 and distilled under
reduced pressure. Azobisisbutyronitrile (AIBN; SCRC, Shanghai)
were purified by twice recrystallization from ethanol. 3-Mercapto-
propionic acid (99%; AlfaAesar, USA) and benzyl bromide (ꢁ99%;
Aladdin-Reagent, Shanghai) were used without further purification.
Thionyl chloride was distilled before use. Pyridine and 1,4-dioxane
were dried over CaH2 and distilled before use. Carbon disulfide
(>99%) and all other chemicals obtained from Sinopharm Chemical
Regent Company (SCRC) were of analytical grade and were used as
received.
Fig. 2. 1H NMR spectra of (a) 5sPCL star polymer, (b) 5sPCL-b-PLLA star-block
copolymer, (c) macro-CTA 5sPCL-b-PLLA-BSPA.
2.2. Characterization
Attenuated total reflection Fourier transform infrared (ATR FT-IR)
spectra were recorded on an AVATAR 360 ESP FT-IR spectrometer. 1H
NMR spectra were obtained using a Bruker DMX-500 NMR spec-
trometer with CDCl3 or D2O as solvent at 25 ꢀC. The chemical shifts
thermostatically controlled using an electronic thermostatic
cell holder and a temperature controller; the heating rate was set at
0.5 ꢀC/min. The LCST (lowercriticalsolution temperature)valueof the
polymer solution was defined as the temperature producing a 50%
decrease in optical transmittance [4].
were relative totetramethylsilane (TMS) at
d
¼ 0 ppm for protons. The
average molecular weight and its distributionwere determined using
a gel permeation chromatographic (GPC) system equipped with
a Waters 150 C separations module and a Waters differential refrac-
tometer. Polymer samples were dissolved inTHFat a concentration of
1–2 mg/mL. THF was eluted at 1.0 mL/min through two Waters
Styragel HT columns and a linear column. The internal and column
temperatures were kept constant at 35 ꢀC. The molecular weights
were calculated against polystyrene standards. The measurements of
static contact angles were carried out by commercial contact angle
analysis instruments (OCA 20, DataPhysics, Germany). A distilled
Table 1
Preparation of star polymer 5sPCL and star-block copolymer 5sPCL-b-PLLAs.
a
b
c
c
Sample [CL]/ [LLA]/ Mn,th
Mn,NMR
Mn,GPC
Mw/Mn
Conversion
(%)d
[OH] [OH]
1
2
3
4
5
20:1
11,400 12,190
17,920 18,790
25,300 27,500
31,530 33,270
37,750 39,860
11,060 1.27
17,100 1.23
24,760 1.11
30,450 1.29
36,500 1.28
98.1
95.2
96.9
94.7
92.6
10:1
20:1
30:1
40:1
water droplet of 3
thickness of w120
m
L was used as the indicator. The films with
m
m were obtained by casting polymer solutions on
a
Mn,th ¼ [monomer]/[OH] ꢂ 5 ꢂ Mmonomer ꢂ Conversion (%) þ Minitiator; Mn,th
the clean glass slides using chloroform as a solvent, followed by slow
solvent evaporation at room temperature for about one day. Optical
transmittance of aqueous polymer solutions at various temperatures
denotes the number-average molecular weight of star-shaped polymer.
b
Determined by 1H NMR spectroscopy of star-shaped polymer.
Determined by GPC analysis with polystyrene standards. THF was used as
c
or pH was measured at
spectrophotometer. The temperature of the sample cell was
l
¼ 500 nm using a Hitachi U-3310 UV–VIS
eluent.
d
Conversion of monomer obtained from gravimetry.

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J. Li et al. / Polymer 51 (2010) 1301–1310
Fig. 3. GPC traces of 5sPCL star polymer (Sample 1), 5sPCL-b-PLLA star-diblock
copolymer (Sample 3), and 5sPCL-b-PLLA-b-PDMAEMA star-triblock copolymer
(Sample 8).
2.3. Preparation
2.3.1. Synthesis of 3-benzylsulfanylthiocarbonylsufanylpropionic
acid (RAFT acid)
The RAFT agent, 3-benzylsulfanylthiocarbonylsufanylpropionic
acid (BSPA) was synthesized according to the literature [18] with
minor modification. 3-Mercaptopropionic acid (20 mL, 0.23 mol)
was slowly added into a solution of potassium hydroxide (26 g,
0.46 mol) in 250 mL of water. And carbon disulfide (30 mL) was
added dropwise into the solution for more than 40 min with
vigorous stirring, and the solution was further stirred for 8 h. After
that, benzyl bromide (39.6 g, 0.23 mol) was added into the solution,
and then the reaction mixture was heated for 12 h at 80 ꢀC. After
cooling and the addition of chloroform (300 mL), the reaction
mixture was acidified with hydrochloric acid until the organic layer
became yellow. The water phase was extracted with chloroform
(2 ꢂ 100 mL). The combined organic layers were washed with
100 mL of saturated sodium chloride and then with 100 mL of water
twice and finally dried over anhydrous magnesium sulfate over-
night. After evaporation of the solvent, the remaining product was
recrystallized in dichloromethane three times, and 52 g of yellow
solid with a yield of 83% was obtained.
Fig. 5. 1H NMR spectra of (a) 5sPCL-b-PLLA-b-PDMAEMA star-triblock copolymer in
CDCl3 and (b) micelles formed by the star-triblock copolymer in D2O.
1H NMR (CDCl3,
d, ppm): 10.1 (b, 1H, –COOH), 7.32–7.25 (m, 5H,
–Ph), 4.61 (s, 2H, –CH2Ph), 3.61 (t, 2H, –CH2S), 2.84 (t, 2H,
–CH2C]O).
2.3.2. Synthesis of 3-benzylsulfanylthiocarbonylsufanylpropionic
acid chloride (BSPAC)
BSPA (5.0 g, 0.18 mol) and 20 mL of anhydrous dichloromethane
were introduced into a dried flask with a magnetic stirring bar.
Freshly distilled thionyl chloride (5 mL) was added dropwise to the
BSPA mixture solution over 30 min. The mixture was then gradually
warmed and refluxed until a clear solution was obtained. After
another hour of refluxing, the product was isolated by evaporation
Table 2
RAFT polymerization of DMAEMA with 5sPCL-b-PLLA-BSPAa as macro-CTA. (Poly-
merization condition: [macro-CTA] ¼ 0.2 ꢂ 10ꢃ2 mol/L; [macro-CTA]:[AIBN] ¼ 2:1;
[DMAEMA] ¼ 1.5 mol/L; temperature: 80 ꢀC; solvent: dioxane).
Conversion (%)e
b
c
d
d
Sample Time (h) Mn,th
Mn,NMR
Mn,GPC
Mw/Mn
6
7
8
9
1
2
4
6
8
32,850 33,900
36,860 38,250
43,350 45,630
47,800 49,750
50,300 52,180
30,420
35,190
40,830
43,260
47,600
1.19
1.26
1.21
1.35
1.37
5.9
9.3
14.8
18.6
20.7
10
a
Mn,macro-CTA (5sPCL-b-PLLA-BSPA) ¼ 25,900, Mw/Mn ¼ 1.15.
b
Mn,th ¼ [DMAEMA]/[macro-CTA] ꢂ MDMAEMA ꢂ Conversion (%) þ Mn,macro-CTA
;
Mn,th denotes the number-average molecular weight of star-shaped copolymer.
c
Determined by 1H NMR spectroscopy of star-shaped copolymer.
Determined by GPC analysis with polystyrene standards. THF was used as
d
Fig. 4. Dependence of Mn and Mw/Mn on the molar ratio of [LLA]/[OH] with 5sPCL star
polymer initiator (sample 1) and tin 2-ethylhexanoate catalyst in bulk at 120 ꢀC.
eluent.
e
Conversion of monomer obtained from gravimetry.

J. Li et al. / Polymer 51 (2010) 1301–1310
1305
3560 (yO–H), 2948 (yC–H), 2869 (yC–H), 1730 (yC]O), 1472 (yC–H), 1245
yC–O). 1H NMR (CDCl3,
, ppm): 4.21–4.25 (m, CH2OH in BIS-RIS),
(
d
4.06 (m, CH2O in PCL), 3.65 (t, terminal CH2O in PCL), 2.37 (m, NCH2
in BIS-RIS), 2.31 (m, COCH2 in PCL),1.65 (m, CH2 in PCL),1.38 (m, CH2
in PCL).
2.3.4. Synthesis of the hydroxyl-terminated star-diblock copolymers
(5sPCL-b-PLLA)
A
typical polymerization procedure was as follows: The
hydroxyl-terminated 5sPCL (4.25 g, 0.384 mmol, containing
1.92 mmol of –OH groups), L-LA (5.54 g, 38.43 mmol), and a dried
magnetic stirring bar were added to a fire-dried polymerization
tube quickly. The tube was then connected to a Schlenk line, where
evacuating–refilling processes were repeated three times. The tube
was put into an oil bath at 120 ꢀC with vigorous stirring for 5 min. A
catalytic amount of Sn(Oct)2 in anhydrous toluene was added to the
melted mixture, and the evacuating–refilling process was carried
out again to remove the toluene. The tube was put into an oil bath
at 120 ꢀC under nitrogen atmosphere with stirring and cooled to
room temperature after polymerization for 24 h. The resulting
product was dissolved in chloroform and precipitated two times
with methanol. The purified polymer was dried in a vacuum oven at
room temperature until constant weight.
Fig. 6. Semilogarithmic plot of monomer consumption versus time for the RAFT
polymerization of DMAEMA using macro-CTA as the RAFT agent in dioxane.
of the solvent with vacuum distillation. The remaining yellow oil
was dried under a high vacuum. The product was used immediately
for the next synthesis.
IR (cmꢃ1): 3430–3560 (yO–H), 2948 (yC–H), 2865 (yC–H), 1760
1H NMR (CDCl3,
d, ppm): 7.32–7.26 (m, 5H, –Ph), 4.61 (s, 2H,
(
yC]O), 1726 (yC]O), 1453 (yC–H), 1245 (yC–O). 1H NMR (CDCl3,
d,
–CH2Ph), 3.61 (t, 2H, –CH2S), 3.34 (t, 2H, –CH2C]O).
ppm): 5.18 (m, CHO in PLLA), 4.38 (m, terminal CHO in PLLA), 4.12–
4.27 (m, CH2OH in BIS-RIS), 4.07 (m, CH2O in PCL), 2.38 (m, NCH2 in
BIS-RIS), 2.31 (m, COCH2 in PCL), 1.65 (m, CH2 in PCL), 1.59 (m, CH3
in PLLA), 1.51 (m, terminal CH3 in PLLA), 1.39 (m, CH2 in PCL).
2.3.3. Synthesis of the hydroxyl-terminated star-shaped poly
(3
-caprolactone) (5sPCL)
The hydroxyl-terminated star-shaped poly(3-caprolactone)
(5sPCL) was synthesized by ring-opening polymerization of CL with
BIS-TRIS as initiator. Briefly, CL (15 g, 131.4 mmol), BIS-TRIS (0.275 g,
1.314 mmol) and a catalytic amount of Sn(Oct)2 were added to
a flame-dried polymerization tube quickly. The tube was then
connected to a Schlenk line, where evacuating–refilling processes
were repeated for three times. Then, the tube was put into an oil
bath at 115 ꢀC under nitrogen atmosphere with stirring and cooled
to room temperature after polymerization for 24 h. The crude
polymer was dissolved in chloroform and precipitated two times in
methanol. The purified polymer was dried in a vacuum oven at
room temperature until a constant weight.
2.3.5. Synthesis of macro-chain transfer agent (macro-CTA,
5sPCL-b-PLLA-BSPA)
Dried 5sPCL-b-PLLA (Sample 3) (13.75 g, 0.5 mmol, containing
2.5 mmol of ꢃOH groups) and anhydrous pyridine (0.784 g,
10 mmol) were dissolved into 80 mL of dried methylene chloride at
room temperature. The mixture was stirred and cooled to 0 ꢀC.
Then, excess BSPAC (2.92 g, 10 mmol) in 20 mL of dried methylene
chloride was added dropwise to the mixture within 40 min. After
stirring at room temperature for 12 h, the solution was extracted
three times with 50 mL of water. The organic phase was dried over
anhydrous sodium sulfate for 5 h, and filtered. The filtrate was
concentrated and then precipitated two times with methanol. The
resulting product was dried in vacuo at room temperature in the
yield of 86% and stored in a sealed bottle in a cool and dark place.
Mn,NMR ¼ 28,700, Mn,GPC ¼ 25,900, Mw/Mn ¼ 1.15. IR (cmꢃ1):
2948 (yC–H), 2865 (yC–H), 1760 (yC]O), 1726 (yC]O), 1453 (yC–H), 1245
Number–average molecular weight determined by 1H NMR
(Mn,NMR): 12,190. Number–average molecular weight determined
by GPC (Mn,GPC): 11,060. Weight–average molecular weight/
number–average molecular weight (Mw/Mn): 1.27. IR (cmꢃ1): 3430–
(
yC–O). 1H NMR (CDCl3,
d, ppm): 7.32–7.27 (m, 5H, –Ph), 5.18 (m,
CHO in PLLA), 4.62 (s, 2H, –CH2Ph), 4.07 (m, CH2O in PCL), 3.61 (t,
2H, –CH2S), 2.84 (t, 2H, –CH2C]O), 2.31 (m, COCH2 in PCL), 1.65 (m,
CH2 in PCL), 1.58 (m, CH3 in PLLA), 1.38 (m, CH2 in PCL).
2.3.6. Synthesis of the star-triblock copolymers (5sPCL-b-PLLA-b-
PDMAEMA)
The 5sPCL-b-PLLA-b-PDMAEMA star-triblock copolymers were
synthesized by RAFT polymerization of DMAEMA in 1,4-dioxane
with 5sPCL-b-PLLA-BSPA as macro-RAFT agent. A typical polymer-
ization procedure was as follows: A dry Schlenk flask with magnetic
stirrer was charged with DMAEMA (2.358 g, 15 mmol), the star-
shaped macro-RAFT agent (5sPCL-b-PLLA-BSPA) (0.574 g,
0.02 mmol, containing 0.1 mmol of BSPA groups), AIBN (16.4 mg,
0.01 mmol), and 10 mL of dried 1,4-dioxane. The flask was degassed
with three freeze–evacuate–thaw cycles at the temperature of
liquid nitrogen. After the polymerization was performed at 80 ꢀC
for 4 h, the flask was cooled for half an hour in an ice bath and
precipitated in 250 mL of diethyl ether for two times. The
Fig. 7. Dependence of Mn and Mw/Mn of the star-triblock copolymer 5sPCL-b-PLLA-b-
PDMAEMA on the conversion of the monomer DMAEMA.

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J. Li et al. / Polymer 51 (2010) 1301–1310
Fig. 8. Photograph of the water contact angles of a) 5sPCL (Sample 1), b) 5sPCL-b-PLLA (Sample 3), c) 5sPCL-b-PLLA-BSPA (macro-CTA), d) 5sPCL-b-PLLA-b-PDMAEMA (Sample 6),
and e) 5sPCL-b-PLLA-b-PDMAEMA (Sample 10).
precipitate was filtered, and the product was dried at room
temperature in a vacuum oven for 48 h to give a yield of 14.8%.
IR (cmꢃ1): 3130–3560 (yC–N), 2943 (yC–H), 2865 (yC–H), 2767
(pH ¼ 1.0, 4.0, 7.0,10.0,12.0) to form transparent solution (2 mg/mL),
sonicated for 30 s, and filtered through a 0.45
remove large aggregates.
mm filter (Millipore) to
(
yC–H), 1760 (yC]O), 1726 (yC]O), 1453 (yC–H), 1245 (yC–O). 1H NMR
The morphology of the micelles was determined on a Trans-
mission Electron Microscopy (TEM) (Hitachi H-600, Japan) at an
accelerating voltage of 120 kV. A small drop from the aqueous
copolymer solutions was deposited onto a copper grid coated with
carbon film. The excess of copolymer solution was wiped off with
a filter paper, and the grid was dried under ambient atmosphere for
1 h. The specimen on the copper grid was negatively stained with
phosphotungstic acid.
(CDCl3, d, ppm): 7.32–7.29 (m, 5H, –Ph), 5.16 (m, CHO in PLLA), 4.62
(s, 2H, –CH2Ph), 4.09 (m, OCH2 in PDMAEMA), 4.06 (m, CH2O in
PCL), 3.61 (t, 2H, –CH2S), 2.84 (t, 2H, –CH2C]O), 2.67 (m, CH2N in
PDMAEMA), 2.37 (m, NCH3 in PDMAEMA), 2.31 (m, COCH2 in PCL),
1.78–2.09 (m, CH2 in PDMAEMA), 1.66 (m, CH2 in PCL), 1.58 (m, CH3
in PLLA), 1.38 (m, CH2 in PCL), 0.89–1.06 (m, CH3 in PDMAEMA).
The atom force microscopy (AFM) images of the copolymer
micelles were recorded on a SPA-300HV atomic force microscope
(SII NanoTechnology, Japan). The sample preparation was similar to
that for TEM, but newly cleaved fresh mica surface was used as the
substrate.
2.4. Preparation of 5sPCL-b-PLA-b-PDMAEMA micelles
Dialysis method was used to prepare the copolymer micelles.
Briefly, the star-shaped copolymer 5sPCL-b-PLA-b-PDMAEMA
(100 mg) was dissolved in 4 mL of DMF. The solution was dropped
into 16 mL distilled water slowly under agitation. The copolymer
solution was left to stir overnight prior to dialysis against distilled
water for 48 h to remove DMF using a dialysis membrane with
a molecular weight cut-off of 14,000 (Sinopharm Chemical Regent
Company, Shanghai). The water was replaced hourly for the first
3 h. After dialysis, the blue aqueous solution in the dialysis bag was
3. Results and discussion
3.1. Synthesis and characterization of the star-shaped poly-
(3-caprolactone)
collected and filtered with 0.45
for 2 days.
mm syringe filter and freeze-dried
The star-shaped poly(3-caprolactone) homopolymer was
synthesized by ring-opening polymerization of CL at 115 ꢀC. The
BIS-TRIS with five hydroxyl groups was chose as the initiator in
order to produce the hydroxyl-terminated star-shaped PCL. The IR
spectrum of the 5sPCL is shown in Fig. 1(a). The intensive absorp-
tion peak at 1730 cmꢃ1 was assigned to the carbonyl band of PCL. 1H
NMR spectrum of the star-shaped PCL is shown in Fig. 2(a). The
typical signals of the methylene protons of the initiator BIS-TRIS
could be clearly detected at 4.21–4.25 ppm and 2.37 ppm. The
major resonance peaks (a–d) were attributed to PCL. The peak of
the methylene (d) protons was detected at 4.06 ppm when the peak
of the protons of the terminal methylene (d’) could be discovered at
2.5. Morphology characterizations of copolymer micelles
(DLS, TEM and AFM)
The hydrodynamic diameter and the particle size distribution of
the copolymer micelles in buffer solutions of different pH were
determined by dynamic light scattering spectrophotometer (DLS,
Autosizer 4700, Malvern) equipped with an argon ion laser oper-
ating at 532 nm with a fixed scattering angle of 90ꢀ. Before
measurement, all samples were redispersed in buffer solutions
Fig. 9. Temperature dependence of optical transmittance at 500 nm for aqueous
5sPCL-b-PLLA-b-PDMAEMA (sample 8) solution with concentration of 2 mg/mL.
Fig. 10. pH dependence of optical transmittance at 500 nm for aqueous 5sPCL-b-PLLA-
b-PDMAEMA (sample 8) solution with concentration of 10 mg/mL.

J. Li et al. / Polymer 51 (2010) 1301–1310
1307
star-diblock copolymer 5sPCL-b-PLLA (sample 3) is shown in Fig. 3.
These trace was comparatively symmetrical and monomodal, sug-
gesting that these purified polymers were pure homopolymer or
star-block copolymers.
3.3. Synthesis and characterization of the macro-chain transfer
agent (macro-CTA) and star-triblock 5sPCL-b-PLLA-b-PDMAEMA
copolymers
The star-shaped 5sPCL-b-PLLA-BSPA macro-RAFT agent was
obtained by the reaction of 5sPCL-b-PLLA with BSPAC. The molec-
ular weight of 5sPCL-b-PLLA-BSPA increased slightly and the
molecular weight distribution was similar to that of 5sPCL-b-PLLA.
In IR spectrum (Fig. 1(c)), the peak at 1726 cmꢃ1 corresponding to
the carbonyl absorption of PCL units and terminal BSPAs became
slightly intensive, which could be used to prove that the BSPA
molecules existed in the copolymer as a terminal unit. 1H NMR
spectrum was shown in Fig. 2(c). The signal at 4.38 ppm dis-
appeared, while novel signals corresponding to methylene protons
(g, h, i) and phenyl protons (j) of terminal BSPAs appeared at
2.84 ppm, 3.61 ppm, 4.62 ppm, and 7.32–7.27 ppm, indicating that
all the terminal hydroxyl groups have been reacted completely.
Star-triblock 5sPCL-b-PLLA-b-PDMAEMA copolymer was
prepared from 5sPCL-b-PLLA-BSPA macro-CTA and DMAEMA via
RAFT at 80 ꢀC. According to the IR spectrum shown in Fig. 1(d), the
carbonyl absorption band became wide and split into two peaks
obviously. The peak at 1760 cmꢃ1 corresponded to the carbonyl
absorption of PLLA units, while the peak at 1726 cmꢃ1 was assigned
to the superposition of carbonyl absorption of PDMAEMA units, PCL
units, and BSPA units. 1H NMR spectrum of the copolymer is shown
in Fig. 5(a). All the protons signals of the copolymer could be
detected. The degree of polymerization of the DMAEMA block was
obtained from the integration of the proton signals at 5.16 ppm (e in
PLLA block) and 2.67 ppm (n in PDMAEMA block). The GPC trace of
the amphiphilic star copolymer is shown in Fig. 3 (Sample 8). It
could be seen that the trace was monomodal but showed a small
tailing toward the low molecular weight. Furthermore, according to
the data given in Table 2, the molecular weights determined by GPC
(Mn,GPC) were much lower than those determined by 1H NMR
(Mn,NMR) and theoretic values (Mn,th). Since GPC operates on the
principal of hydrodynamic volume of the polymer in solvent, it is
often incorrect for highly branched polymers such as star polymers.
The most important characteristic of star polymers is their high
segment density in comparison to their linear homologs of the
same molecular weight. This implies that star polymers exhibit
a smaller hydrodynamic volume, which leads to higher elution
volumes in certain time frame in a size exclusion chromatography
apparatus. It means that the apparent molecular weight of such
species, as obtained from standard GPC calibrated with well-
defined linear homologs, are lower than their real molecular
weight [40,41]. In addition, the absorption of PDMAEMA onto the
GPC column also resulted in an increase of retention time detected
by GPC and led to the tailing phenomenon of GPC trace [42,43].
The polymerization kinetics of DMAEMA using macro-CTA as
the RAFT agent was studied. The monomer conversion was deter-
mined by weighing the samples. Semilogarithmic plot of the
monomer conversion of DMAEMA versus the reaction time is
shown in Fig. 6. The conversion of DMAEMA reached 20.7% at 8 h in
dioxane. The plot of ln([M]0/[M]) increased nearly linearly with the
reaction time as expected for a controlled polymerization, which
suggests that most of the 5sPCL-b-PLLA-BSPA macro-CTA retained
the trithiocarbonate functionality at the chain terminus and that it
was available for subsequent reactivation. It could be seen from
Fig. 7 that Mn,NMR values were close to Mn,th, increased linearly with
conversion, indicating that the molecular weight of the star
Fig. 11. pH dependence of hydrodynamic radius (Rh) of micelles formed from aqueous
5sPCL-b-PLLA-b-PDMAEMA (sample 8) solution with concentration of 2 mg/mL.
3.65 ppm which indicated that PCL was terminated by hydroxyl
groups. The average degrees of polymerization for the PCL arms
could be calculated from the integration ratio between the meth-
ylene protons in the repeat units (d) and those in the terminal unit
(d0) based on 1H NMR spectrum. The molecular weight data of
5sPCL determined by 1H NMR spectrum and GPC analysis were
listed in Table 1. The GPC trace of 5sPCL (Sample 1) is shown in
Fig. 3. It could be seen that the trace was monomodal, which
indicated that the sample was pure star-shaped PCL homopolymer.
All these demonstrated that well-defined 5-arm star-shaped PCL
with narrow number-average molecular weight distributions could
be successfully synthesized by ROP of CL with BIS-TRIS initiator.
3.2. Synthesis and characterization of the star-diblock 5sPCL-b-
PLLA copolymers
The 5sPCL-b-PLLA star-diblock copolymers were synthesized by
the reaction of hydroxyl-terminated star-shaped PCL with L-LA at
120 ꢀC with bulk polymerization. The IR spectrum of the 5sPCL-b-
PLLA star-diblock copolymer is shown in Fig. 1(b). The main
difference in the IR spectrum between 5sPCL-b-PLLA and 5sPCL was
the carbonyl absorption band region. In the IR spectrum of 5sPCL-b-
PLLA, the carbonyl absorption band became wide and split into two
peaks. The peak at 1760 cmꢃ1 corresponded to the carbonyl
absorption of PLLA units, while the peak at 1726 cmꢃ1 was assigned
to the carbonyl absorption of PCL units. It was important to prove
that the PLLA chains existed in the copolymer as a block [17]. The 1H
NMR spectrum of 5sPCL-b-PLLA is shown in Fig. 2(b). The peak
assigned to the methylene protons of the PCL block at 3.65 ppm
disappeared, and a new peak at 4.38 ppm for the produced end
group of the PLLA block was observed. This indicated that the
terminal hydroxyl groups of the 5sPCL macroinitiator successfully
initiated the polymerization of L-LA.
The average polymerization degree of L-LA was also determined
by the integration ratio of methine protons of the PLLA block at
4.38 ppm and the methylene protons of PCL at 2.31 ppm. As shown
in Table 1 and Fig. 4, the number-average molecular weight of the
resulting copolymers linearly increased with the molar ratio of
monomer to macroinitiator, which indicated that the hydroxyl-
terminated star-shaped polyester could be used as effective prop-
agation centers and all of the five hydroxyl groups of the star-shaped
polyester molecule could initiate the ROP of L-LA. In addition, the
number–average molecular weight distributions of these polymers
were narrow (1.11 ꢄ Mw/Mn ꢄ 1.29). The GPC trace of the

1308
J. Li et al. / Polymer 51 (2010) 1301–1310
Fig. 12. (a) AFM and (b) TEM images of the micelles formed from aqueous 5sPCL-b-PLLA-b-PDMAEMA (sample 8) solution at pH ¼ 7.
copolymer could be manipulated by the control of monomer
conversion. Moreover, the molecular weight distributions of the
copolymers were narrow (Mw/Mn ꢄ 1.37) and increase at higher
conversions. Obviously, the star-shaped 5sPCL-b-PLLA-BSPA could
be used as an efficient macro-RAFT agent for living polymerization
of DMAEMA to form amphiphilic star-block copolymer 5sPCL-b-
PLLA-b-PDMAEMA.
NMR resonances attributed to PCL, PLLA and PDMAEMA blocks
were detected as shown in Fig. 5(a). However, the 1H NMR spec-
trum of micelles in D2O showed a complete loss of PCL and PLLA
resonances due plausibly to suppressed molecular motion of the
aggregated hydrophobic chains (Fig. 5(b)). 1H NMR study in
aqueous solution showed mainly hydrophilic PDMAEMA signals
but not hydrophobic blocks signals, indicating a stable core–shell
micellar structure with a hydrophobic viscous inner core and
a hydrophilic shell [45].
3.4. Hydrophilicity investigation of polymers
The hydrophilicity of the films prepared from 5sPCL, 5sPCL-b-
PLLA, 5sPCL-b-PLLA-BSPA, and 5sPCL-b-PLLA-b-PDMAEMA was
measured with water contact angles. As shown in Fig. 8, the contact
angle of the 5sPCL surface was 75.2ꢀ. The contact angle of the
5sPCL-b-PLLA surface increased to 83.7ꢀ owing to the weaker
hydrophilicity of PLLA blocks [44]. The contact angle of the 5sPCL-
b-PLLA-BSPA surface increased to 85.5ꢀ, which should be ascribed
to the substitution of the terminal hydroxyl groups of the copoly-
mer by BSPA. As for the surfaces of 5sPCL-b-PLLA-b-PDMAEMA
(sample 6) and 5sPCL-b-PLLA-b-PDMAEMA (sample 10), the
contact angles were 21.2ꢀ and 10.4ꢀ, respectively. This should be
attributed to the presence of PDMAEMA blocks with good hydro-
philicity. Therefore, the hydrophilicity of copolymers could be
improved and adjusted by the alteration of the composition of the
PCL, PLLA and PDMAEMA segments in copolymers. The changes of
the hydrophilicity can also prove indirectly the structure and
composition of copolymers composed of the hydrophobic PCL and
PLLA and the hydrophilic PDMAEMA.
3.6. Thermal-responsive behaviours of copolymer micelles
To determine whether the 5sPCL-b-PLLA-b-PDMAEMA micelles
exhibit a thermal sensitivity as expected, we examined the optical
transmittance of a copolymer micelle aqueous solution as a func-
tion of temperature. Fig. 9 represents typical transmittance against
temperature curves for the synthesized copolymer 5sPCL-b-PLLA-
b-PDMAEMA, which shows the temperature dependence of optical
transmittance at 500 nm for 5sPCL-b-PLLA-b-PDMAEMA micelles
in aqueous solution. With increasing of temperature, the solution
can be found to be transformed form transparent to opaque grad-
ually. In the lower temperature range (30–43 ꢀC), the optical
transmittance decreases only slightly. In contrast, the optical
transmittance decreases drastically in the temperature range of
43–53 ꢀC. The turning point appears to be around 48 ꢀC. It is
a typical LCST of temperature-responsive PDMAEMA blocks. Whilst
the PCL-b-PLLA blocks are hydrophobic, the PDMAEMA blocks are
hydrophilic at ambient temperature and become hydrophobic
above the demixing temperature as a result of the lower critical
solution temperature (LCST) behavior [46]. The visual illustration of
the optical transmittance changes is illustrated on the enclosed
photographs in Fig. 9, where clear and turbidity dispersions are
observed upon reversible cooling and heating cycles of the
copolymer aqueous solution.
3.5. Micelle formation
The amphiphilic block copolymer can self-assembly to form
nano-micelles in aqueous media. The insoluble block aggregates
into a core that is held into solution by the outer soluble block. The
core–shell structure of the micelles can be studied by NMR analyses
[39]. Fig. 5 shows 1H NMR spectra of 5sPCL-b-PLLA-b-PDMAEMA
star-triblock copolymer in CDCl3 and the micelles formed by the
star-triblock copolymer in D2O. The solvent CDCl3 is capable of
dissolving both hydrophobic and hydrophilic blocks while D2O can
only dissolve the hydrophilic PDMAEMA blocks. In CDCl3, all the 1H
3.7. pH-responsive behaviours of copolymer micelles
In order to determine pH responsiveness of the copolymer
micelles, the optical transmittance and particle size of copolymer
micelles in aqueous solution was analyzed as a function of pH at

J. Li et al. / Polymer 51 (2010) 1301–1310
1309
ambient temperature. Fig. 10 illustrates pH dependence of optical
transmittance at 500 nm for aqueous 5sPCL-b-PLLA-b-PDMAEMA
solution. As seen, with the increase of pH value, the solution was
transformed form transparent to opaque gradually, indicating the
obvious pH-responsive property of PDMAEMA blocks. The enclosed
photographs in Fig. 10 has provided a better overview of the optical
transmittance changes with reversible increasing and decreasing
pH values of the copolymer aqueous solution. DLS was used to
measure the size of 5sPCL-b-PLLA-b-PDMAEMA micelles in
aqueous solution at a concentration of 2 mg/mL at different pH
values, and the results are shown in Fig. 11. The hydrodynamic
radius (Rh) decreases from 119 to 76 nm as the pH values increase
from 1.0 to 12.0 at ambient temperature. This behavior was
attributed to the protonation/deprotonation of the tertiary amine
functional groups in PDMAEMA component. At pH 1.0, the
PDMAEMA chains are entirely protonated and highly stretched
along the radial direction because of the geometrical constraint and
the electrostatic repulsion between polymer chains. As pH changes
from 1.0 to 12.0, PDMAEMA chains gradually shrink and precipitate
from solution due to the deprotonation of amine groups [47,48].
copolymers via RAFT. The spherical micelles with degradable core
and pH/thermo-double sensitive shell had been prepared from the
aqueous solutions of the amphiphilic star-shaped copolymers by
dialysis method. Both pH and thermal-responsive behaviours of
copolymer micelles obtained in this study were investigated. The
micelle size and morphology were measured by DLS, AFM and TEM.
The average diameters of copolymer nanoparticles were below
200 nm.
Acknowledgments
The authors gratefully acknowledge the financial support of the
Program of Shanghai Subject Chief Scientist (No. 07XD14029) and
the National Natural Science Foundation of China (No. 20804029).
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