Research article

Received: 6 July 2013, Revised: 26 August 2013, Accepted: 23 September 2013, Published online in Wiley Online Library: 4 November 2013

(wileyonlinelibrary.com) DOI: 10.1002/pat.3212

Antimicrobial activities of polymeric

quaternary ammonium salts from poly(glycidyl
methacrylate)s
Zhixiang Lianga, Mingran Zhua, Ying-Wei Yangb* and Hui Gaoa**

Amino poly(glycerol methacrylate)s (PGOHMAs) were synthesized from linear and 8-arm poly(glycidyl methacrylate)s
(PGMAs) via ring opening reactions with methylethylamine (MEA), diethylamine, and dipropylamine, respectively,
which were further modified by quaternization reaction using methyl iodide to obtain quaternized PGMAs (QPGMAs
for short). The products were characterized by Fourier transform infrared spectroscopy, proton nuclear magnetic
resonance, gel permeation chromatography, and thermogravimetric analysis. The amination percentage of amino
PGOHMAs and the degree of quaternization of QPGMAs were calculated by elemental analysis and X-ray photoelectron
spectroscopy, respectively. According to the solubility test results, 8-arm PGOHMA modified with MEA (S8-MEA) is the
only water-soluble derivative of amino PGOHMAs and was employed as a positive control for the comparison with
QPGMAs. Antimicrobial studies on these PGMA derivatives were carried out by testing the minimum inhibitory
concentration and the bacteria inhibitive rate against Escherichia coli and Staphylococcus aureus. The results
indicated that QPGMAs possessed higher antimicrobial activity than S8-MEA and exhibited increased antimicrobial
activity against both bacteria with an increased degree of quaternization in weak basic conditions. Moreover, the
chemical structure of PGMA derivatives and pH value of the assay conditions were found to affect the antimicrobial
activity. Copyright © 2013 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this paper.

Keywords: synthesis; poly(glycidyl methacrylate); QPGMA; quaternization reaction; antibacterial activity

INTRODUCTION toxicity and a wide range of antimicrobial spectrum.[21,22] Tomiki

Over the past decades, the risk of bacterial infection has been
rising to be a global concern.[1] Misusing of antibiotics has been
observed for many years, leading to an increased antibiotic
resistance of bacterial pathogens in hospitals and communities,
both in gram-negative and gram-positive bacteria.[2–5] Therefore,
significant efforts have been made by many scientists to
improve the efficacy and antimicrobial spectrum of existing
drugs.[6–8] At present, the most commonly used antimicrobial
reagents mainly include four broad categories[9–11]: (i) the
oxidants, such as peroxides; (ii) the electrophilic agents, such as
copper and mercury; (iii) organic biocides, such as formaldehyde;
and (iv) cationic active biocides, such as chlorhexidine and
quaternary ammonium compounds. However, these small
molecules were highly toxic to the environment, and their
protection was short-lived because of the difficulty in controlling
the diffusion rate.[12] During the last two decades, continuous
effort has been made to develop new antimicrobial polymers
that are generally nonvolatile, chemically stable, and do not
permeate through the skin of human body.[13–18]
Although hundreds of polymeric compounds have been
prepared, few of them were of visible antimicrobial activities.[19]
Recently, much attention has been paid to quaternary
ammonium compounds, which are very attractive for their
antimicrobial applications because they target primarily at the
microbial membrane and accumulate in cells driven by the
potential of cell membrane.[20] Many researches have employed
and Shigeo[23] investigated the antimicrobial activity of polymeric
quaternary ammonium salts and found out that the polymeric salts
were more active than the corresponding monomer with the
longest alkyl chain. Water-soluble quaternary ammonium salts of
chitosan derivatives with a high charge density have been described
to have a significant antimicrobial activity.[24,25] Polyurethane
cationomers, polymerized from base polyurethane with chain
extenders having a quaternary ammonium group, have been
electrospun into nonwoven nanofibermats for antimicrobial
nanofilter applications.[26] The antimicrobial ability of natural
polysaccharides can also be improved by quaternization, as reported
by Badawy and Kim et al.[27,28]
As a highly versatile polymeric building block for postpolymerization
modifications of polymers,[29] poly(glycidyl methacrylate)s (PGMAs)
* Correspondence to: Ying-Wei Yang, State Key Laboratory of Supramolecular
Structure and Materials, College of Chemistry, Jilin University, Changchun
130012, China.
E-mail: ywyang@jlu.edu.cn
** Correspondence to: Hui Gao, School of Chemistry and Chemical Engineering,
Tianjin University of Technology, Tianjin 300384, China.
E-mail: ghhigher@hotmail.com
a Z. Liang, M. Zhu, H. Gao
School of Chemistry and Chemical Engineering, Tianjin University of Technol-
ogy, Tianjin 300384, China
b Y.-W. Yang
State Key Laboratory of Supramolecular Structure and Materials, College of
117

quaternary ammonium salts as biocides, owing to their low Chemistry, Jilin University, Changchun 130012, China

Polym. Adv. Technol. 2014, 25 117–122 Copyright © 2013 John Wiley & Sons, Ltd.

have been synthesized in our laboratory and functionalized
with different amines.[30–32] Their antimicrobial activities are still
unknown. In the present study, amino poly(glycerol methacry-
late)s (PGOHMA)s were synthesized from PGMA via ring
opening reactions with different fatty amines, following by
further modification by quaternization reaction using methyl
iodide (MeI) to give QPGMAs. The resulting polymers were
characterized by elemental analysis, X-ray photoelectron
spectroscopy (XPS), Fourier transform infrared spectroscopy,
nuclear magnetic resonance (NMR), thermogravimetric analysis,
and so on. Their bactericidal activities were evaluated by
determining the minimum inhibitory concentration (MIC) and
the bacteria inhibitive rate (BIR) against gram-positive bacteria
and gram-negative bacteria, respectively, and are expected to
show better bactericidal activities than their precursors before
quaternization. The effect of the polymer architecture, degree of
quaternization (DQ), and pH value of the assay conditions on the
antimicrobial activity was extensively studied, which will provide
a foundation to develop new antimicrobial agent.
EXPERIMENTAL
Materials
Glycidyl methacrylate, 2-bromoisobutyryl bromide, bipyridyl, CuBr,
and dipropylamine (DPA) were purchased from Shanghai Adamas
Reagent Co., Ltd (Shanghai, China). Methylethylamine (MEA),
diethylamine (DEA), and DPA were obtained from Tianjin Guangfu
Fine Chemical Research Institute (Tianjin, China). MeI was obtained
from Josiah chemical Co., Ltd (Chengdu, China). Tetrahydrofuran
(THF) was dried by refluxing with sodium, in the presence of
benzophenone as indicator. All other reagents were obtained
from Tianjin Chemical Reagent Co. (Tianjin, China).
Synthesis of amino poly(glycerol methacrylate)s and
quaternized poly(glycidyl methacrylate)s
Linear (L-PGMA) and 8-arm (S8-PGMA) PGMAs were synthesized
and modified with different amines according to our previous
reports.[33,34] Briefly, GMA was polymerized in THF using the
corresponding atom transfer radical polymerization initiator to
yield L-PGMA and S8-PGMA products. The L-PGMA and S8-PGMA
were then modified with three kinds of aliphatic amines, i.e.
MEA, DEA, and DPA, by ring opening of the epoxide groups to
obtain L-MEA and S8-MEA, L-DEA and S8-DEA, and L-DPA and
S8-DPA (L represents linear polymer, S8 represents eight-arm
star-shaped polymer). The quaternization reaction of the tertiary
amino groups was carried out using MeI.[35,36] For example,
L-MEA was diluted with methanol, followed by the addition of
MeI. The reaction mixture was stirred for 24 hr at room tempera-
ture. Purification was carried out by dialyzing (molecular weight
cut-off of 7000, Tianjin Unite Stars Biotech Co., Ltd) against
distilled water for 4–5 days to obtain QPGMA, named as QL-MEA.
Similarly, QS8-MEA, L-DEA and QS8-DEA, and QL-DPA and
QS8-DPA were synthesized using the same method.
Characterization of the polymers
Attenuated total reflectance Fourier transform infrared spectros-
copy spectra were recorded with KBr pellets on a Bio-Rod 6000
spectrophotometer. Proton NMR (1H NMR) spectra were
recorded in CDCl3 or D2O using a 400 MHz Bruker Avance-400
118
spectrometer. Gel permeation chromatography measurements
wileyonlinelibrary.com/journal/pat Copyright © 2013 John Wiley & Sons, Ltd.
Z. LIANG ET AL.
were performed in THF or AcOH aqueous solution (10 mM of
AcOH, 500 mM of NaCl in water). Adequate molecular weight
separation was achieved using three Waters Styragel columns
(HT3, HT4, and HT5) in series at a flow rate of 1.0 ml/min at 35°C.
Calibration curves were obtained with nearly monodisperse
polyethylene glycol. The molar content of amino groups per gram
of polymer was measured with an elemental analysis instrument
(elementar vario EL, GER). The DQ of the QPGMA polymers was
determined by XPS.
Solubility of amino poly(glycerol methacrylate)s and
quaternized poly(glycidyl methacrylate) derivatives
The solubility of amino PGOHMAs and QPGMAs was determined
by dissolving 2 or 10 mg of amino PGOHMA or QPGMA
derivatives in 1 ml of solvent (deionized water, 1 M CH3COOH,
and 1 M NaOH) at 25°C. The solubility of amino PGOHMAs and
QPGMAs was observed by the naked eye.
Thermogravimetric analysis
Thermogravimetry analysis was conducted using Simultaneous
Thermal Analysis (STA409PC, Germany). The samples were
heated from 25°C to 600°C at a heating rate of 20°C/min under
nitrogen atmosphere.
Antimicrobial tests
The antimicrobial activity of the obtained polymers was
determined by measuring the MIC and BIR in both dilute acidic
and weak basic conditions.
Zone of inhibition
The filter paper disks (1 × 1 cm) disinfected was impregnated
with S8-MEA, QS8-MEA, and QL-MEA, followed by lying on the
agar plates seeded with 0.1 ml test bacteria solutions (106 CFU/
ml) of Escherichia coli ATCC 8099 and Staphylococcus aureus
ATCC 6538; the agar plates of bacteria were incubated at 37°C
for 18 hr. Blank sterile filter paper disks and sterile water were
used as control in this study.
Determination of minimum inhibitory concentration
Antimicrobial activity of S8-MEA and QPGMA derivatives was
assessed by using E. coli ATCC 8099 (gram-negative) and S. au-
reus ATCC 6538 (gram-positive). Bacteria were grown at 37°C
in nutrient broth until exponential growth. Then, bacterial
concentrations were determined by measuring optical density
(OD) at λ = 600 nm at 0.2 (OD of 0.2 corresponded to a concen-
tration of 108 CFU/ml) with a UV-2450 (Shimadzu Co., Japan).
Finally, this solution was further diluted four times using sterile
nutrient broth. The cell count of bacteria solution was
predetermined to be 2 × 107 cells/ml. In order to test the
antimicrobial activity of the polymers, the diluted bacterial
culture was incubated at 37°C for 16 hr in glass culture tubes
in the presence of the polymer with final concentrations
ranging from 8 to 256 μg/ml in multiple of 2, respectively.
Control tests were simultaneously run to ensure the proper
bacterial growth within the diluted bacterial culture in the
absence of any polymer and no bacterial growth in polymer
solutions in the absence of any bacterial culture. After incuba-
tion, the growth of bacteria was determined by measuring
Polym. Adv. Technol. 2014, 25 117–122
ANTIMICROBIAL ACTIVITIES OF PGMA QUATERNARY AMMONIUM SALTS

the OD at 600 nm using a Shimadzu UV-2450. MIC90% values Table 2. Characterization of quaternized poly(glycidyl meth-
were defined as the lowest polymer concentration at which acrylate)s
more than 90% bacteria was inhibited.
Polymer XPS DQ Mn/Da PDI
Determination of bacteria inhibitive rate (%)
C% O% N% I
The samples were prepared at a concentration of 1 mg/ml, then
QL-MEA 65.02 25.25 2.87 6.87 27.42 13,700 1.27
autoclaved at 121°C for 20 min. Twofold serial dilution of each
QS8-MEA 65.19 22.50 2.73 9.58 38.44 14,300 1.30
polymer was added to nutrient broth (pH 5.5, pH 6.5, and pH
QL-DEA 62.77 22.13 3.93 11.18 32.16 14,500 1.33
7.4) at a concentration of 256, 128, 64, 32, 16, and 8 μg/ml. The
QS8-DEA 64.87 24.54 2.65 7.94 35.03 15,100 1.14
pH was adjusted by adding 1% acetic acid or 1% sodium hydrox-
QL-DPA 63.65 22.23 3.98 10.14 32.64 16,500 1.25
ide. After incubation at 37°C for 24 hr, 90 μl of the bacterial
QS8-DPA 60.08 20.24 4.98 14.50 29.21 16,200 1.29
suspension was added in a 96 well plate, followed by
supplementing of 10 μl of cell counting kit-8 (Dojindo Laborato- XPS, X-ray photoelectron spectroscopy; DQ, degree of
ries, Kumamoto, Japan), shaking gently for 1 min, and then quaternization; MEA, methylethylamine; DEA, diethylamine;
incubated at 37°C for 30–45 min. The OD of each well was DPA, dipropylamine.
measured at a wavelength of 450 nm by Microplate Reader
(Epoch, BioTek) and compared with a blank and the positive
control. All experiments were performed in triplicates for each
Table 3. Solubility of amino poly(glycerol methacrylate)s
tested microorganism.
and quaternized poly(glycidyl methacrylate)s at 2 mg/ml

RESULTS AND DISCUSSION Sample 1 M CH3COOH 1 M NaOH H2O

Synthesis and characterization of the polymers S8-MEA ++ -- ++

L-MEA ++ -- --
Two PGMA derivatives, possessing a linear (L), 8-arm (S8) backbone S8-DEA ++ -- --
and an average molecular weight (Mn) of about 9000, were synthe- L-DEA ++ -- --
sized (Table S1) and then functionalized with three different amines, S8-DPA ++ -- --
namely, MEA, DEA, and DPA, by ring-opening addition to give a L-DPA ++ -- --
series of polymers, i.e. L-MEA, S8-MEA, L-DEA, S8-DEA, L-DPA, and QS8-MEA ++ + ++
S8-DPA, respectively. The amination conversion of polymers, QL-MEA ++ ++ ++
calculated from the “N” percentage, was determined by elemental QS8-DEA ++ ++ ++
analysis (Table 1). After quaternization reaction, the tertiary amines QL-DEA ++ ++ ++
of the polymers were partially converted into quaternary ammo- QS8-DPA ++ ++ ++
nium groups, resulting in new polymeric quaternary ammonium QL-DPA ++ ++ ++
salts—QPGMAs, i.e. QL-MEA, QS8-MEA, QL-DEA, QS8-DEA, QL-
DPA, and QS8-DPA, respectively. All of these polymers were MEA, methylethylamine; DEA, diethylamine; DPA, dipropylamine;
characterized by FT-IR (Fig. S1) and 1H NMR (Fig. S2). The DQ of +, partially soluble; ++, completely soluble; --, insoluble.
the QPGMAs were determined by XPS (Table 2).

Solubility of amino poly(glycerol methacrylate)s and

quaternized poly(glycidyl methacrylate) derivatives
Table 3 listed the solubility of amino PGOHMAs and QPGMA
derivatives in water, aqueous acetic acid, and aqueous sodium
hydroxide at concentration of 2 mg/ml. Amino PGOHMAs cannot
be dissolved in water (except for S8-MEA) and aqueous sodium
hydroxide because of their strong intermolecular hydrogen

Table 1. Characterization of amino poly(glycidyl methacrylate)s

Polymer Elemental analysis Amination Mn/Da PDI

conversion
C% H% N%
(%)
L-MEA 56.65 9.97 6.34 97.19 11,200 1.21
S8-MEA 55.47 10.58 6.72 96.32 10,900 1.32
L-DEA 61.51 10.71 6.01 92.56 11,300 1.25
S8-DEA 58.31 9.96 5.79 88.65 10,800 1.22
L-DPA 64.42 11.03 5.53 96.21 13,100 1.26
S8-DPA 63.82 11.09 5.08 88.78 12,600 1.45
MEA, methylethylamine; DEA, diethylamine; DPA, dipropylamine. Figure 1. Thermogravimetric analysis thermograms of S8-methylethylamine
119

(MEA) and quaternized poly(glycidyl methacrylate)s.

Polym. Adv. Technol. 2014, 25 117–122 Copyright © 2013 John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/pat

Figure 2. Typical results of contact tests with (A) Staphylococcus aureus and (B) Escherichia coli for the qualitative evaluation of the antibacterial activity.
bonding interactions[37] but can be dissolved in the aqueous
solution of acetic acid. The QPGMA derivatives are soluble in
water, aqueous acetic acid, and aqueous sodium hydroxide,
respectively. As the quaternization reaction occurred, the
introduction of quaternary ammonium groups with some steric
hindrance greatly reduced the intermolecular interactions,
resulting in a good hydration capacity.[38] The concentration of
the polymers was then increased to 10 mg/ml to obtain a semi-
quantitatively results of their solubility. L-DEA and S8-DPA
became insoluble in 1 M CH3COOH, QL-MEA became insoluble
in 1 M NaOH, and S8-MEA became insoluble in water at 10 mg/
ml. All the other polymers kept the same solubility as that of
2 mg/ml, indicating that quaternization could significantly
increase the solubility of amino PGMA. Considering the results
of the solubility, we performed the following experiments using
S8-MEA as a positive control.
Thermogravimetric analysis
The thermogravimetric analysis thermograms of S8-MEA and
QPGMA derivatives were shown in Fig. 1, exhibiting two stages of
weight loss. The first one, started at about 80°C with 5–13% of
weight loss, was attributing to the loss of adsorbed and bounded
water.[39] In the second stage, T-max (the temperature when the
rate of weight loss reaches a maximum) of S8-MEA was observed
to be at 340°C. While T-max of all QPGMAs were observed to be
at 290–330°C, and lower than that of S8-MEA, which may be due
to the decomposition of quaternary groups and the removal of
pendant groups.[40] It was obvious that quaternization reaction led
to a lower thermal stability of amino PGOHMAs.
Antimicrobial activity
Qualitative evaluations of the antibacterial activity were carried
out on S8-MEA, QS8-MEA, and QL-MEA. During incubation
period, the spread bacteria can grow only where there is no
antimicrobial agent (in Fig. 2), which indicated that the three
polymers all have antibacterial activity.
The in vitro antimicrobial activity of amino PGOHMAs and
QPGMAs was then evaluated quantitatively by determination
of MIC and BIR against S. aureus (gram-positive) and E. coli
(gram-negative) bacteria. Table 4 shows MIC of S8-MEA and
QPGMAs. Compared with S8-MEA, QPGMAs displayed more
effective antimicrobial activity against both E. coli and S. aureus
(Table 4), which was in concordance with previous literature
reports.[41,42] In addition, all polymers showed higher activity
against S. aureus than against E. coli, probably because of the
120
different cell envelopes of these two bacteria species. The cell
wileyonlinelibrary.com/journal/pat Copyright © 2013 John Wiley & Sons, Ltd.
Z. LIANG ET AL.
Table 4. The minimum inhibitory concentration of S8-MEA
and quaternized poly(glycidyl methacrylate) at pH 7.4 against
Escherichia coli and Staphylococcus aureus
Sample Staphylococcus aureus Escherichia coli
(μg/ml) (μg/ml)
S8-MEA 64 256
QL-MEA 32 128
QS8-MEA 16 64
QL-DEA 32 128
QS8-DEA 16 64
QL-DPA 16 128
QS8-DPA 32 128
MEA, methylethylamine; DEA, diethylamine; DPA, dipropylamine.
envelope of a gram-positive bacterium is fully made up of
peptide polyglycogen. In contrast, a gram-negative bacterium
cell envelope is composed of a thin layer of peptide
polyglycogen and an outer lipopolysaccharide layer. The outer
lipopolysaccharide layer is a potential barrier against extraneous
molecules with high molecular weights.[43] Therefore, it is more
difficult for S8-MEA and QPGMAs to infiltrate the outer
membrane of E. coli. Moreover, QS8-MEA and QS8-DEA with the
highest DQ showed the lowest MIC, indicating that the antimi-
crobial activity was increased with an increasing DQ. These
results were comparable with the chitosan derivatives.[44] High
density of quaternary amino groups could enhance the effective
activity of QPGMAs against the bacteria.
Figure 3 shows the effect of pH on the BIR of S8-MEA and
QPGMAs. All polymers here were more active at higher pH values
(Fig. 3), which indicated that S8-MEA and QPGMAs had higher
antimicrobial activity under weak basic conditions. Neutral or
weak basic conditions can increase the negative charge of
protein on bacterial cell wall.[45] The target site of the cation is
the negatively charged cell surface of bacteria.[46] Thus, QPGMAs
bearing high density of cationic charge can interact and form
polyelectrolyte complexes with the proteins on the bacterial cell
surface.[20] Besides, at pH 5.5, the BIR of S8-MEA showed higher
activity against either E. coli or S. aureus than QPGMAs, probably
because the lower pH could benefit the protonation of tertiary
amine, but repress the ionization of quaternary ammonium
group,[47] and the protonated amino groups were contributed
to the antimicrobial activity in weak acid condition.[48] It seems
difficult to accurately compare the current results with other
quaternized antimicrobial agents because many factors can
Polym. Adv. Technol. 2014, 25 117–122
ANTIMICROBIAL ACTIVITIES OF PGMA QUATERNARY AMMONIUM SALTS
Figure 3. The bacteria inhibitive rate of S8-methylethylamine (MEA) and quaternized poly(glycidyl methacrylate) against (A) Staphylococcus aureus and
(B) Escherichia coli at a fixed concentration of 32 μg/ml and 256 μg/ml, respectively, in buffers of pH 5.5, 6.5, and 7.4.
impact the testing results, such as the structure and physico-
chemical property of raw materials, DQ, and molecular weight
of quaternized agent, culture temperature, pH value, and ion
strength of the assay conditions.[49] Actually, different species
of bacteria have been used, and the strains within each species
may also change obviously.
CONCLUSION
Linear PGMA and S8-PGMA were synthesized and modified with
different amines to obtain amino PGOHMAs and further
modified by quaternization reaction using MeI to give QPGMAs,
whose physicochemical properties were evaluated in details. All
QPGMAs were water-soluble. The antimicrobial activity of S8-
MEA and QPGMAs were investigated against E. coli and S. aureus
by evaluation of the MIC and the BIR under different pH
conditions. Our results showed that the main factors affecting
the antimicrobial activity of QPGMAs were the chemical
structure, pH value of the assay conditions, and the DQ of
QPGMAs. Finally, QPGMAs were proved to be able to serve as a
potential new antimicrobial agent.
ACKNOWLEDGMENTS
Financial support from NSFC (21074092, 21244004, and
21272093), Program for New Century Excellent Talents in
University (NCET-11-1063), Tianjin Municipal Natural Science
Foundation (10JCYBJC26800), Studying Abroad Program of
Tianjin Municipal Education Commission for Prominent Young
College Teachers, Foundation of Tianjin Educational Committee
(20090505), and Open Project of State Key Laboratory of
Supramolecular Structure and Materials (SKLSSM201311) is
highly acknowledged.
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