shell polymer microspheres for controlled release: Structural effect

European Polymer Journal xxx (2015) xxx–xxx

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European Polymer Journal journal homepage: www.elsevier.com/locate/europolj

Independent temperature and pH dual-stimuli responsive yolk/ shell polymer microspheres for controlled release: Structural effect Lei Liu, Pengcheng Du, Xubo Zhao, Jin Zeng, Peng Liu ⇑ State Key Laboratory of Applied Organic Chemistry, and Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China

a r t i c l e

i n f o

Article history: Received 8 February 2015 Received in revised form 15 March 2015 Accepted 17 March 2015 Available online xxxx Keywords: Drug delivery system Yolk/shell nanoparticles Structural effect Multi-stimuli responsive Controlled release

a b s t r a c t The yolk/shell nanoparticles exhibiting independent dual-stimuli responsive characteristics show attractable potential as drug delivery system. Unfortunately, their structural effect has not been explored by now. Here, the yolk/shell PMAA/PNIPAM microspheres were prepared under different conditions as the model drug-carriers to investigate the effects of the diameters of the cavity of the middle layers, thicknesses and crosslinking degrees of the PNIPAM shells on the temperature sensitive drug-loading and pH responsive controlled release characteristics, with doxorubicin (DOX) as a model drug. Compared with the core/shell PMAA/PNIPAM microspheres without inner cavity, the yolk/shell PMAA/ PNIPAM microspheres possessed higher drug-loading capacity, and the crosslinking degree of the PNIPAM shells is the most determinate factor for the drug-loading and controlled release performance. Such understanding would lead to a better design of excellent smart drug delivery platform. Ó 2015 Elsevier Ltd. All rights reserved.

1. Introduction In recent years, the yolk/shell or rattle/type microspheres, which consist of a movable core in a hollow capsule, have attracted a great deal of attention due to their tunable physical and chemical properties, such as low density and big void space [1–4]. This type of microspheres has many potential application in catalysis [5–7], drug/gene delivery [8,9] and lithium-ion battery [10]. There are some unique advantages of such yolk/shell microspheres for drug/gene delivery. The movable cores could afford some different exposed active sites for materials, and the shells could protect the cores from aggregation and leakage [11]. The yolk/shell microspheres contain a large hollow space between the cores and the shells, providing space ⇑ Corresponding author. Fax: +86 931 8912582. E-mail address: [email protected] (P. Liu).

for the volume expansion of the cores when loading fluorescent or drug molecules [1–3,8,9,12]. A lot of researches on the stimuli-responsive nanoparticles as drug/gene delivery systems including temperature, pH and redox have been reported by many groups [13–16]. Weak acids and bases like carboxylic acids and amines (or imine) exhibit a change in the ionization state with different media pH values. This leads to a change in the swelling behavior of the hydrogels when these ionizable groups are linked to the polymer chains [17]. In aqueous solution, poly(N-isopropylacrylamide) (PNIPAM) exhibits a lower critical solution temperature (LCST) of 32–33 °C, below which PNIPAM is water soluble and above which it becomes water insoluble [18–22], exhibiting the temperature-responsive characteristic. Based on such stimuli-responsive polymers, the multi-stimuli responsive drugcarriers have been developed in order to achieve the smart drug delivery [23].

http://dx.doi.org/10.1016/j.eurpolymj.2015.03.026 0014-3057/Ó 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Liu L et al. Independent temperature and pH dual-stimuli responsive yolk/shell polymer microspheres for controlled release: Structural effect. Eur Polym J (2015), http://dx.doi.org/10.1016/j.eurpolymj.2015.03.026

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Zha et al. fabricated the monodisperse temperature/pH dual stimuli responsive hollow nanogels with an interpenetrating polymer network (IPN) structure based on a PNIPAM network and a poly(acrylic acid) (PAA) network (PNIPAM/PAA IPN hollow nanogels) for temperature controlling drug loading and pH triggering drug release, by a two-step sequential colloidal template polymerization and subsequent removal of the cavity templates [24]. Chu et al. prepared novel graft-type poly(NIPAM-co-AAc) microgel with linear grafted poly(NIPAM-co-AAc) side chains by incorporating the dual stimuli-responsive chains into conventional copolymerized poly(NIPAM-co-AAc) backbones as side chains through a grafted modification of molecular structure. The prepared microgels were verified to have a synchronously rapid thermo- and pH-responsive property, due to the mobile nature and the tractive force of the grafted poly(NIPAM-co-AAc) side chains [25]. In order to elicit two disparate pH and temperature responses, the nanocapsules with temperature-responsive cross-linked polymer shells and pH-responsive polymer brushes on their inner walls [26] and the dual-responsive double-walled hollow microspheres with pH-responsive crosslinked poly(methacrylic acid) (PMAA) layer as the inner shell and the temperature responsive crosslinked PNIPAM layer as the outer shell [27,28] have designed. Also with the same aim, the pH and temperature dualstimuli responsive yolk/shell microspheres with pH responsive core and temperature sensitive shell have been intensely investigated as the smart drug delivery system (DDS) via distillation precipitation polymerization and seed precipitation polymerization recently [29,30]. However, the structural effect of these dual-stimuli responsive yolk/shell microspheres on their drug-loading and controlled release has not been demonstrated by now. In our previous work, the effect of the crosslinking degree of the cores on the dipyridamole (DIP) loading and release performance was investigated with the poly (methacrylic acid) (PMAA) nanogels as drug carrier model [31]. Here, the yolk/shell PMAA/PNIPAM microspheres were prepared under different conditions as the model drug-carriers to investigate the effects of the diameters of the cavity of the middle layers, thicknesses and crosslinking degrees of the PNIPAM shells on the temperature sensitive drug-loading and pH responsive controlled release characteristics, with doxorubicin (DOX) as a model drug.

2. Experimental 2.1. Materials Ethylene glycol dimethacrylate (EGDMA) was purchased from Aldrich and without any purification. Methacrylic acid (MAA) was obtained from Tianjin Chemical Reagent II Co. and purified by vacuum distillation. 2,20 -Azobisisobutyronitrile (AIBN, Tianjin Chemical Co. Ltd.) was recrystallized from ethanol. Ammonium hydroxide (25%, aqueous solution) was obtained from Tianjin Dongsheng Fine Chemical Reagent Factory, China. 3-(Methacryloxy)propyl trimethoxysilane (MPS) and

tetraethylorthosilicate (TEOS) were provided by Tianjin Chemical Reagent II Co., and used without further purification. N-Isopropylacrylamide (NIPAM, Aldrich) was recrystallized from n-hexane. N,N0 -Methylenebisacrylamide (MBA) was obtained from Tianjin Chemical Co. Ltd. and recrystallized from methanol. Hydrofluoric acid (HF, containing 40 wt% of HF) was purchased from Tianjin Chemical Reagent Institute. Doxorubicin (DOX) was obtained from Beijing Huafeng Lianbo Technology Co. Ltd., Beijing, China. Acetonitrile (Tianjin Chemical Reagent II Co.) was dried over calcium hydride and purified by distillation before utilization. All other regents were of analytical grade and used without any further treatment. Double distilled water was used throughout. 2.2. Synthesis of the PMAA cores The monodisperse PMAA cores were prepared via the distillation precipitation copolymerization of MAA and EGDMA with AIBN as initiator in neat acetonitrile. A typical procedure was as follows: MAA (1.20 mL) and EDGMA (0.80 mL) (monomer total as 2.5 vol% of the reaction system), and AIBN (0.04 g, 2.0 wt% corresponding to the comonomers) were dissolved in 80 mL neat acetonitrile in a dried 100 mL two-necked flask. The two-necked flask was equipped with a Vigreux column, Liebig condenser and receiver, and submerged in a heating mantle. The reaction mixture was heated from room temperature to boiling state in 30 min. Then the reaction was carried out with distilling the solvent out of the reaction system and ended after 40 mL acetonitrile had been distilled off the reaction mixture in 90 min. After the reaction, the resultant PMAA nanoparticles were purified by repeating centrifugation, decantation and re-suspension in acetonitrile for three times, and dried in a vacuum oven in 50 °C until a constant weight. 2.3. Synthesis of the PMAA/SiO2 core/shell microspheres with different shell-thicknesses The PMAA/SiO2 core/shell microspheres with different shell-thicknesses were prepared via a sol–gel procedure: 0.20 g PMAA nanoparticles were dispersed in 160 mL ethanol and 40 mL deionized water in 500 mL three-necked flask. After 2.4 mL ammonia and 1.0 mL TEOS were added into the mixture with vigorous stirring, the sol–gel process was allowed to proceed for 12 h. Finally, another 2.4 mL ammonia and 1.0 mL TEOS were added into the reaction mixture and stirred for further 12 h at room temperature. The resultant core–shell particles were separated by centrifugation and washing with water and dried in vacuum. Then the PMAA/SiO2 microspheres were modified with MPS to introduce the vinyl groups on their surface by adding 2.0 mL MPS into the ethanol dispersion of the core– shell particles followed by being stirred for 48 h at room temperature. The resultant microspheres were purified by repeated centrifugation, decantation and re-suspension in ethanol for three times, finally dried in a vacuum oven until a constant weight. The shell-thicknesses of the core/shell PMAA/SiO2 microspheres were altered by changing the adding times of TEOS from 2 to 5 with each of 1.0 mL (with TOES amount

Please cite this article in press as: Liu L et al. Independent temperature and pH dual-stimuli responsive yolk/shell polymer microspheres for controlled release: Structural effect. Eur Polym J (2015), http://dx.doi.org/10.1016/j.eurpolymj.2015.03.026

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L. Liu et al. / European Polymer Journal xxx (2015) xxx–xxx Table 1 Particle sizes of the microspheres determined by TEM. Simples

TEOS (mL)

Crosslinker (mol%)

Dn (nm)

PMAA PMAA/SiO2-2 PMAA/SiO2-3 PMAA/SiO2-4 PMAA/SiO2-5 PMAA/PNIPAM-7.5% PMAA/SiO2/PNIPAM-2–7.5% PMAA/SiO2/PNIPAM-3–7.5% PMAA/SiO2/PNIPAM-4–7.5% PMAA/SiO2/PNIPAM-5–7.5% PMAA/SiO2/PNIPAM-2–10% PMAA/SiO2/PNIPAM-3–10% PMAA/SiO2/PNIPAM-4–10% PMAA/SiO2/PNIPAM-5–10%

– 2 3 4 5 – – – – – – – – –

– – – – – 7.5% 7.5% 7.5% 7.5% 7.5% 10% 10% 10% 10%

84.7 142.3 158.1 170.8 180.9 124.1 155.2 175.4 181.4 189.3 174.6 180.2 193.2 196.4

of 2.0–5.0 mL) and the corresponding products were denoted as PMAA/SiO2-2, PMAA/SiO2-3, PMAA/SiO2-4 and PMAA/SiO2-5 (Table 1), respectively.

2.4. Synthesis of the sandwich PMAA/SiO2/PNIPAM microspheres The sandwich PMAA/SiO2/PNIPAM microspheres with different crosslinking degrees of the PNIPAM shells were prepared by precipitation polymerization in the presence of the core/shell PMAA/SiO2 microspheres or PMAA nanoparticles as seeds, respectively. In a typical route, the PMAA/SiO2 microspheres (with different thicknesses of the SiO2 middle layer but each containing 0.04 g PMAA cores) were dispersed in 95 mL deionized water in 250 mL three-necked flask. 0.40 g NIPAM, 0.0666 g MBA and 3.0 mg SDS were added into the flask. The mixture was heated up to 70 °C after degassing under purging nitrogen. After 0.5 h, 5 mL H2O containing 0.0132 g APS was added to initiate the polymerization. The reaction was continued for 6 h with continuous stirring. The resultant microspheres were purified by repeated centrifugation, decantation and re-suspension in deionized water three times. The obtained sandwich core/shell microspheres were denoted as PMAA/SiO2/PNIPAM-m–n (m is the volume of TEOS added for the PMAA/SiO2 and n is the feeding ratio of the crosslinker MBA to the monomer NIPAM, as summarized in Table 1), respectively. For comparison, the core/shell PMAA/PNIPAM microsphere was prepared by the same procedure with 0.04 g PMAA cores (the feeding ratio of the crosslinker MBA to the monomer NIPAM was controlled to be 7.5%).

2.5. Synthesis of the yolk/shell PMAA/PNIPAM microspheres The resultant sandwich PMAA/SiO2/PNIPAM microspheres were dispersed in aqueous HF solution for 12 h with stirring. The multifunctional yolk/shell PMAA/ PNIPAM microspheres were washed with water for five times to remove the excess HF.

Thickness of the SiO2 shells (nm)

Thickness of the PNIPAM shells (nm)

28.8 36.7 43.1 48.1 – – – – – – – – –

– – – – – 19.7 6.5 8.7 5.3 4.2 16.2 11.1 11.2 7.5

2.6. Drug loading and controlled release 10.0 mg core/shell or yolk/shell PMAA/PNIPAM microspheres were ultrasonically dispersed into the 5 mL of 1.0 mg mL1 DOX solution and then the solution was adjusted to pH = 7.4. After shaking for 48 h in the dark, the DOX-loaded core/shell or yolk/shell PMAA/PNIPAM microspheres were separated by centrifugation. Their drug-loading capacities (DLC) were calculated from the drug concentrations in the solutions before and after adsorption, using UV–vis spectrometry at a wavelength of maximum absorbance (233 nm). Then the DOX-loaded microspheres were diluted to 10.0 mL aqueous dispersion, and transferred into dialysis tubes with a molecular weight cutoff of 14,000 and immersed into 140 mL of phosphate-buffered saline (PBS) at pH 5.0 or 7.4 at 37 °C, respectively. 5.0 mL of the solution was taken out at certain time intervals to measure the drug concentrations in the dialysates with a TU-1901 UV–vis spectrometer. Then, 5.0 mL fresh solution with the same pH value was added after each sampling to keep the total volume of the solution constant. The cumulative release is expressed as the total percentage of drug molecule released through the dialysis membrane over time.

2.7. Analysis and characterization Fourier transform infrared spectra were determined on a Bruker IFS 66 v/s FT-IR spectrometer in the range of 400– 4000 cm1 with a resolution of 4 cm1. The samples were pressed into potassium bromide (KBr) pellets. The morphology and size of the synthesized materials were determined by transmission electron microscopy (TEM) using a JEM1200 EX/S microscope (JEOL, Tokyo, Japan). The samples were dispersed in deionized water and a drop of the dispersion was dropped onto the surface of a copper grid covered with a carbon membrane. The element analysis of the PMAA/PNIPAM microsphere samples was conducted with Elementar vario EL instrument (Elementar Analysen systeme GmbH, Munich, Germany).

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The hydrodynamic diameters of the microspheres were analyzed via dynamic light scattering (DLS, BI-200SM) using deionized water as the solvent. Scattered light was collected at a fixed angle of 90° for duration of 5 min.

3. Results and discussion 3.1. Preparing of yolk/shell PMAA/PNIPAM microspheres The yolk/shell PMAA/PNIPAM microspheres were prepared by the consecutive distillation precipitation polymerization, sol–gel reaction, precipitation polymerization and selective etching procedure (Scheme 1). Firstly, the PMAA nanoparticles were prepared as the pH responsive core materials via the distillation precipitation polymerization of MAA. They were spherical in shape and monodisperse in size, with an average diameter of 84.7 nm (Fig. 1a). A strong absorbance peak at 1722 cm1 corresponding to the carbonyl groups could be seen in the FT-IR spectrum of the PMAA (Fig. 2a) [32,33]. Then a silica shell was coated on the PMAA nanoparticles by the condensation of TEOS with ammonia as catalyst via the modified sol–gel process, as shown in Scheme 1. The TEM images of the core/shell PMAA/SiO2 microspheres with different thicknesses of the silica shells were shown in Fig. 1(b–e), in which the typical core/shell structure was clearly observed with a light contrast of the PMAA cores and a deep contrast of the silica shells. The sizes of the PMAA/SiO2 microspheres increased from 142.3 nm to 180.9 nm with increasing the adding times of TEOS from 2 to 5 (Table 1). The thickness of the SiO2 shells in the obtained core/shell PMAA/SiO2 microspheres was 28.8, 36.7, 43.1 and 48.1 nm of the PMAA/SiO2-2, PMAA/SiO2-3, PMAA/SiO2-4 and PMAA/SiO2-5 prepared with the TEOS amount of 2.0, 3.0, 4.0 and 5.0 mL, respectively. The FT-IR spectrum of the core/shell PMAA/SiO2 microsphere is shown in Fig. 2b. The strong absorbance peak at 1091 cm1 is associated with the stretching vibration of Si–O bonds. The absorbance peak in 1637 cm1 is

associated with the vinyl groups of the immobilized MPS [28], indicating that the polymerizable groups had been successfully introduced onto the core/shell microspheres. The tri-layered sandwich PMAA/SiO2/PNIPAM microspheres were prepared by precipitation polymerization of NIPAM and MBA with the PMAA/SiO2 microspheres as seeds (Scheme 1). The yolk/shell morphology could be obviously seen for the sandwich PMAA/SiO2/PNIPAM-2– 7.5% microspheres with the thinnest middle SiO2 layer and the thinnest PNIPAM shell. The crosslinking degree of the outer PNIPAM shells was controlled by adding different amounts of the crosslinker MBA, with feeding ratio as 7.5 mol% or 10 mol% to NIPAM. The sandwich structure was clearly observed with a light contrast of the outer PNIPAM shells and a deep contrast of the middle silica shells (Fig. 1g–n). The size of the sandwich PMAA/SiO2/ PNIPAM microspheres with 7.5 mol% or 10 mol% crosslinker increased from 155.2 or 174.6 nm to 189.3 or 196.4 nm respectively, with increasing the TEOS amount from 2.0 to 5.0 mL for the core/shell PMAA/SiO2 microspheres (Table 1). The strong absorbance peaks at 1654 and 1549 cm1 in the FT-IR spectrum of the microspheres revealed the amide characteristic absorbance of the PNIPAM shells (Fig. 2c) [34,35]. Ultimately, the temperature-sensitive hollow microspheres with movable pH responsive cores were obtained by etching the silica interlayer with HF for 12 h. The FTIR spectrum was used to prove the successful etching of the middle SiO2 layer (Fig. 2d). The disappearance of the Si–O peak at 1091 cm1 and the simultaneous increase in intensity of the peak characteristic of the PMAA and PNIPAM segments in indicated that the hollow microspheres with movable cores (yolk/shell PMAA/PNIPAM microspheres) had been prepared successfully [28]. By comparing the yolk/shell PMAA/PNIPAM samples with 7.5 mol% or 10 mol% crosslinker dyed with phosphotungstic acid, the inner diameters of the samples increased from 99.6 to 116.4 nm or 104.6 to 117.2 nm, with the average diameter of the PMAA cores of 84.7 nm (Table 2). The

Scheme 1. Schematic illustration of the fabrication of the core/shell and yolk/shell PMAA/PNIPAM microspheres.

Please cite this article in press as: Liu L et al. Independent temperature and pH dual-stimuli responsive yolk/shell polymer microspheres for controlled release: Structural effect. Eur Polym J (2015), http://dx.doi.org/10.1016/j.eurpolymj.2015.03.026

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Fig. 1. TEM images of (a) PMAA microspheres, (b–e) PMAA/SiO2 core/shell microspheres with TEOS form 2 mL to 5 mL, (f) PMAA/PNIPAM-7.5%, (g–j) PMAA/ SiO2/PNIPAM-n–7.5% (n from 2 to 5) microspheres, (k–n) PMAA/SiO2/PNIPAM-n–10% (n from 2 to 5) microspheres, (o–r) PMAA/PNIPAM-n–7.5% (n from 2 to 5) dyed with phosphotungstic acid, (s–v) PMAA/PNIPAM-n–10% (n from 2 to 5) dyed with phosphotungstic acid.

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Fig. 1 (continued)

size of the cavity could be calculated through the size of the sample and the inner diameter. The yolk/shell

PMMA/PNIPAM-3 had a big cavity than that of the PMMA/PNIPAM-4, it might be caused by the collapse and

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3.2. pH and temperature responsive characteristics

d

Transmittance (%)

c b

a

4000

3500

3000

2500

2000

1500

1000

500

Wavenumbers (cm-1) Fig. 2. FT-IR spectra of (a) PMAA microspheres, (b) PMAA/SiO2-3 microspheres, (c) PMAA/SiO2/PNIPAM-3–7.5% microspheres and (d) yolk/shell PMAA/PNIPAM-3–7.5% microspheres.

shrinkage degree of the PNIPAM shells without of the supporting of the SiO2 interlayer, regardless of the feeding ratios of crosslinker for the PNIPAM shells. The particle sizes of the yolk/shell PMAA/PNIPAM microspheres are smaller than those of the corresponding PMAA/SiO2/ PNIPAM microspheres, indicating that their particle sizes shrank after the etching of the middle SiO2 layer. In the sandwich PMAA/SiO2/PNIPAM microspheres with the middle SiO2 layer, the thickness of the middle SiO2 layer increased with the increasing the amount of TEOS added. Thus the thickness and crosslinking degree of the outermost PNIPAM shells decreased. After etching the middle SiO2 layer, the outermost PNIPAM shells with thinner thickness and lower crosslinking degree showed higher shrinkage degree. As for the PMAA/SiO2/PNIPAM-5 microspheres prepared with the TEOS amount of 5.0 mL, the inner diameter of their outermost PNIPAM shells was big enough, so they showed bigger cavity after etching the middle SiO2 layer, although the outermost PNIPAM shells had also shrunk. Furthermore, the particle collapse is more obvious with more TEOS added (Table 2). And the shrinkage degree of the yolk/shell PMAA/PNIPAM microspheres with higher feeding ratio of crosslinker (PMAA/PNIPAM-n–10%) is higher than those with the lower feeding ratio of crosslinker (PMAA/PNIPAM-n–7.5%), even with the same TEOS added for the middle SiO2 layer.

To confirm the independent temperature and pH responsive characteristics of the yolk/shell microspheres with movable cores, the DLS technique was used to investigate hydrodynamic diameter of the PMAA cores in aqueous dispersions with different pH values, and the final yolk/shell PMAA/PNIPAM microspheres in aqueous dispersions at different temperatures. Fig. 3a shows the sizes distribution of the PMAA cores in aqueous dispersions with different pH values at 25 °C. The hydrodynamic diameters of the PMAA cores increased from 131 nm to 321 nm with increasing the media pH values, resulting from the electrostatic repulsive force between the carboxyl groups of the PMAA at higher pH media [36]. As the media pH value increases, the carboxylic acid groups dissociate into carboxyl anions, and then the PMAA chains extended substantially. The swelling/shrinking behaviors of the temperature-sensitive hollow microsphere with movable cores were measured by DLS at different temperatures in aqueous dispersion, as shown in Fig. 3b and c. The volume phase transition of the PNIPAM shells takes place at about 32 °C and their volumes clearly shrink upon increasing the environmental temperature. The results revealed the independent temperature and pH responsive characteristics of the yolk/shell PMAA/ PNIPAM microspheres. Due to the presence of the inner cavity in the yolk/shell PMAA/PNIPAM microspheres, their volume swelling and shrinking are mainly dependent on the PNIPAM shells. The volume swelling and shrinking ratios of the core/shell PMAA/PNIPAM-7.5% microspheres and the yolk/shell PMAA/PNIPAM microspheres are calculated from the TEM analysis (Fig. 1 and Table 2) and the DLS analysis (Fig. 2) [37], as summarized in Table 3. Compared with the core/ shell PMAA/PNIPAM-7.5%, both the volume swelling and shrinking ratios of all the yolk/shell PMAA/PNIPAM microspheres are lower. For the yolk/shell PMAA/PNIPAM microspheres prepared with the different feeding ratios of the crosslinker, PMAA/PNIPAM-n–7.5% and PMAA/PNIPAM-n– 10%, the series with the high crosslinker feeding ratios (PMAA/PNIPAM-n–10%) showed the higher volume swelling ratios upon swelling at 25 °C and the lower volume shrinking ratios upon heating from 25 °C to 37 °C. And for all the yolk/shell PMAA/PNIPAM-n–7.5% and PMAA/ PNIPAM-n–10% microspheres, their volume swelling ratios increased and then decreased, and their volume shrinking

Table 2 Particle size of the yolk/shell PMAA/PNIPAM microspheres.

a b

Samples

Dn (nm)a

Size of the inner diameter (nm)a

Size of the cavity (nm)b

PMAA/PNIPAM-2–7.5% PMAA/PNIPAM-3–7.5% PMAA/PNIPAM-4–7.5% PMAA/PNIPAM-5–7.5% PMAA/PNIPAM-2–10% PMAA/PNIPAM-3–10% PMAA/PNIPAM-4–10% PMAA/PNIPAM-5–10%

144.0 150.2 152.9 155.8 147.4 150.9 153.4 158.9

99.6 109.4 106.7 116.4 104.6 109.8 106.9 117.2

7.3 12.2 10.9 15.7 9.8 12.4 11.0 16.1

Dn is the number-average diameter in dry state by TEM. Size of the cavity (nm) = (Dn (nm)  size of the inner diameter (nm))/2.

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350

Diameter (nm)

300

250

200

150

100

2

4

6

8

10

12

pH

(a)

higher permeability of the middle cavity in the yolk/shell microspheres [38], as well as the different particle sizes of the PNIPAM shells. Due the high reaction activity of MBA, more MBA was consumed in the original stage of the polymerization onto the PMAA/SiO2 microspheres, thus a gradient in crosslinking degree of the PNIPAM shells formed [39]. In the irregular crosslinked PNIPAM shells synthesized with the higher feeding ratio of crosslinker (10%), the part near the inner surface has the highest crosslinking degree, whereas that near the outer surface shows the lowest. So the volume swelling ratios and the volume shrinking ratios of the PMAA/PNIPAM-n–10% microspheres were higher and lower than those of the PMAA/PNIPAM-n–7.5% microspheres prepared with the lower feeding ratio of crosslinker (7.5%). 3.3. Drug loading and controlled release

PMAA/PNIPAM-2-7.5% PMAA/PNIPAM-3-7.5% PMAA/PNIPAM-4-7.5% PMAA/PNIPAM-5-7.5% PMAA/PNIPAM-7.5%

500

Diameter (nm)

450 400 350 300 250 200 24

26

28

30

32

34

36

38

Temperature ( οC)

(b) PMAA/PNIPAM-2-10%

550

PMAA/PNIPAM-3-10% PMAA/PNIPAM-4-10% PMAA/PNIPAM-5-10%

Diameter (nm)

500 450 400 350 300 250 24

26

28

30

32

34

Temperature ( οC)

36

38

(c) Fig. 3. The average hydrodynamic diameters of the PMAA microspheres in different pH values at 25 °C (a) and the average hydrodynamic diameters of the PMAA/PNIPAM microspheres in different temperatures at pH = 7.0 (b and c).

ratios decreased and then increased with the increasing of the TEOS feeding ratios (n) from 2.0 to 5.0 mL. It is wellknown that the volume swelling ratio decreases with the increasing in crosslinking degree, while the volume shrinking ratio increases with the increasing in crosslinking degree. Here the unusual results might be due to the

DOX was used as a model drug to investigate the potential application of the yolk/shell PMAA/PNIPAM microspheres as drug-carriers. The microspheres were loaded with DOX (1:0.5 w/w) at pH 7.4 by shaking in the dark for 48 h at 25 °C. The DLC and drug-encapsulation efficiency (DEE) were shown in Table 4. At pH 7.4, DOX (pKa = 8.5–9.0) is protonated. So the cationic DOX was associated to anionic charged carboxyl groups (pKa = 4.5) of the PMAA cores via the electrostatic interaction as well as hydrogen bond [36]. It is interesting to find that the higher DLC values were achieved for the yolk/shell PMAA/PNIPAM-2–7.5%, PMAA/PNIPAM-3–7.5% and PMAA/PNIPAM-4–7.5% microspheres, compared with the core/shell PMAA/PNIPAM-7.5% microspheres. It indicated that the cavity in the yolk/shell microspheres can provide space for the volume expansion of the PMAA cores during the drug-loading [29,30]. Increasing the feeding ratio of TEOS or the crosslinker, the DLC values decreased, due to the higher crosslinking degree (with the higher N content). The results are not in agreement with changing trend in the volume swelling ratio, indicating that the volume swelling of the yolk/shell PMAA/PNIPAM microspheres is mainly due to the swelling of the PNIPAM shells. With increased feeding ratio of TEOS, the cavity diameter increased (Table 2). But it did not result to the increased DLC; this is due to that the partially swollen PMAA cores had been encapsulated with the middle SiO2 layer in the proposed strategy. The N contents of the yolk/shell PMAA/PNIPAM-n–10% microspheres were higher than those of the corresponding yolk/shell PMAA/PNIPAM-n– 7.5% microspheres, indicating that the crosslinked PNIPAM shells contained more MBA with the increased feeding ratio of crosslinker. However, the DLC and DEE of the yolk/shell PMAA/ PNIPAM-3–7.5% and PMAA/PNIPAM-3–10% at the same condition at 37 °C were measured to be 44.8% and 31.7%, 89.6% and 63.4%, respectively. All the data are lower than those at 25 °C, revealing the temperature controlling drug loading characteristics as reported previously [24]. The PNIPAM shells shrank after heating from 25 °C to 37 °C, so the DLC decreased. Furthermore, with the higher crosslinking degree (PMAA/PNIPAM-3–10%), the volume

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L. Liu et al. / European Polymer Journal xxx (2015) xxx–xxx Table 3 Volume swelling and shrinking ratios of the microspheres.

a b c

Samples

Dh (nm)25°C,a

Dh (nm)37°C,a

Swelling ratiob

Shrinking ratioc

PMAA/PNIPAM-7.5% PMAA/PNIPAM-2–7.5% PMAA/PNIPAM-3–7.5% PMAA/PNIPAM-4–7.5% PMAA/PNIPAM-5–7.5% PMAA/PNIPAM-2–10% PMAA/PNIPAM-3–10% PMAA/PNIPAM-4–10% PMAA/PNIPAM-5–10%

482.4 275.8 448.2 416.2 342.3 419.7 531.3 538.5 449.5

384.0 221.0 309.0 277.0 242.3 290.5 344.5 346.8 301.1

58.88 7.03 26.57 20.17 10.61 23.08 43.65 43.26 22.64

0.50 0.51 0.33 0.29 0.35 0.33 0.27 0.27 0.30

Dh is the hydrodynamic diameter measured by DLS. Swelling ratio = (Dh (nm)25°C/Dn (nm))3. Shrinking ratio = (Dh (nm)37°C/Dh (nm)25°C)3.

Table 4 Effect of the N element content on the loading capacity (LC) and encapsulation efficiency (EE) of the PMAA/PNIPAM microspheres. Samples

N content (wt%)

LC (%)

EE (%)

PMAA/PNIPAM-7.5% PMAA/PNIPAM-2–7.5% PMAA/PNIPAM-3–7.5% PMAA/PNIPAM-4–7.5% PMAA/PNIPAM-5–7.5% PMAA/PNIPAM-2–10% PMAA/PNIPAM-3–10% PMAA/PNIPAM-4–10% PMAA/PNIPAM-5–10%

7.40 8.50 9.12 9.09 9.17 9.44 10.28 10.02 9.99

48.4 49.0 48.7 48.9 47.2 41.7 33.9 34.1 35.4

96.8 98.0 97.4 97.8 94.4 83.4 67.8 68.2 70.8

shrinking ratio is lower (Table 3), leading to the lower DLC. The reducing extent of the yolk/shell PMAA/PNIPAM-3– 7.5% was higher than that of the PMAA/PNIPAM-3–10%, compared with the DLC values obtained at 25 °C and 37 °C. It also showed that the gradient in crosslinking degree in the PNIPAM shells is adverse to drug-loading. Then the in vitro release profiles of DOX from the PMAA/ PNIPAM microspheres in phosphate buffer saline (PBS) were investigated. In pH 5.0 PBS at 37 °C mimicking the acidic cancer microenvironment, all the core/shell and yolk/shell PMAA/PNIPAM microspheres showed the fast release of DOX in the original stage, due to the drug loaded onto the PNIPAM shells via hydrogen bonds and hydrophobic interaction [40]. The series of the yolk/shell PMAA/ PNIPAM-n–7.5% microspheres showed the faster release than the core/shell PMAA/PNIPAM-7.5% microspheres, except for the yolk/shell PMAA/PNIPAM-5–7.5% microspheres with the highest cavity diameter due to more TEOS had been used (Fig. 4a). The shrinking of the PNIPAM shells had the weakest compression on the DOXloaded PMAA cores. Furthermore, the release rate increased and then decreased with the increasing of their cavity size, consistent with the law in their volume change upon heating. It showed that the size of the cavity in the yolk/shell PMAA/PNIPAM-7.5% microspheres also possessed the controlling ability for the drug release. Compared to the release performance of the yolk/shell PMAA/PNIPAM-n–7.5% microspheres, the yolk/shell PMAA/PNIPAM-n–10% microspheres with higher feeding ratio of crosslinker showed the much faster release rate in the initial stage of releasing (about 10 h) (Fig. 4b), due

to their lower volume shrinking ratios upon heating (Table 3), while the yolk/shell PMAA/PNIPAM-n–7.5% microspheres with lower feeding ratio of crosslinker exhibited the better sustained release. It might also be led from the stronger compression produced by the lower volume shrinking ratio of the PNIPAM shells upon heating [41]. This could also be revealed by the drug release at different temperature. For the DOX-loaded yolk/shell PMAA/ PNIPAM-3–7.5% and PMAA/PNIPAM-3–10% microspheres, both of them showed the better sustained release at 25 °C, whereas the faster release rate in the initial stage of releasing (about 10 h) at 37 °C (Fig. 4c), due to the shrinking of the PNIPAM shells [41]. The results demonstrated the temperature responsive controlled release characteristics of the yolk/shell PMAA/PNIPAM-3–7.5% microspheres. The faster release rate from the DOX-loaded PMAA/PNIPAM-3–10% microspheres was resulted from their gradient in crosslinking degree of the PNIPAM shells. The inner section with the higher crosslinking degree shows hydrophilic property due to the higher content of MBA units, which is beneficial to the diffusion of water as well as drug molecules. Comprehensive consideration the particle size, drugloading and release performance, the yolk/shell PMAA/ PNIPAM-3–7.5% microspheres might be the optimum one. Then the effect of the media pH on the release performance of the DOX-loaded PMAA/PNIPAM-3–7.5% microspheres was compared at pH 5.0 and 7.4 PBS media. At pH 5.0, the DOX release profiles showed a rapid release rate, and the cumulative release reached 56.0% within 50 h, and it is still on the rise (Fig. 4d). When the pH value of the release media increased to 7.4, no burst release was observed, and only 15.1% of DOX was released within 10 h, and the cumulative release only reached 17.8% within 50 h. The pH responsive controlled release of DOX from the yolk/ shell PMAA/PNIPAM-3–7.5% microspheres mainly due to the two reasons: the first one is that DOX is soluble in acidic media; the other one is the dramatically reduced PMAA ionization in acidic media induces the disruption of the electrostatic binding of PMAA cores with DOX species [42]. Drug release behavior fitted in Higuchi and Korsmeyer– Peppas models of different conditions was showed in Fig. S1. For the Higuchi model with equation of Mt = kt1/2 (Mt shows the drug cumulative release in t (min) and k is

Please cite this article in press as: Liu L et al. Independent temperature and pH dual-stimuli responsive yolk/shell polymer microspheres for controlled release: Structural effect. Eur Polym J (2015), http://dx.doi.org/10.1016/j.eurpolymj.2015.03.026

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L. Liu et al. / European Polymer Journal xxx (2015) xxx–xxx

40 30 PMAA/PNIPAM-2-7.5% PMAA/PNIPAM-3-7.5% PMAA/PNIPAM-4-7.5% PMAA/PNIPAM-5-7.5% PMAA/PNIPAM-7.5%

20 10 0 0

10

20

30

40

50 40 30 20

10

20

30

Time (h)

a

c

Cumulative Release (%)

60

40 PMAA/PNIPAM-2-10% PMAA/PNIPAM-3-10% PMAA/PNIPAM-4-10% PMAA/PNIPAM-5-10%

20

20

30

40

50

40

50

o

37 C

50 40 30 20 PMAA/PNIPAM-3-7.5% pH=7.4 PMAA/PNIPAM-3-7.5% pH=5.0

10 0

0 10

0

Time (h)

60

0

PMAA/PNIPAM-3-7.5%- 25OC PMAA/PNIPAM-3-10%-25 OC PMAA/PNIPAM-3-7.5% -37OC PMAA/PNIPAM-3-10% -37OC

10 0

50

pH=5.0

80

Cumulative Release (%)

pH=5.0

60 50

Cumulative Release (%)

Cumulative Release (%)

70

pH=5.0

60

0

10

20

30

40

50

Time (h)

Time (h)

d

b

Fig. 4. In vitro release profiles of DOX from the PMAA/PNIPAM microspheres in PBS: (a) yolk/shell PMAA/PNIPAM-n–7.5% and Core/shell PMAA/PNIPAM– 7.5% microspheres at pH 5.0 at 37 °C, (b) yolk/shell PMAA/PNIPAM-n–10% microspheres at pH 5.0 at 37 °C, (c) yolk/shell PMAA/PNIPAM-3–7.5% and PMAA/ PNIPAM-3–10% microspheres at pH 5.0 at 25 and 37 °C, and (d) yolk/shell PMAA/PNIPAM-3–7.5% microspheres at pH 5.0 and 7.4 at 37 °C.

Table 5 Drug release data fitted in Higuchi and Korsmeyer–Peppas models. Samples

PMAA/PNIPAM-7.5% PMAA/PNIPAM-2–7.5% PMAA/PNIPAM-3–7.5% PMAA/PNIPAM-4–7.5% PMAA/PNIPAM-5–7.5% PMAA/PNIPAM-2–10% PMAA/PNIPAM-3–10% PMAA/PNIPAM-4–10% PMAA/PNIPAM-5–10% PMAA/PNIPAM-3–7.5% PMAA/PNIPAM-3–10% PMAA/PNIPAM-3–7.5%

Temperature (°C)

37 37 37 37 37 37 37 37 37 25 25 37

pH

5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 7.4

the slope obtained from the linear relation), the R2 values of the yolk/shell PMAA/PNIPAM-n–7.5% microspheres are higher than those of the yolk/shell PMAA/PNIPAM-n–10% microspheres (Table 5). It indicated that only the release from the yolk/shell PMAA/PNIPAM-3–7.5% microspheres at pH 5.0 and 37 °C was determined by diffusion, because its slope is higher than 1 (k > 1) [43].

Higuchi

Korsmeyer–Peppas

R2

k

R2

n

0.878 0.903 0.895 0.884 0.954 0.814 0.822 0.774 0.794 0.990 0.986 0.842

0.8586 0.9794 1.018 0.9301 0.7863 1.323 1.336 1.270 1.563 0.6579 0.8874 0.2635

0.933 0.929 0.903 0.911 0.966 0.965 0.932 0.963 0.995 0.983 0.970 0.961

0.4994 0.5098 0.4997 0.4934 0.5621 0.6145 0.6601 0.5822 0.4795 0.5681 0.6333 0.2509

As for the Korsmeyer–Peppas model with equation of Mt/M1 = ktn (Mt/M1 is the release percentage in t (min) and k is determined by release system and condition), all the R2 values are higher than 0.9 (Table 5), indicating the correlation coefficient of the fitting equation was ideal. The release exponent (n) is an important parameter to decide release behavior, which is obtained by fetching

Please cite this article in press as: Liu L et al. Independent temperature and pH dual-stimuli responsive yolk/shell polymer microspheres for controlled release: Structural effect. Eur Polym J (2015), http://dx.doi.org/10.1016/j.eurpolymj.2015.03.026

L. Liu et al. / European Polymer Journal xxx (2015) xxx–xxx

logarithm on both sides of the equation on the condition Mt/M1 < 0.6 [44]. The release model follows Fickian diffusion as n 6 0.5, while non-Fickian as 0.5 < n < 1 [45]. In most of the yolk/shell PMAA/PNIPAM-n–7.5% microspheres, they yield comparatively good linearity with release exponents (n) of approximately 0.5 as well as the core/shell PMAA/ PNIPAM7.5% microspheres, suggesting that the release mechanism of DOX fitted the Fickian diffusion [46]. In contrast, the n values of the most of the yolk/shell PMAA/ PNIPAM-n–10% microspheres at pH 5.0 and 25 °C were found to be higher than 0.5, indicating the transport process of DOX was anomalous, corresponding to a pseudo-Fickian or Case III mechanism [46,47], due to their gradient in crosslinking degree in the PNIPAM shells. Interestingly, the two yolk/shell PMAA/PNIPAM microspheres with the largest cavity (PMAA/PNIPAM-5–7.5% and PMAA/PNIPAM5–10%) were the exception in each series. It indicated that the PMAA/SiO2 seeds with thick middle SiO2 shells might cause more complicated effect on the PNIPAM shells under the same polymerizing conditions. 4. Conclusions The pH and temperature dual-stimuli responsive yolk/ shell microspheres with pH responsive core and temperature sensitive shell were prepared via distillation precipitation polymerization and seed precipitation polymerization as a model drug-carrier for the exploration of the structural effect on their drug-loading and controlled release performance. The results demonstrated that the cavity diameters played a slight role in the drug-loading capacity due to that the partially swollen PMAA cores were used for the fabrication of the sandwich PMAA/SiO2/ PNIPAM microspheres, when the feeding ratio of crosslinker was lower. However, it affected the drug release; therefore a better sustained drug release was achieved. As for the higher feeding ratio of crosslinker, the drug-loading capacity decreased and the drug release was faster due to the gradient in crosslinking degree in the PNIPAM shells. So it could be concluded that the smaller cavity and the lower PNIPAM crosslinking degree were beneficial to the drug-loading and controlled release performance of the pH and temperature dual-stimuli responsive yolk/shell microspheres with pH responsive cores and temperature sensitive shells prepared via distillation precipitation polymerization and seed precipitation polymerization approach. Acknowledgments This project was granted financial support from the National Nature Science Foundation of China (Grant No. 20904017), and the Program for New Century Excellent Talents in University of Ministry of Education of China (Grant No. NCET-09-0441). Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.eurpolymj.2015.03.026.

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Please cite this article in press as: Liu L et al. Independent temperature and pH dual-stimuli responsive yolk/shell polymer microspheres for controlled release: Structural effect. Eur Polym J (2015), http://dx.doi.org/10.1016/j.eurpolymj.2015.03.026