Preparation and characterization of smart magnetic hydrogels and its use for drug release

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Journal of Magnetism and Magnetic Materials 304 (2006) e397–e399

Preparation and characterization of smart magnetic hydrogels and its

use for drug release

Ting-Yu Liu

a

, Shang-Hsiu Hu

a

, Kun-Ho Liu

a

, Dean-Mo Liu

b

, San-Yuan Chen

a, a_{Department of Materials Sciences and Engineering, National Chiao Tung University, Hsinchu, Taiwan 300, ROC}

b_{ApaMatrix Technologies Inc. 7431 Bates Road, Richmond, British Columbia, Canada V7A 1C8} Available online 3 March 2006

Abstract

The magnetic hydrogels were successfully fabricated by chemically cross-linking of gelatin hydrogels and Fe3O4 nanoparticles

(ca. 40–60 nm) through genipin (GP) as cross-linking agent. The cross-sectional SEM observation demonstrates that the Fe3O4

nanoparticles were fairly uniformly distributed in the gelatin matrix. Moreover, in vitro release data reveal that drug release profile of the resulting hydrogels is controllable by switching on or off mode of a given magnetic field. While applying magnetic fields to the magnetic hydrogels, the release rate of vitamin B12of the hydrogels was considerably decreased as compared with those when the field was turned

off, suggesting a close conﬁguration of the hydrogels as a result of the aggregation of Fe3O4nanoparticles. Based on this on-&-off

mechanism, the smart magnetic hydrogels based on the gelatin-ferrite hybrid composites can be potentially developed for application in novel drug delivery systems.

Keywords: Magnetic hydrogels; Swelling rate; Smart drugs release

1. Introduction

In recent years, stimuli-responsive polymers, which can respond to external stimuli, such as pH, temperature and electric ﬁeld, have attracted a great deal of interest due to their potential applications in controlled drug delivery[1]. Gelatin is a widely used polymer in pharmaceutical products [2]. Furthermore, it is of special interest in controlled release applications because of their soft tissue biocompatibility, the ease with which the drugs are dispersed in the matrix, and the high degree of control achieved by selecting the physical and chemical properties of the polymer network.

Magnetic materials have been widely used in the field of biotechnology in bio-separation, artificial muscles and drug carriers[3–5]. Some researchers have reported that the drug carriers of magnetic gels could be applied in targeting[6]. However, to our best knowledge, it is barely found to use magnetic fields (MF) for controlled release of drug. Therefore, a combination of gelatin and magnetic particles

is a potential approach to prepare a responsive composite that can be applied as a drug delivery system by MF.

2. Experimental

For the preparation of the magnetic hygrogels (or called ferrogel), gelatin (15 wt%) was ﬁrst dissolved in deionized water at 45 1C to ensure that the gelatin can be fully dissolved. After that, 4 wt% Fe3O4 nanoparticles (from

Alfa Aesar) including 0.03 wt% drugs (vitamin B12, from

Sigma) and genipin (GP, Challenge Bioproducts Co., Ltd., Taiwan) with different weight ratio were added to the above gelatin solution under stirring for 30 min at 40 1C and then incubated at 25 1C for 2 days. The GP-cross-linked ferrogels were designated as Ge0.06, Ge0.03, Ge0.01 and Ge0.003 according to their different cross-link density. For example, Ge0.06 indicates that GP content is 0.06 wt%.

The swelling rate of the ferrogels was measured as described in our previous study [7] and a given MF of about 400 Oe was used during the on-off operation. For drug release test, the ferrogels containing vitamin B12were

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ﬁrst immersed in 20 ml of phosphate buffer (PBS) (pH7.4) and then UV-visible spectroscopy was used for the characterization of absorbance peaks at 361 nm to deter-mine the release concentration of the vitamin B12.

3. Results and discussion

As the gelatin hydrogels were loaded with vitamin B12

(without Fe3O4 particles) and cross-linked by GP with

various weight ratios, the photographs inFig. 1(a)present different colors. After the gelatin/GP solution was incu-bated for 2 days, the color (vitamin B12) of the gels changed

from pink to purple (lower cross-linked density) or dark blue (higher cross-linked density). The UV spectra in

Fig. 1(b) also demonstrate a color change. The above results may suggest that the gelatin could react with a variety of the GP concentrations to display different color and morphology. In general, the darker the color of the gels, the denser the structure of the gels obtained. There-fore, the porosity or pore size of the gelatin gels would inﬂuence the drug release proﬁle. In addition, it was observed that the Fe3O4 nanoparticles were fairly

uni-formly distributed in the gelatin matrix as evidenced from a cross-sectional SEM image illustrated inFig. 2(a).

The swelling properties of the magnetic hydrogels as a function of switching MF were illustrated in Fig. 2(b). While switching on mode of a given MF, it was found that not only swelling rate decreased sharply but also de-swelling in the differential curve. On the other hand, while switching off, it will restore to original state. The sensitive properties can be attributed to the fact that the porosity or the pore size in the ferrogels possibly change with the switching ‘‘on or off’ mode. Such a decreased porosity or pore size suggests a ‘‘close’’ conﬁguration of the ferrogels and can be further illustrated inFig. 3. While the MF was on, the Fe3O4particles tend to aggregate together and this

causes the porosity of the ferrogel to decrease. As a result, a

swelling rate was reduced and a decreased drugs release rate was induced.

Fig. 4(a) exhibits the close conﬁguration of Ge0.003 ferrogel. The drug release rate was decreased upon

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400 450 1.6 Blue Light ABS (a.u.) Wavelength (nm) Crosslinking density (a) 1.8 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 300 350 500 550 600 650 Ge0.06 Ge0.03 Ge0.003 Ge0.01 Pure Ge Vitamin B12 HIGH LOW (b)

Fig. 1. (a) Photographs of the gelatin gels with different cross-linked densities, and (b) UV spectroscopy analysis of different cross-linked gelatin hygrogels.

100nm

(b)

Ge0.03 De-swelling

Swelling rate (fraction/min)

0 150 off Magnetic Field Time (min) on 0.05 0.04 0.03 0.02 0.01 0.00 -0.01 50 100 200 250 300 350 (a)

Fig. 2. (a) SEM observation of Fe3O4nanoparticles distributed in gelatin hydrogels, and (b) sensitive swelling rate of the ferrogels dependent on switching MF.

Fig. 3. Mechanism of ‘‘close’’ conﬁguration of the ferrogels due to the aggregation of Fe3O4nanoparticles under ‘‘on’’ MF causes the porosity of the ferrogels to decrease.

0 300 400 0 20 40 60 80 Cumulative Release (%) Time (min) MF “OFF” (b) 0 8000 -9 -6 -3 0 3 6 9 Magnetization (emu/g) MF “ON” (a) Ge0.03 Ge0.003 Field (Oe) -16000 -8000 16000 Ge0.003 100 200

Fig. 4. (a) Drugs release rate proﬁles of the Ge0.003 ferrogels in MF switching ‘‘on’’ or ‘‘off’’ mode, and (b) hysteresis loop analysis of the magnetic hydrogels using VSM.

T.-Y. Liu et al. / Journal of Magnetism and Magnetic Materials 304 (2006) e397–e399 e398

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switching on. Moreover, Table 1 shows the released vitamin B12 amount from the hydrogels cross-linked with

different GP concentrations under a given on or off mode. It was observed that in the ferrogels, the lower the GP concentration, the stronger the magnetic responsive prop-erties (OFF-ON) (9.1%).

This behavior can be related to structure and character-istics of the ferrogels. It was inferred that the ferrogels with a lower GP concentration display the softer properties and this could cause the porosity to be easily modiﬁed through free movement of the chains in the gelatin hydrogels. Furthermore, the Ge0.003 ferrogel show a higher magnetization (Ms) (9.199 emu/g) than Ge0.03 ferrogel (6.023 emu/g) measured using the vibrating sample magnetometer (VSM) inFig. 4(b). Based on the above two reasons, it could be demonstrated that the ferrogels with a lower cross-linked density display more obvious magnetic sensitive properties. Besides, the magnetic responsive properties of the drugs release could be found in a consecutive switching ‘‘on-off’’ mode for a given MF, as shown in Fig. 5. The differential curve showed that the release rate of the drug in the ferrogels was considerably decreased under switching ‘‘on’’ mode but increased upon switching ‘‘off’’ mode.

4. Conclusion

Smart magnetic hydrogels based on gelatin-ferrite composites were investigated and can be applied for the

development of a new magnetically induced drug delivery system. Furthermore, the drug release proﬁle of the resulting hydrogels is controllable by switching ‘‘on’’ or ‘‘off’’ mode of a given magnetic ﬁeld.

References

[1] M. Zrı´nyi, Colloid. Polym. Sci. 278 (2000) 98.

[2] R. Cortesi, C. Nastruzzi, S.S. Davis, Biomaterials 19 (1998) 1641. [3] T. Neuberger, B. Dcho¨pf, H. Hofmann, M. Hofmann, B. Rechenberg,

J Magn. Magn. Mater. 293 (2005) 483.

[4] Q.A. Pankhurst, J. Connolly, S.K. Jones, J. Dobson, J. Phys. D:Appl. Phys. 36 (2003) 167.

[5] A.J. Rosengart, M.D. Kaminski, H. Chen, P.L. Caviness, A.D. Ebner, J.A. Ritter, J Magn. Magn. Mater. 293 (2005) 633.

[6] O. Rotariu, N.J.C. Strachan, J Magn. Magn. Mater. 293 (2005) 639. [7] M.C. Yang, T.Y. Liu, J. Membrane Sci. 226 (2003) 119.

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Table 1

Cumulative drugs release of the ferrogels in ‘‘on’’ or ‘‘off’’ mode of a given magnetic ﬁeld for 120 min

Ferrogel Ge0.003 Ge0.01 Ge0.03 Ge0.06

MF OFF 56.5% 52.2% 49.9% 48.0% MF ON 47.4% 45.5% 44.4% 44.1% OFF-ON 9.1% 6.7% 5.5% 3.9% 0.25 on off Magnetic Field

Release rate (ml/min)

0.00 0.05 0.10 0.15 0.20 50 100 150 200 Time (min) 250 300 Ge0.06

Fig. 5. Sensitive drugs release properties of the ferrogels dependent on switching ‘‘on-off’’ mode for a given MF.