Novel Cationoci Ph-responsive Poly-microcapsules Prepared by a Microfluidic Technique

7/29/2019 Novel Cationoci Ph-responsive Poly-microcapsules Prepared by a Microfluidic Technique

1/8

Novel cationic pH-responsive poly(N,N-dimethylaminoethyl methacrylate)

microcapsules prepared by a microfluidic technique

Jie Wei, Xiao-Jie Ju , Rui Xie, Chuan-Lin Mou, Xi Lin, Liang-Yin Chu

School of Chemical Engineering, Sichuan University, Chengdu, Sichuan 610065, PR China

a r t i c l e i n f o

Article history:

Received 18 December 2010

Accepted 27 January 2011

Available online 3 February 2011

Keywords:

pH-responsive microcapsules

Cationic pH-responsive property

Microcapsule membranes

Poly(N,N-dimethylaminoethyl

methacrylate) (PDM)

Microfluidic technique

a b s t r a c t

Novel monodisperse cationic pH-responsive microcapsules are successfully prepared using oil-in-water-

in-oil double emulsions as templates by a microfluidic technique in this study. With the use of a double

photo-initiation system and the adjustment of pH value of the monomer solution, cross-linked poly( N,N-

dimethylaminoethyl methacrylate) (PDM) microcapsules with good sphericity and monodispersity can

be effectively fabricated. The obtained microcapsule membranes swell at low pH due to the protonation

ofAN(CH3)2 groups in the cross-linked PDM networks. The effects of various preparation parameters,

such as pH of the aqueous monomer fluid, concentration of cross-linker, concentration of monomer

N,N-dimethylaminoethyl methacrylate (DM) and addition of copolymeric monomer acrylamide (AAm),

on the pH-responsive swelling characteristics of PDM microcapsules are systematically studied. The

results show that, when the PDM microcapsules are prepared at high pH and with low cross-linking den-

sity and low DM monomer concentration, they exhibit high pH-responsive swelling ratios. The addition

of AAm in the preparation decreases the swelling ratios of PDM microcapsules. The external temperature

has hardly any influence on the swelling ratios of PDM microcapsules when the external pH is less than

7.4. The prepared PDM microcapsules with both biocompatibility and cationic pH-responsive properties

are of great potential as drug delivery carriers for tumor therapy. Moreover, the fabrication methodology

and results in this study provide valuable guidance for preparation of coreshell microcapsules via free

radical polymerization based on synergistic effects of interfacial initiation and initiation in a confinedspace.

2011 Elsevier Inc. All rights reserved.

1. Introduction

Environment-responsive microcapsules are capable of changing

their physicalchemical properties and colloidal properties in re-

sponse to various external stimuli such as temperature [15], pH

[610], magnetic field [11,12] and so on. Due to their smart

responsive abilities and certain advantages such as small size, huge

total surface area, large inner volume, and stable membrane,

environment-responsive microcapsules have attracted great inter-

ests in recent years in therapeutical and biotechnological fields,

such as drug delivery systems [1315], biosensors [16], chemical

separations [17], and so on. The pH variation is an important stim-

ulus for stimuliresponsive materials in biomedical applications,

because pH change occurs at many specific and pathological body

sites, such as the stomach, intestine, endosome, lysosome, blood

vessels, vagina, tumor extracellular sites. Certain tumors as well

as inflamed or wound tissues exhibit abnormal pH values different

from 7.4 as it is in normal circulation. For example, chronic wounds

have been reported to have pH values between 7.4 and 5.4 [18],

and tumor tissue is also reported to be acidic extracellularly

[19,20]. Therefore, pH-responsive drug delivery systems have been

studied intensively and significant progresses in this field have

been achieved [21]. Up to now, a lot of researches have been

carried out on anionic pH-responsive microcapsules based on

poly(acrylic acid) [2226] and poly(methacrylic acid) [2731].

Such microcapsules are capable of swelling at high pH and shrink-

ing at low pH because of the carboxyl groups being ionized at high

pH and unionized at low pH. As drug delivery carriers, these anio-

nic pH-responsive microcapsules can release drugs at acidic sites

such as tumor sites by extruding inner matters with the volume

shrinkage of polymeric network in acidic environment. This extru-

sion way has some limitations such as incomplete and unsustained

drug release. On the contrary, the cationic pH-responsive micro-

capsules have pH-responsive swelling property in acidic condition

due to protonation. They might be suitable for rate-controlled re-

lease and sustained drug release, because cationic pH-responsive

microcapsule membrane can control the drug release rate via

self-regulated adjustment of molecular diffusion permeation with

the cationic pH-responsive swelling/shrinking function. Unfortu-

nately, very little report on cationic pH-responsive microcapsules

has been found up to now.

0021-9797/$ - see front matter 2011 Elsevier Inc. All rights reserved.doi:10.1016/j.jcis.2011.01.105

Corresponding authors. Fax: +86 28 8546 0682.

E-mail addresses: [email protected] (X.-J. Ju), [email protected] (L.-Y. Chu).

Journal of Colloid and Interface Science 357 (2011) 101108

Contents lists available at ScienceDirect

Journal of Colloid and Interface Science

www.elsevier .com/locate / jc is
http://dx.doi.org/10.1016/j.jcis.2011.01.105mailto:[email protected]:[email protected]://dx.doi.org/10.1016/j.jcis.2011.01.105http://www.sciencedirect.com/science/journal/00219797http://www.elsevier.com/locate/jcishttp://www.elsevier.com/locate/jcishttp://www.sciencedirect.com/science/journal/00219797http://dx.doi.org/10.1016/j.jcis.2011.01.105mailto:[email protected]:[email protected]://dx.doi.org/10.1016/j.jcis.2011.01.105


2/8

Poly(N,N-dimethylaminoethyl methacrylate) (PDM) is a cat-

ionic pH-responsive material with good biocompatibility. Besides

its traditional applications such as water treatment, rubber and

paint, PDM has been used for developing controlled drug delivery

systems in recent years [3234] owing to its acid-induced

swelling characteristics. There have been a lot of reports on

PDM hydrogels/microgels [35,36] and PDM-based copolymer

hydrogels/microgels, such as poly(N,N-dimethylaminoethyl meth-acrylate-co-acrylamide) [37,38], poly(N,N-dimethylaminoethyl

methacrylate-co-methyl methacrylate) [39,40], poly(N,N-dimeth-

ylaminoethyl methacrylate-co-N-isopropylacrylamide) [41,42],

and so on. However, little research has been carried out on the

PDM microcapsules. Wen et al. [43] reported the formation of

PDM-based microcapsules by polyelectrolyte complexation of

methacrylic acid (MAA) based polyelectrolytes and protonated

or quaternized dimethylaminoethyl methacrylate (DM) contain-

ing polyelectrolytes; however, the microcapsules obtained by this

method were polydispersed and aspheric. Ma et al. [44] prepared

PDM-based microcapsules with hexadecane (HD) core and

poly(styrene-N,N-dimethylaminoethyl methacrylate) (P(St-DM))

shell by Shirasu porous glass (SPG) emulsification technique, in

which DM was added only for the purpose of decrease in the

interfacial tension between polymer and aqueous phase to encap-

sulate HD completely. But the pH-sensitivity of the prepared

microcapsules was not studied at all. Addison et al. [6] reported

the preparation of hollow microcapsule with a membrane con-

structed from a cationic/zwitterionic pair of responsive block

copolymer using layer-by-layer approach, and PDM was used just

as one part of the block copolymer. Still, the pH-responsive

behaviors were not mentioned either and the preparation process

was relatively complicated.

Up to now, a lot of methods have been reported for the prepa-

ration of microcapsules, such as interfacial polymerization, solvent

evaporation, spray-drying and layer-by-layer assembly. However,

these traditional methods have more or less limitations, such as

complicated process, time-consuming procedure, and so on. In

addition, for applications in the controlled drug delivery systems,microcapsules with narrow size distribution are preferable, since

the loading levels and release kinetics are directly affected by the

size distribution of microcapsules. Microfluidic techniques, which

have been developed for generating highly monodisperse emul-

sions in recent years [45,46], provide a new route for preparing

micro-particles with uniform size.

In this study, monodisperse PDM microcapsules with cationic

pH-responsive characteristics are designed and prepared using a

microfluidic technique for the first time. The PDM microcapsules

are synthesized using monodisperse double emulsions as the poly-

merization templates, where the double emulsions are generated

in a capillary microfluidic device. A double initiation system that

composed of water-soluble and oil-soluble photo-initiators is ap-

plied to ensure the successful synthesis of PDM microcapsules. Un-der the UV-irradiation, the oil-soluble photo-initiator dissociates to

generate a great deal of active free radicals that diffuse across the

oilwater interface to the aqueous phase of O/W/O emulsions to

start the polymerization at the oilwater interface. Such interface

initiation would ensure the obtained microcapsules being of a good

sphericity. On the other hand, the water-soluble photo-initiator in

aqueous phase can initiate the monomers to polymerize suffi-

ciently. As shown in Fig. 1a and b, the membrane of the proposed

microcapsule is made of cross-linked PDM, which can swell in

acidic environment due to the protonation ofAN(CH3)2 groups in

the polymeric network (Fig. 1c). To the best of our knowledge, this

is the first time to prepare monodisperse cationic pH-responsive

PDM microcapsules using a microfluidic technique. In order to

provide more guidance for the design and preparation of suchcationic pH-responsive microcapsules, the influences of various

preparation parameters, including pH of the monomer solution,

concentration of cross-linker, concentration of monomer, and addi-

tion of comonomer acrylamide (AAm), on the pH-responsive char-

acteristics of the proposed PDM microcapsules are experimentally

studied systematically. The fabrication methodology and results in

this study provide valuable guidance for preparation of coreshell

microcapsules via free radical polymerization based on synergistic

effects of interfacial initiation and initiation in a confined space.

2. Experimental

2.1. Materials

N,N-dimethylaminoethyl methacrylate (DM, Jiangsu Feixiang

Chemical Co., Ltd., China) was distilled under reduced pressure be-

fore use. N,N-methylene-bis-acrylamide (MBA, Chengdu Kelong

Chemicals, China) was used as a cross-linker. 2,2-Dimethoxy-

2-phenylacetophenone (BDK, Haining Paulyuan Dyestuffs Co.,

Ltd., China) and 2,20-azobis(2-amidinopropane dihydrochloride)

(V50, Qingdao Runxing Photoelectric Materials, China) were used

as the oil-soluble and water-soluble initiators, respectively. Poly-

glycerol polyricinoleate (PGPR, Danisco, Denmark) and Pluronic

F127 (SigmaAldrich) were used as emulsifier. Glycerin (ChengduKelong, Chemicals, China) were used to adjust the viscosity of

Fig. 1. Schematic illustration of the proposed cationic pH-responsive microcapsule

with cross-linked PDM membrane. (a) Chemical structure of cross-linked PDM, (b)

pH-responsive swelling/shrinking characteristic of cross-linked PDM microcapsule,

and (c) cationic pH-responsive swelling/shrinking mechanism of cross-linked PDM.

102 J. Wei et al. / Journal of Colloid and Interface Science 357 (2011) 101108


3/8

the aqueous monomer fluid. Other solvents and chemicals were all

of analytical grade and used as received. Deionized water

(18.2 MX, 25 C) from a Milli-Q Plus water purification system

(Millipore) was used throughout the experiments.

2.2. Preparation of PDM microcapsules

The microcapsules were prepared by using oil-in-water-in-oil(O/W/O) double emulsions as the templates for polymerization.

The O/W/O double emulsions were generated by a microfluidic

technique. The capillary microfluidic device, as schematically illus-

trated in Fig. 2a, was assembled according to our previous work

[45,46]. The inner diameters of the injection tube (D1), transition

tube (D2) and collection tube (D3) were 580 lm, 150 lm and

350lm respectively.

The compositions of different aqueous monomer fluids are

listed in Table 1. Soybean oil containing 3% (w/v) PGPR and 0.1%

(w/v) Sudan III was used as the inner fluid, and soybean oil con-

taining 5% (w/v) PGPR was employed as the outer fluid. The middle

fluid was aqueous monomer solution containing monomer DM,

cross-linker MBA, surfactant Pluronic F127 (1%, w/v), initiator

V50 (0.05%, w/v) and glycerin (5%, w/v).The generated O/W/O emulsions were collected in a beaker con-

taining excess soybean oil which contains 5% (w/v) PGPR and 1%

(w/v) photo-initiator BDK. The microcapsules with cross-linked

PDM membranes were prepared via UV-initiated polymerization

in an ice-bath for 30 min. After polymerization, the PDM microcap-

sules were washed with isopropyl alcohol to remove the outer and

inner oil, then washed with buffer solution of pH 7.4 for several

times to remove residual monomers and isopropyl alcohol, and fi-

nally re-dispersed in buffer solution of pH 7.4 for further

characterization.

2.3. Characterization of emulsions and microcapsules

Optical microscope images of O/W/O emulsions and PDMmicrocapsules were obtained by optical microscope (BX 61,

Olympus Co., Ltd., Japan), and the inner and outer diameters of

different samples were measured using automatic analytic

software on the basis of optical microscope images.

The size monodispersity of emulsions and PDM microcapsules

was evaluated by an index called coefficient of variation (CV),

which was defined as the ratio of the standard deviation of size dis-

tribution to its arithmetic mean. The CVvalue was calculated from

the following equation:

CV 100%

XN

i1

Di Dn2

N 1

" #12,

Dn 1

where Di is the diameter of the ith emulsion/microcapsule (lm), Dnis the arithmetic average diameter of emulsions/microcapsules

(lm), and N is the total number of measured emulsions/microcap-

sules. The smaller the CV value, the better the monodispersity.

2.4. pH-responsive swelling behaviors of PDM microcapsules prepared

in different conditions

The pH-sensitivity of PDM microcapsules was studied by evalu-

ating the pH-responsive swelling behaviors of the microcapsules

prepared with various preparation conditions. The pH of normal

tissue in the body is about 7.4. Therefore, to aim the potential prac-

tical applications as far as possible, the pH change was designed to

be from 3 to 7.4 in this study. Here, 0.005 M citric acid and 0.005 Mdisodium were used to adjust pH values of the external buffer

solutions ranging from 3.0 to 7.4. The pH adjustments were carried

out using a Mettler-Toledo pH meter (SevenMulti, Mettler-Toledo

Instruments). The ionic concentration of all pH buffers was

Fig. 2. Schematic illustration of the capillary microfluidic device for generating O/W/O emulsions (a), and optical microscope images of sample 2# O/W/O emulsions (b) andPDM microcapsules in buffer solution of pH 7.4 at 37 C (c). The scale bar is 100 lm.

Table 1

The compositions of different aqueous monomer fluids.

Code DM (M) AAm (M) MBA (M) pH

1# 1.0 / 0.050 4.3

2# 1.0 / 0.050 7.8

3# 1.0 / 0.025 4.3

4# 1.0 / 0.100 4.3

5# 1.5 / 0.075 7.8

6# 1.0 0.1 0.050 4.3

Note: In all the compositions of different monomer fluids, deionized water was used

as solvent, and 0.05% (w/v) V50, 5% (w/v) glycerin, and 1% (w/v F127) were added.

Concentrated HCl was used to modulate pH of the solution.

J. Wei et al. / Journal of Colloid and Interface Science 357 (2011) 101108 103


4/8

adjusted to 0.1 M beforehand. The PDM microcapsules were im-

mersed in a series of buffer solutions with different pH values at

room temperature for 24 h, and then were kept at 37 C for 1 h be-

fore measurement. The size changes of these PDM microcapsules

in specific buffer solutions were measured according to their corre-

sponding micrographs taken by optical microscope equipped with

a CCD camera and a thermostatic stage system (TS62, Instec, USA)

at 37

C.

2.5. Effect of temperature on the membrane thickness swelling ratios

of microcapsules in different buffer solutions

For investigation of the effect of temperature on the membrane

thickness swelling ratios of PDM microcapsules in different buffer

solutions, all PDM microcapsule samples were immersed in differ-

ent buffer solutions for 24 h firstly. At a specific external pH condi-

tion, the microcapsules were kept at designed temperature for

30 min to reach the swelling/shrinking equilibrium state, and then

micrographs of microcapsules were taken by the optical micro-

scope. The test temperatures were adjusted from 25 to 44 C by a

thermostatic stage system.

3. Results and discussion

3.1. Strategy for the preparation of PDM microcapsules

During the preparation process, if only the water-soluble

photo-initiator V50 is used as initiator, the microcapsules are poly-

merized very slowly and the obtained microcapsules are almost

non-spherical. While, if only the oil-soluble photo-initiator BDK

is used, the UV-initiated polymerization only takes place at the

oilwater interface of emulsion droplets [47]. Therefore, a double

photo-initiator system that composed of both water-soluble and

oil-soluble photo-initiators is applied to ensure successful synthe-

sis of monodisperse and spherical coreshell PDM microcapsules.

V50 is added into the middle water-phase as the water-soluble

photo-initiator, and the generated O/W/O emulsions are collectedin excess soybean oil containing oil-soluble photo-initiator BDK.

The microcapsules with cross-linked PDM membranes are pre-

pared via UV-initiated polymerization. Under the UV-irradiation,

BDK dissociates to generate a great deal of active free radicals,

and then the free radicals diffuse across the oilwater interface

0

10

20

30

40

50

120 150 180 210 240 270

Particle size [m]

Frequency

[%]

OD

ID

(a)

0

10

20

30

40

50

260 310 360 410 460

Particle size [m]

Frequency[%]

OD

ID

(b)

Fig. 3. Size distributions of outer diameter (OD) and inner diameter (ID) of sample

2#. O/W/O emulsions at room temperature (a), and PDM microcapsules in buffersolution of pH 7.4 at 37 C (b).

0

100

200

300

400

500

Diame

ter[m]

OD

ID

pH value of monomer fluid in preparation7.8 4.3

T=37oC

Buffer solution pH 7.4

(a)

1.00

1.05

1.10

1.15

1.20

3 4 5 6 7 8pH

DpH/D7.4

4.3 7.8

pH value in preparation(b)

1.00

1.05

1.10

1.15

1.20

3 4 5 6 7 8

D

D7.4

4.3 7.8

pH value in preparation

1.00

1.05

1.10

1.15

1.20

1.25

3 4 5 6 7 8pH

pH/7.4

4.3 7.8

pH value in preparation(c)

Fig. 4. Diameters (a) and pH-responsive swelling ratios (b and c) of PDMmicrocapsules prepared at different pH. The test temperature is 37 C.



5/8

to the aqueous phase of O/W/O emulsions to start the polymeriza-

tion at the oilwater interface. Such an interface initiation canensure that the obtained microcapsules are of good sphericity.

On the other hand, V50 in aqueous phase of O/W/O emulsions

can initiate the monomers to polymerize sufficiently in the

confined space.

Furthermore, without pH adjustment of the aqueous monomer

fluid in the preparation process, the PDM microcapsules cannot be

effectively polymerized after UV-initiation for even more than 10

days. The reason may be that, the V50 is hydrolyzed to 2,20-azo-

bis(2-carbamylpropane) to some extent in alkaline solution, which

results in a reduction in the initiation function. The hydrolysis rate

of V50 has been reported to increase with the increase of pH [48],

so the photolysis rate of aqueous initiator V50 decreases with

increasing pH. The pH value of aqueous phase containing monomer

DM and other additives without pH adjustment is about 9.5 at

room temperature. So, the photolysis rate of V50 in this original

solution is very slow. Therefore, to ensure effective PDM polymer-

ization in the confined space in O/W/O emulsions, the pH value of

the aqueous monomer fluid is adjusted using concentrated HCl in

this study.

With the use of above-mentioned double photo-initiation sys-

tem and the adjustment of pH of monomer solution, cross-linked

PDM microcapsules with good sphericity and monodispersity are

efficiently fabricated.

3.2. Size and morphology of PDM microcapsules

The optical microscope images of O/W/O emulsions prepared by

the microfluidic technique are shown in Fig. 2b, and the PDM

microcapsules polymerized from these double emulsions are

shown in Fig. 2c. It can be clearly seen that the obtained O/W/O

emulsions and hollow PDM microcapsules exhibit good spherical

shape and monodispersity. From Fig. 2c, it can also be seen thatthe membrane thicknesses of some microcapsules are not so even.

The reason is that, during the preparation process, the densities of

oil-phase and water-phase solutions are different. For the O/W/O

emulsion templates, although the thickness of the middle water-

phase almost looks like even in the top-viewed optical microscope

images (Fig. 2b), the oil-phase with the lighter density is always

floating up in the water-phase, which would result in microcap-

sules with decentered cores. After polymerization of the middle

water-phase, the polymerized microcapsules could turn in any

direction in aqueous solution, so some of them show decentered

hollow cavity structures. The hollow core can be adjusted in the

center of the microcapsule if the densities of oil-phase and

water-phase solutions in the O/W/O emulsions can be adjusted

to be the same.

Both the double emulsions and microcapsules in buffer solution

of pH 7.4 at 37 C have narrow size distributions as shown in Fig. 3.

The CV values for the inner diameters (ID) and outer diameters

(OD) of O/W/O double emulsions are 0.3% and 0.6% respectively,

and the CV values for the ID and OD of PDM microcapsules are

1.93% and 2.64% respectively, which means that both double emul-

sions and microcapsules are highly monodisperse. The correspond-

ing average ID and OD of emulsions are about 160 lm and 246 lm

respectively, while the average ID and OD of the sample 2# PDM

microcapsules in buffer solution of pH 7.4 at 37 C are about

294 lm and 402 lm respectively.

3.3. Influences of preparation conditions on the pH-sensitivity of PDM

microcapsules

3.3.1. Effect of pH of the aqueous monomer fluid

PDM is a well-known cationic pH-responsive material with

good biocompatibility, which can swell in acidic environment

due to the protonation ofAN(CH3)2 groups in the PDM polymeric

network. To characterize the pH-responsive behaviors of these pre-

pared PDM microcapsules, three parameters called swelling ratios

of outer diameter (DpH/D7.4), swelling ratios of membrane thick-

ness (dpH/d7.4), and inner volume change ratios (VpH/V7.4) of PDM

1.00

1.20

1.40

1.60

1.80

3 4 5 6 7 8pH

VpH/V7.4

4.3 7.8

pH value in preparation

Fig. 5. pH-responsive volume change ratios of PDM microcapsules prepared at

different pH. The test temperature is 37 C.

Fig. 6. Schematic illustration of pH-responsive mechanism of cross-linked PDM polymeric network prepared at different pH. (a) pH = 4.3 and (b) pH = 7.8.



6/8

microcapsules induced by external pH changing from 7.4 to certain

pH, are defined as follows:

DpH

D7:4

ODpH

OD7:42

dpH

d7:4

ODpH IDpHOD7:4 ID7:4

3

VpH

V7:4

IDpH

ID7:4

34

During the preparation process, the pH values of the middle

aqueous monomer fluids are adjusted to pH 4.3 and pH 7.8

respectively using concentrated HCl. The microcapsules prepared

at pH 4.3 have smaller sizes than those prepared at pH 7.8

when they are immersed in the same buffer solution (Fig. 4a).

Both batches of these PDM microcapsules prepared in two dif-

ferent pH conditions obviously exhibit pH-responsive character-

istics, as shown in Fig. 4b and c. Both the swelling ratio of outerdiameter and the swelling ratio of membrane thickness decrease

with increasing external pH value. Interestingly, the swelling

0

100

200

300

400

500

600

Diameter[m]

OD

ID

0.025/1 0.050/1 0.100/1

[MBA] / [DM]

T=37oC


(a)

1.00

1.05

1.10

1.15

1.20

3 4 5 6 7 8pH

DpH/D7

.4

0.025/1

0.050/1

0.100/1

[MBA]/[DM](b)

1.00

1.05

1.10

1.15

1.20

1.25

3 4 5 6 7 8pH

pH/7.4

0.025/1

0.050/1

0.100/1

[MBA]/[DM]

/

(c)

Fig. 7. Diameters (a) and pH-responsive swelling ratios (b and c) of PDM

microcapsules prepared with different cross-linking densities. The test temperatureis 37 C.

0

100

200

300

400

500

D

iameter[m]

OD

ID

[DM]1.0M 1.5M

T=37oC


(a)

Buffer solution

1.00

1.05

1.10

1.15

1.20

3 4 5 6 7 8pH

DpH/D

7.4

1.0M

1.5M

[DM](b)

1.00

1.05

1.10

1.15

1.20

1.25

3 4 5 6 7 8pH

pH/7.4

1.0M

1.5M

[DM](c)

Fig. 8. Diameters (a) and pH-responsive swelling ratios (b and c) of PDM

microcapsules prepared with different concentrations of DM monomer. The testtemperature is 37 C.



7/8

ratios of PDM microcapsules prepared at pH 4.3 are lower than

the swelling ratios of those prepared at pH 7.8, as shown in

Fig. 4b and c.

The inner volume change ratios of PDM microcapsules also ex-

hibit similar results, as shown in Fig. 5. The explanation for the pH-

responsive phenomenon is illustrated in Fig. 6. When the pH of the

middle aqueous monomer fluid is 4.3, the polymeric networks of

the PDM microcapsules have already swollen to some extent dueto the partial protonation ofAN(CH3)2 groups in the PDM structure

during the preparation process. Therefore, the length of the poly-

meric chain between two cross-linking points of PDM network is

shorter due to the electrostatic repulsion of protonatedAN(CH3)2groups, which leads to lower pH-responsive swelling ratios of the

PDM microcapsules (as shown in Fig. 6a). Moreover, in the network

of the PDM microcapsule prepared at pH 4.3, the number of

AN(CH3)2 groups that capable of protonation decreases. The de-

crease ofAN(CH3)2 groups would also lead to a lower swelling ra-

tio when these microcapsules are put in acidic solutions. On the

contrary, the PDM microcapsules prepared with the pH value of

monomer fluids being 7.8 have longer polymeric chain between

two cross-linking points because the PDM network is in the

shrunken state during the preparation process. Therefore, the

PDM microcapsules prepared at pH 7.8 exhibit larger swelling

ratios than those prepared at pH 4.3, as shown in Fig. 6b.

3.3.2. Composition of the aqueous monomer fluid

To determine the effect of the composition of monomer solution

on the pH-sensitivity of PDM microcapsules, aqueous monomer

fluids with various components are applied to generate O/W/O

emulsions as templates for the preparation of microcapsules. The

compositions of monomer fluids are listed in Table 1.

It canbe observedthat, withthe increaseof cross-linkingdegrees,

both the outer and inner diameters of PDM microcapsules decrease

in the same buffer solution (Fig. 7a). The swelling behaviors of PDM

microcapsules with different cross-linking degrees as a function of

pH change in external solution are shown in Fig. 7b and c. All pre-

pared PDM microcapsules exhibit good pH-sensitivities. The swell-ing ratios of outer diameter and membrane thickness decrease

with the increase of pH in the external solution. The swelling ratios

of PDM microcapsules also decrease with increasing the cross-

linking degree of polymeric network. With the increase of cross-

linking degree, the cross-linking density of polymeric network in

the microcapsule membrane increases, which results in a decreased

elasticity of the network chains and then a decreased swelling ratio.

The effect of monomer DM concentration on the pH-responsive

swelling ratios of microcapsules are also investigated by keeping

the same molar ratio of [MBA]/[DM] as 0.050/1. The sizes of PDM

microcapsules in buffer solution of pH 7.4 decrease with increasing

the DM content, as shown in Fig. 8a. The PDM microcapsules with

lower DM content show larger pH-responsive swelling ratios than

those with higher DM content. To keep the same molar ratio of[MBA]/[DM], the cross-linker concentration also increases with

increasing the DM concentration, which results in a larger density

of the polymeric network and decreased apertures of the PDM net-

work. Therefore, the swelling ratios decrease with the increase of

DM concentration.

The PDM microcapsules are also prepared by adding another

comonomer AAm which does not have pH-sensitivity. With the

addition of AAm, the PDM-based AAm-copolymerized microcap-

sules also have pH-sensitivity, but the swelling ratios of these

microcapsules decrease as shown in Fig. 9. The reason is due to

the formation of hydrogen bonds between amide groups in AAm

andAN(CH3)2 groups in DM, which protectsAN(CH3)2 groups from

exposing to the outside [49]. Therefore, the AN(CH3)2 groups that

capable of protonation decrease, and then a decrease of the swell-ing ratio is resulted.

3.4. Effect of external temperature on the membrane thickness

swelling ratios of microcapsules in different buffer solutions

The effect of external temperature on the size change of PDM-

based materials in deionized water has been reported a lot [36,37].

The PDM-based materials show a thermo-responsive phase transi-

tion in aqueous solution due to the hydrophilic/hydrophobic groups

existing in the polymeric structures. With the increase of tempera-ture, the polymeric network becomes hydrophobic and then the

deswelling of PDM network is resulted. In this work, the effect of

external temperature on the membrane thickness swelling ratios

of PDM microcapsules in different buffer solutions is also studied.

0

100

200

300

400

500

600

Diam

eter[m]

OD

ID

PDM P(DM-co-AAm)

T=37oC


(a)

1.00

1.05

1.10

1.15

1.20

3 4 5 6 7 8pH

DpH/D7.4

PDM

P(DM-co-AAm)co

(b)

7.4

1.00

1.05

1.10

1.15

1.20

1.25

3 4 5 6 7 8pH

pH/7.4

PDM

P(DM-co-AAm)

(c)

co

7.4

co

Fig. 9. Diameters (a) and pH-responsive swelling ratios (b and c) of PDMmicrocapsules prepared with the addition of AAm. The test temperature is 37 C.



8/8

Unexpectedly, there is little change in the membrane thickness of

the microcapsules when the temperature increases from 25 to

44 C in buffer solutions of pH 7.4 or pH 6.5 (see Fig. S1 for detailed

datain the Supportinginformation). Wealso investigate theeffect of

temperature on the swelling ratios of microcapsules in buffer solu-

tions with pH less than 6.5, and the results show that there is little

size change for the microcapsules when the external temperature

changes. The effect of the protonation ofA

N(CH3)2 groups may bethe reason for this phenomenon. When thepH values of buffer solu-

tions are less than 7.4, the AN(CH3)2 groups in PDM structure are

protonated and the increased electrostatic repulsive force is devel-

oped between charged sites on the PDM structure. This interferes

with the hydrophobic interactions betweenAN(CH3)2 groups which

should increase with increasing the temperature [49]. As a result,

the membrane thickness swelling ratios of PDM microcapsules in

conditions with pH less than 7.4 are nearly not affected by external

temperature.

4. Conclusions

Novel monodisperse cationic pH-responsive PDM microcap-

sules have been successfully prepared using a microfluidic tech-

nique in this study. The PDM microcapsules with good sphericity

and monodispersity are effectively synthesized with the introduc-

tion of a new double initiation system and the adjustment of pH of

the monomer solution. The obtained PDM microcapsules all

obviously exhibit cationic pH-sensitivity and the preparation

conditions significantly affect the pH-responsive swelling ratios

of these PDM microcapsules. The swelling ratios of PDM microcap-

sules prepared at pH 7.8 are higher than the swelling ratios of

those prepared at pH 4.3. When the microcapsules are prepared

with lower cross-linking density and lower monomer concentra-

tion, they show higher swelling ratios. The addition of comonomer

AAm depresses the pH-responsive swelling ratios of PDM micro-

capsules. Unexpectedly, in the range from 25 to 44 C, the external

temperature has hardly any influence on the membrane thickness

swelling ratios of PDMmicrocapsules in buffer solutions withpH less

than 7.4. With both biocompatibility and cationic pH-responsive

property, such monodisperse microcapsules are highly attractive

for developing drug delivery systems, such as pH-responsive drug

carriers for site-specific tumor therapy. Furthermore, the fabrication

methodologydemonstrated in thisstudyprovides a uniqueapproach

for effective preparation of coreshell microcapsules via free radical

polymerization based on synergistic effects of interfacial initiation

and initiation in a confined space.

Acknowledgments

This work has been supported by the National Natural Science

Foundation of China (20906064, 20825622, 20990220, 21036002,

21076127), the National Basic Research Program of China(2009CB623407), and the Specialized Research Fund for the Doc-

toral Program of Higher Education by the Ministry of Education

of China (20090181120045, 200806100038).

Appendix A. Supplementary material

Supplementary data associated with this article can be found, in

the online version, at doi:10.1016/j.jcis.2011.01.105.

References

[1] L. Liu, W. Wang, X.J. Ju, R. Xie, L.Y. Chu, Soft Matter 6 (2010) 37593763.[2] Y.L. Yu, R. Xie, M.J. Zhang, P.F. Li, L.H. Yang, X.J. Ju, L.Y. Chu, J. Colloid Interface

Sci. 346 (2010) 361369.[3] A.H. Wang, C. Tao, Y. Cui, L. Duan, Y. Yang, J.B. Li, J. Colloid Interface Sci. 332

(2009) 271279.[4] L.Y. Chu, S.H. Park, T. Yamaguchi, S. Nakao, Langmuir 18 (2002) 18561864.[5] L.Y. Chu, S.H. Park, T. Yamaguchi, S. Nakao, J. Membr. Sci. 192 (2001) 2739.

[6] T. Addison, O.J. Cayre, S. Biggs, S.P. Armes, D. York, Langmuir 26 (2010) 62816286.[7] J. Yun, H.I. Kim, J. Appl. Polym. Sci. 115 (2010) 18531858.[8] Y.H. Park, J.H. Han, K.D. Suh, Macromol. Chem. Phys. 209 (2008) 938943.[9] C. Dejugnat, G.B. Sukhorukov, Langmuir 20 (2004) 72657269.

[10] A.O. Okhamafe, B. Amsden, W. Chu, M.F. Goosen, J. Microencapsulation 13(1996) 497508.

[11] W.C. Yang, R. Xie, X.Q. Pang, X.J. Ju, L.Y. Chu, J. Membr. Sci. 321 (2008) 324330.

[12] B. Zebli, A.S. Susha, G.B. Sukhorukov, A.L. Rogach, W.J. Park, Langmuir 21(2005) 42624265.

[13] W.S. Yin, M.Z. Yates, J. Colloid Interface Sci. 336 (2009) 155161.[14] F. Zhang, Q. Wu, Z.C. Chen, M. Zhang, X.F. Lin, J. Colloid Interface Sci. 317

(2008) 477484.[15] X.Y. Liu, C.Y. Gao, J.C. Shen, H. Mohwald, Macromol. Biosci. 5 (2005) 1209

1219.[16] S. Chinnayelka, M.J. McShane, Anal. Chem. 77 (2005) 55015511.[17] N.Y. Borovkov, G.V. Sibrina, K.N. Zheleznov, Khim. Khim. Tekhnol. 39 (1996)

5861.

[18] J. Dissemond, M. Witthoff, T.C. Brauns, D. Haberer, M. Goos, Hautarzt 54 (2003)959965.

[19] D. Schmaljohann, Adv. Drug Delivery Rev. 58 (2006) 16651670.[20] P. Vaupel, F. Kallinowski, P. Okunieff, Cancer Res. 49 (1989) 64496465.[21] X.J. Ju, R. Xie, L.H. Yang, L.Y. Chu, Expert Opin. Ther. Pat. 19 (2009) 683.[22] J. Yun, H.I. Kim, J. Ind. Eng. Chem. 15 (2009) 902906.[23] D. Halozan, U. Riebentanz, M. Brumen, E. Donath, Colloids Surf., A 342 (2009)

115121.[24] Y. Guan, Y. Zhang, T. Zhou, S. Zhou, Soft Matter 5 (2009) 842849.[25] K. Akamatsu, T. Yamaguchi, Ind. Eng. Chem. Res. 46 (2007) 124130.[26] W.J. Tong, C.Y. Gao, H. Mohwald, Macromolecules 39 (2006) 335340.[27] M.K. Kang, J.C. Kim, J. Appl. Polym. Sci. 118 (2010) 421427.[28] K. Manokruang, E. Manias, Mater. Lett. 63 (2009) 11441147.[29] G.L. Li, G. Liu, E.T. Kang, K.G. Neoh, X.L. Yang, Langmuir 24 (2008) 90509055.[30] V. Kozlovskaya, E. Kharlampieva, M.L. Mansfield, S.A. Sukhishvili, Chem. Mater.

18 (2006) 328336.[31] T. Mauser, C. Dejugnat, G.B. Sukhorukov, Macromol. Rapid Commun. 25 (2004)

17811785.[32] C.H. Zhu, S. Jung, S.B. Luo, F.H. Meng, X.L. Zhu, T.G. Park, Z.Y. Zhong,

Biomaterials 31 (2010) 24082416.[33] Y.H. Liu, X.H. Gao, M.B. Luo, Z.G. Le, W.Y. Xu, J. Colloid Interface Sci. 329 (2009)

244252.[34] S. Brahio, D. Narinesingh, A. Guiseppi-Elie, Biomacromolecules 4 (2003) 1224

1231.[35] L. Hu, L.Y. Chu, M. Yang, H.D. Wang, C.H. Niu, J. Colloid Interface Sci. 311 (2007)

110117.[36] Y.F. Chen, M. Yi, Radiat. Phys. Chem. 61 (2001) 6568.[37] B. Yildiz, B. Isik, B. Kis, O. Birgul, J. Appl. Polym. Sci. 88 (2003) 20282031.[38] S.H. Cho, M.S. Jhon, S.H. Yuk, Eur. Polym. J. 35 (1999) 18411845.[39] A.I. Triftaridou, S.C. Hadjiyannakou, M. Vamvakaki, C.S. Patrickios,

Macromolecules 35 (2002) 25062513.[40] D. Quintanar-Guerrero, R. Villalobos-Garcia, E. Alvarez-Colin, J.M. Cornejo-

Bravo, Biomaterials 22 (2001) 957961.[41] Y. Zhang, L.S. Zha, S.K. Fu, J. Appl. Polym. Sci. 92 (2004) 839846.[42] L. Zha, J. Hu, C. Wang, S. Fu, A. Elaissari, Y. Zhang, Colloid Polym. Sci. 280 (2002)

16.[43] S. Wen, H. Alexander, A. Inchikel, W.T.K. Stevenson, Biomaterials 16 (1995)

325335.[44] G.H. Ma, Z.G. Su, S. Omi, D. Sundberg, J. Stubbs, J. Colloid Interface Sci. 266(2003) 282294.

[45] L.Y. Chu, A.S. Utada, R.K. Shah, J.W. Kim, D.A. Weitz, Angew. Chem., Int. Ed. 46(2007) 89708974.

[46] W. Wang, L. Liu, X.J. Ju, D. Zerrouki, R. Xie, L.H. Yang, L.Y. Chu, ChemPhysChem10 (2009) 24052409.

[47] C.J. Cheng, L.Y. Chu, P.W. Ren, J. Zhang, L. Hu, J. Colloid Interface Sci. 313 (2007)383388.

[48] K. Ito, J. Polym. Sci., Part A: Polym. Chem. 11 (1973) 16731681.[49] S.H. Cho, M.S. Jhon, S.H. Yuk, H.B. Lee, J. Polym. Sci., Part B: Polym. Phys. 35

(1997) 595598.

http://-/?-http://-/?-http://dx.doi.org/10.1016/j.jcis.2011.01.105http://dx.doi.org/10.1016/j.jcis.2011.01.105http://-/?-http://-/?-

Novel Cationoci Ph-responsive Poly-microcapsules Prepared by a Microfluidic Technique

Documents

Transcript of Novel Cationoci Ph-responsive Poly-microcapsules Prepared by a Microfluidic Technique