ARTICLES Chinese Science Bulletin 2005 Vol. 50 NO.8 752-757

Synthesis and characterization of nanoscale magnetic drug-inorganic com posites SUN Hui, ZHANG Hui, David G. Evans & DUAN Xue Ministry of Education Key Laboratory of Science and Technology of Controllable Chemical Reactions, Beijing University of Chemical Technology, Beijing 100029, China Correspondence should be addressed to Duan Xue (email: duanx@mail. buct.edu.cn) and Zhang Hui (email: [email protected])

Abstract The synthesis by direct coprecipitation and characterization of captopril (Cpl) and 5-aminosalicylic acid (5-ASA) intercalated ZnAllayered double hydroxides coated on MgFe204 magnetic core particles are reported. Powder XRD analysis shows the well-defined crystallite structure of the composites. TEM and XPS results reveal that a core-shell structure involving a drug-LDHs layer coated on MgFe204 particles is formed through Zn-O-Mg and/or AI-O-Mg linkages. VSM measurements demonstrate that the novel magnetic drug-inorganic composites possess considerable magnetization. Keywords: magnetic targeted drug, zinc aluminum layered double hydroxide, captopril, 5-aminosalicyiic acid, coprecipitation, coreshell structure.

DOl: 10.1360/982004-82

Targeted drug delivery systems can selectively deliver drug molecules to the diseased site, rather than evenly distributing them throughout the body and thus can prevent adverse effects on normal organs[IJ. Drug targeting refers to drug molecules conjugated with pharmaceutical carriers or coated by them, such that the local concentration of the drug at the diseased site(s) is high, while its concentration in other non-target organs and tissues is below certain minimal levels in order to prevent any negative side-reactions. As a result, drug targeting can sharply reduce drug administration, achieve therapeutic effects, decrease non-specific toxicity and other adverse side effects and enhance drug specific affinity toward a pathological site. Magnetic agents belong to the fourth generation of drug targeting agents[2J, under the guidance of an external magnetic field, in which drug and pharmaceutical carrier are conjugated with magnetic materials such as Fe304 particles, they can selectively deliver drug molecules to the diseased site. Widder et al. [3J employed colloidal magnetite (Fe304) coated with cross-linked albumin. The resultant microspheres were used to encapsulate doxorubicin, and were captured magnetically in Yoshida sarcoma tumors implanted in rat-tails. These results represent a significant advance in targeted chemotherapy in that 77% of the animals in the magnetically localized doxorubicin microsphere treatment groups exhibited total 752

remission after only one regimen of drug therapy. In the present work, magnesium ferrite (MgFe204) spinel was employed as the magnetic material. Ferrites have widely been applied in many areas, such as bioseparation of enzyme[4J and purification of protein[sJ. Ferrites can be synthesized by many methods, for instance, high-energy ball milling[6J, sol-gel processes[7 J and coprecipitation[8 J. However, as-synthesized ferrites generally have weak saturation magnetization and a large range of particle size. A stoichiometric synthesis of a pure ferrite from a tailored layered double hydroxide precursor has been recently developed in our laboratory and this method settles some problems in conventional syntheses[9J. We have reported a novel nanoscale magnetic solid base catalyst involving a layered double hydroxide supported on a ferrite core (MgFe204 or NiFe204ilO,llJ. This suggests that drugs could be supported on the ferrite core instead of conventional magnetic species (Fe304) and the resulting composites could be used in magnetically controlled drug targeting. Layered double hydroxides (LDHs), also called anionic clays or hydrotalcite-like compounds, can be represented by the general formula [Ml_x2"Mx3+ (OHh]' A n- x/n ' yH 20, where M 2+ and M3+ are bi- and tri-valent metal cations, x 3 2 3 n = M +j(M ++M +) and A - denotes the interlayer anions. In these compounds the layers are built up by metal cations occupying OH octahedra. Exchange of interlayer anions with various other inorganic or organic anions is designated as intercalation[12,13J. Hydrotalcite-like anionic clays are able to intercalate drugs, and deintercalate them in order to modify their release as a controlled release formulation. O'Hare et alY4 J intercalated diclofenac into LiAI layered double hydroxides by the anion exchange method, and their initial in vitro release studies suggest that these materials may have potential application as the basis of a novel tunable drug delivery system. Captopril, 1-[(2S)-3-mercapto-2-methyl-I-oxypropyl]L-proline (C9H 1SN0 3S), is an angiotensin converting enzyme inhibitor, and has been widely used to treat hypertensive disease and in the treatment of congestive heart failure, as such or in combination with other drugs, due to its effectiveness and low toxicity[lsJ. 5-aminosalicylic acid (its commercial name is Masalazine) is widely used in the treatment of inflammatory bowel disease, including ulcerative colitis and Crohn's disease[16J. To date, the majority of pharmaceuticals in clinical application are currently employed directly or in a controlled release form; in these cases however, they don not accumulate in the target organ selectively[l7 J. So as to avoid having to administer the drug in large quantities in order to achieve the required therapeutic effect, drug targeting can be employed. In this work, we describe a composite of drug-inorganic hybrid materials and a magnetic material, i.e. a novel core-shell structured magnetic composite containing captopril or 5-aminosalicylic acid intercalated in a ZnAllayChinese Science Bulletin

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ARTICLES ered double hydroxides assembled by a coprecipitation method which has potential application in drug targeting. The structure and magnetic properties for the composites were studied. Our work emphasizes both synthesis and characterization of the composites of drug-inorganic hybrid materials and magnetic material, and trials of the drug release under in vitro conditions will be reported in a future paper.

1 Experimental 1.1

Synthesis of magnetic nanoparticles of MgFe204

The magnetic nanoparticles were prepared following the method described in ref. [10]. A mixed aqueous solution of Mg(N0 3h . 6H 20 (0.033 mol) and Fe(N03)3· 9H 20 (0.067 mol) in deionized water and a second solution containing NaOH ([NaOH]=1.6 [Mg2++Fe 3+]) and Na2C03 ([C032-]=2.0[Fe 3+]) in deionized water (pH~9) were simultaneously added to a colloid mill[18,19] rotating at 4000 rpm and mixed for 2 min. The resulting slurry was transferred from the reactor into a three-neck flask and aged at 373 K for 6 h. The final precipitate was filtered, washed thoroughly with deionized water and dried at 343 K for 24 h. The resulting sample (MgFe-LDHs) was then calcined at 1173 K for 2 h giving the magnetic material MgFe204. 1.2

Synthesis of magnetic drug-inorganic composites

(i) Synthesis of Cpl-LDHs/MgFe204' Typically, a mixed aqueous solution of Zn(N03h· 6H 20 (0.0142 mol) and Al(N0 3)3· 9H 20 (0.0035 mol) in decarbonated deionized water (30 mL) and a second aqueous solution of NaOH (0.0497 mol) and Cpl (0.0142 mol) in decarbonated deionized water (30 mL) were simultaneously added dropwise over 120 min to a vigorously stirred solution (100 mL) containing MgFe204 with a Zn(N03h· 6H 20/ MgFe204 weight ratio of 27 in decarbonated deionized water kept at pH of about 9 under an N 2 atmosphere. The resulting slurry was aged with stirring at 25 'C for 48 h, filtered, washed thoroughly with decarbonated deionized water, and finally dried in vacuo at room temperature for 48 h. The product was denoted as Cpl-LDHs /MgFe204' (ii) Synthesis of 5-ASA-LDHs/MgFe204' An aqueous solution of Zn(N03h· 6H 20 and Al(N0 3)3· 9H 20 (Zn2+/ Ae+= 4, [Zn2+] = 0.06 mol/L) in decarbonated deionized water (200 mL) was firstly mixed with MgFe204 with Zn(N03h·6H20/MgFe204 weight ratio of 18 giving a suspension. This suspension was kept at pH of about 8.4 by dropwise addition of NaOH solution (0.038 mol/L) containing 5-ASA (0.008 mol) with vigorous stirring under an N 2 atmosphere. The resulting slurry was aged at 333 K for 48 11, centrifuged, washed and dried for 12 hat 343 K. The product was denoted as 5-ASA-LDHs/ MgFe 20 4. (iii) Synthesis of reference compounds. For comparison, Cpl-LDHs and 5-ASA-LDHs were also prepared folChinese Science Bulletin

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lowing the methods in l.2(i) and l.2(ii) without addition of MgFe204. ZnAICOrLDHs was also synthesized as follows: Zn(N03h· 6H 20 (0.012 mol) and Al(N03)3· 9H20 (0.003 mol) were dissolved in deionized water (100 mL) to make a mixed salt solution; NaOH (0.038 mol) and Na2C03 (0.006 mol) were dissolved in deionized water (100 mL) to make a mixed alkali solution. The two solutions were simultaneously added to a colloid mill rotating at 4000 rpm and mixed for 2 min. Subsequent procedures were the same as described in 1.1. The product was denoted as COrLDHs. 1.3

Characterization

Powder X-ray diffraction (XRD) data were recorded on a Shimadzu XRD-6000 diffractometer using Cu Ka radiation (1 = 1.5418 A, 40 kY, 30 rnA). The samples, as unoriented powders, were step-scanned in steps of 0.02 0 (28) in the range 2 0 -70 0 using a count time of 4 s per step. The FT-IR spectra were obtained using a Broker Vector-22 FT-IR spectrophotometer. KEr pellets containing 1% sample were used to obtain the FT-IR spectra. The TEM micrographs were recorded on a Hitachi-800 transmission electron microscope. Surface chemical compositions were studied by X-ray photoelectron spectroscopy (XPS) using a VG Escalab-MK II X-ray photoelectron spectrometer. The pressure in the analysis chamber during the experiments was 3 x 10-7 Pa. Spectra were acquired using a standard Al Ka source at hv = 1486.6 eV operating at 15 kV and 20 rnA. The binding energy scale was referenced to the CIs line of aliphatic carbon contamination set at 284.6 eV Metal contents were measured by inductively coupled plasma (lCP) emission spectroscopy using a Shimadzu ICPS-7500 instrument. Thermo-gravimetric analyses (TG) were performed on a locally made PCT-IA instrument with a heating rate of lO'C . min- 1 in flowing air. C, H, and N elemental microanalyses were obtained on an Elementar Vario Elemental Analyzer. Magnetic properties of the samples were studied on a JSM-13 Vibrating Sample Magnetometer (VSM) with a magnetic field of 15 kOe (Temperature: 25'C, sample mass: 50 mg).

2 Results and discussion 2.1 Structure and magnetic property of the MgFe204 magnetic particles The X-ray diffraction patterns of MgFe204 and its layered precursor are shown in Fig. 1. The XRD pattern of the MgFe-LDHs precursor shows the characteristic (003), (006), (009) and (110) reflections of hydrotalcite-like compounds[l3]. After calcination at 1173 K, the reflections of the layered structure of LDHs completely disappeared, and were replaced by well-shaped diffraction peaks which correspond to (220), (311), (400), (511) and (440) reflections of magnesium ferrite spinel, which are in good 753

ARTICLES Table 1 o o

Samples

"""

M

o o

>.0

-

0\

o o

-

10

20

30

40 281(')

50

doo,lnm

2.180

1.350

0.751

dooJnm

1.135

0.829

0.377

duo/nm dnm')

0.152

0.153

0.153

6.540

4.050

2.253

0.304

0.306

0.306

1.550

3.300

3.400

a/nm') Zn/Al b)

o

o o

XRD parameters for Cpl-LDHs/MgFe204, 5-ASA-LDHs/ MgFe204 and C0 3-LDHs Cpl-LDHs/MgFe204 5-ASA-LDHs/MgFe20 4 C0 3 -LDHs

(a)

60

70

Fig. 1. XRD patterns of (a) MgFe-LDHs and (b) MgFe204.

agreement with the standard pattern (JCPDS 17-0465). The average crystallite diameter can be determined from the full-width at half-maximum (FWHM) of the (311) diffraction peak by using the Scherrer formula[ll]: D = 0.89A./(jJcosB), where A. is the X-ray wavelength, () is the Bragg diffraction angle, and jJ is the full-width at half-maximum. The calculated value is 18.7 urn. The magnetic properties can be studied by VSM, which gives the hysteresis loop shown in Fig. 2. The specific saturation magnetization O"s of 23.3 emu/g and coercivity of zero demonstrate that the as-synthesized MgFe204 sample possesses strong soft magnetic properties[20], and accordingly is suitable for use as a magnetic substrate for further investigation.

xc)

0.227 0.392 0.230 a) Hydrotalcites crystallizes in hexagonal symmetry, and the structural parameters of the unit cell a and c can be calculated according to c ~ 3do03 , a ~ 2duo[15]; b) determined by rcp; c) x ~ AI/(Zn+AI) denoting the charge density of LDHs layer.

2.180 nm

~~*~_...J*LJ

* (a)

(b)

*

;;.J\', oj

,

.~

.£

i

OJ

]

IbIJ 20

(e)

Hext/Oe -10000

5000

10000 10

Fig. 2. Hysteresis loop of the MgFe204 sample.

2.2

Structure of magnetic drug-inorganic composites

The XRD patterns of Cpl-LDHs/MgFe204, Cpl-LDHs, 5-ASA-LDHs/MgFe204, 5-ASA-LDHs and COrLDHs are depicted in Fig. 3. It can be seen that all samples show the characteristic reflections of LDHs compounds, with basal (003) reflection and higher order (006) reflection. The interlayer distance increases from 0.751 urn in COr LDHs to 2.180 urn for Cpl-LDHs/MgFe204 and to 1.350 urn for 5-ASA-LDHs/MgFe204, indicating that intercalation of Cpl and 5-ASA between the LDH layers has occurred (Table 1)[12]. At the same time, the characteristic reflections of an MgFe204 phase can be clearly observed at 2() angles of 30.36°, 35.68°, 43.33°, 57.23° and 62.82° in Fig. 3(a) and (c) with low diffraction intensity due to 754

20

30

40 28W)

50

60

70

Fig. 3. XRD patterns of (a) Cpl-LDHs/MgFe204, (b) Cpl-LDHs, (c) 5-ASA-LDHs/MgFe204, (d) 5-ASA-LDHs and (e) C0 3-LDHs (*, MgFe 20 4).

their relative low content. Reference to Fig. 3(b) and (d) suggests that the relative independence of MgFe204 and Cpl-LDHs or 5-ASA-LDHs phases are maintained in the magnetic drug-inorganic composites. Fig. 4 shows the FT-lR spectra of Cpl-LDHs/MgFe204, 5-ASA-LDHs/MgFe204 and MgFe204. For Cpl-LDHs/ MgFe204 (Fig. 4(a)) and 5-ASA-LDHs/MgFe204 (Fig. 4(b)), the broad absorption band between 3400 and 3500 cm-I arises from the stretching vibrations of -OH groups in the brucite-like layer and physisorbed water. Furthermore, in Fig. 4(a) the two bands at around 1595 and 1400 cm-I due to the anti-symmetric and symmetric stretching vibrations respectively of -C02 shift to lower wavenumbers, compared to free -C0 2 in Cpl (1748 and 1434 Chinese Science Bulletin

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st

(c)

~v u

§

(a)

534'C

'~

:>:::l.

C/O C/O

(b)

B

1=

~Q

1:i

.~

.~

§ (a) ....

~

E-

100 4000 3500 3000 2500 2000 1500 1000 Wavenumber/cm- 1

tfi

200

300

400

500

600 (b)

408'C

500

tfi

Fig. 4. IR spectra of (a) Cpl-LDHs/MgFe204, (b) 5-ASA-LDHs/ MgFe204 and (c) MgFe204.

cm- I)[21], indicating that intercalation of Cpl in the interlayer galleries involves hydrogen bonding between -C02 and hydroxide layers. Taking account of the reaction pH value and the dissociation constant of 5-ASA (pkal = 2.74, pka2 = 5.84P2], it is likely that 5-ASA exists as a monovalent anion with a -C02 group during the reaction. Consequently, the two bands at ca. 1625 cm-I and 1378 cm-I for 5-ASA-LDHs/MgFe204 can be ascribed to the anti-symmetric and symmetric stretching vibrations of -C02, compared with the free -C02 vibrations in 5-ASA (1647 and 1385 cm-I)!). In spite of the N2 protection, the presence of small amounts of carbonate in the products is indicated by weak and broad absorption bands in both Cpl-LDHs/MgFe204 at 1400 cm- I and 5-ASA-LDHs/ MgFe204 at 1378 cm-I, which possibly overlap the symmetric stretching vibration of -C02. The strong and sharp band (at ca. 578 cm-I) attributed to M-O lattice vibrations in the FT-IR spectrum of MgFe204 is present in both Fig. 4(a) and (b), but is shifted by 20-40 cm- I after incorporation of Cpl-LDHs or 5-ASA-LDHs, implying some association of magnetic material with Cpl-LDHs or 5-ASALDHs. 2.3

Thermal stability and chemical composition

The TG-DTA curves of Cpl-LDHs/MgFe204 and 5ASA-LDHs/MgFe204 are presented in Fig. 5. It can be seen in Fig. 5(a) that the sample of Cpl-LDHs/MgFe204 underwent a mass loss at ca. 104 'C owing to desorption of the adsorbed and cointercalated water; two exothermic Table 2

100

200

300 400 Temperaturel'C

500

600

Fig. 5. TG and DTA profiles of (a) Cpl-LDHs/MgFe204 and (b) 5ASA-LDHs/MgFe20 4.

peaks around 338 'C and 534 'C are due to the thermal desorption of Cpl anions taken up on the surface and thermal decomposition of intercalated Cpl. The mass loss around 534'C is 11.6%. Similarly, in Fig. 5(b), two exothermic peaks around 311 'C and 410 'C can be attributed to the thermal desorption of 5-ASA anions taken up on the surface and thermal decomposition of intercalated 5-ASA; the mass loss around 41O'C is 18.3%. Although the synthesis was performed under an N2atmosphere, a small amount of CO2 contamination could not be completely avoided. In fact, the reflections at 28 ~11.79° in Fig. 3(a) and (c) for (009) plane of Cpl-LDHs/ MgFe204 and (006) of 5-ASA-LDHs/MgFe204, respectively, broaden and overlap the (003) reflection of COr LDHs. Based on elemental analysis, the formula of CplLDHs/MgFe204 is [Z1lo6osAlo392(OHh](C9HI3N03S-)o214(CO~-)OOS9· 0.6H 20 and the formula of 5-ASA-LDHs/ MgFe204 is [Z1lo767Alo233(OHh](C7H6N03)o135(CO~-)oo49· 0.5H 20. As shown in Table 2, the calculated values are in good agreement with experimental data.

Chemical compositions ofCpl-LDHs/MgFe204and 5-ASA-LDHs/MgFe204 based on ICP and C, H, N elemental analysis Elements

Cpl-LDHs/MgFe20 4 5-ASA-LDHs/MgFe20 4

Zn

AI

C

H

N

S

Drug(%)

found (%)

27.80

7.38

15.06

3.97

4.78

2.03

32.4

calculated (%)

27.01

7.23

16.54

4.24

4.69

2.05

31.5

found (%)

40.68

5.12

9.85

3.08

1.52

17.0

calculated (%)

41.69

5.26

9.97

3.19

1.58

16.7

I) SadtIer Standard Spectra. IR. 33100k.

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ARTICLES 2.4

Analysis of surface structure

The surface chemical compositions of Cpl-LDHs/ MgFe204 and 5-ASA-LDHs/MgFe204 were measured by XPS and the results are shown in Table 3. In the 1 urn depth profiles examined by XPS, there are no signals due to Mg and Fe detected on the surface of either product, whereas signals of Z11, Al and 0 are very strong. This indicates that the Mg and Fe are mostly situated in the interior rather than on the surface, suggesting a core-shell structure with MgFe204 as the core coated with the Cpl-LDHs or 5-ASA-LDHs phase. The binding energy of Mg2p in both Cpl-LDHs/MgFe204 and 5-ASA-LDHs/ MgFe204 is larger than that in MgFe204. Chemical shifts arise from the variation in electrostatic screening experienced by core electrons, as valence electrons are drawn towards or away from the atom[23]. The electronegativity of the element varies in the order Fe>Zn>AI>Mg. Consequently, the variation in chemical shifts of Mg2p could account for an interaction between the Cpl-LDHs or 5-ASA-LDHs phase and the magnetic core MgFe204 probably through Zn-O-Mg and AI-O-Mg bonds formed at the interface. In order to confirm the above hypothesis, different depth profiles were investigated by means of argon (4 kY, 25 flA target current) sputtering/cleaning of the specimens. The sputtering rate was 1 nm/min. The Fe2p narrow scanning XPS spectra at different depth profiles reveal surface layer information as shown in Fig. 6. After 5 min sputter ing equal to a 5 urn depth profile, the Fe2p is not observed, indicating that Fe is not located in the surface layer. After

Fig. 6. layer.

710

720 730 Binding energy/eV

740

Fe2p312 XPS signals at different depth profiles below the surface

Table 3

2.5

Morphology and magnetic properties

Fig. 7 depicts the TEM micrographs of Cpl-LDHs/ MgFe204 and 5-ASA-LDHs/MgFe204' The irregular hexagonal plate-like LDHs can be clearly seen in both samples. The core-shell structure is indicated by dark colored MgFe204 cores coated with gray Cpl-LDHs or 5-ASALDHs shells that have approximately hexagonal plate-like crystallites.

Fig. 7. The TEM photos of (a) Cpl-LDHs/MgFe204 and (b) 5-ASALDHs/MgFe20 4'

5 min

700

20 min sputtering, the Fe2p signal begins to appear. After 30 min sputtering, both Fe2p3/2 and Fe2pl/2 peaks are clearly visible, confirming the existence of the magnetic material at this depth. The thickness of the shell can thus be estimated to be about 30 urn.

The magnetic properties of Cpl-LDHs/MgFe204 and 5-ASA-LDHs/MgFe204 composites were measured at ambient temperature by using VSM, as shown in Fig. 8. The saturation magnetization O"s values are 1.23 and 1.53 emu/g respectively. The two values are lower than that of

XPS results for Cpl-LDHs/MgFe204, Cpl-LDHs, 5-ASA-LDHs/MgFe204, 5-ASA-LDHs and MgFe204 Binding energy/eV

Samples Al2p

Mg2p

Fe2p3/2

Ols

Cis

Cpl-LDHs/MgFe204

1022.2

74.5

50.7

710.6

531.5

285.2

Cpl-LDHs

1021.3

73.8

531.3

284.5

5-ASA-LDHs/MgFe204

1021.9

74.5

50.0

710.7

535.2

284.6

5-ASA-LDHs

1021.8

74.3

532.6

284.6

529.9

284.6

48.8

756

710.9

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ARTICLES

.,

(a)

OJ)

S

~

1.0

0.5 Hext/Oe

5000

-10000

.,

(b)

10000

1.5

OJ)

S

1.0 ~ b 0.5

Hext/Oe

-10000

5000

10000

-1.5 Fig. 8. Hysteresis loops of (a) Cpl-LDHs/MgFe204 and (b) 5-ASALDHs/MgFe20 4.

MgFe204 (23.34 emu/g) nanoparticles, attributed mainly to the contribution of the non-magnetic coating layer to the total sample volume. In addition, the non-magnetic coating layer can be considered as a magnetically inert layer on the surface of a magnetic material, thus affecting the uniformity or magnitude of magnetization due to quenching of surface moments. 3

Conclusions

Soft magnetic nanoparticles of magnesium ferrites were synthesized by a layered precursor method and the average crystallite diameter was 18.7 llill. Novel magnetic drug-inorganic hybrid materials Cpl-LDHs/MgFe204 and 5-ASA-LDHs/MgFe204 were prepared by a coprecipitation method. Investigation of the microstructure revealed that the magnetic particles were coated with Cpl-LDHs or 5-ASA-LDHs layers probably through Zn-O-Mg and AI-O-Mg linkages, and a typical core-shell structure was formed. The specific magnetization of Cpl-LDHs/ MgFe204 and 5-ASA-LDHs/MgFe204 is 1.23 and 1.53 emu/g, respectively. Acknowledgements This work was supported by the National Natural Science Foundation of China (Grant No. 90306012).

References Vladimir, P. T., Drug targeting, Eur. 1. Pharmaceutical Sciences II Suppl, 2000, 2: S81-S91. 2. Andreas, S. L., Christoph, A., Christian, B. et aI., Clinical applications of magnetic drug targeting, Surgical Research, 200 I, 95: 200-206. I.

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3. Widder, K. 1., Morris, R. M., Senyei, A. E. et aI., Selective targeting of magnetic albumin microspheres containing low-dose doxorubicin: total remission in Yoshida sarcoma-bearing rats, Eur. 1. Cancer, 1983, 19: 135-139. 4. Kondo, A., Fukuda, H., Preparation of thermo-sensitive magnetic hydrogel microspheres and application to enzyme immobilization, 1. Ferment. Bioeng., 1997,84: 337-341. 5. Kawaguchi, 1. S., Misawa, K., Jpn. Kokai Tokkyo Koho JP patent 2002139496 A2 17. 6. Sepelak, v., Schultze, D., Krumeich, F. et aI., Structural disorder in the high-energy milled magnesium ferrite, Solid State lonics, 2001, 141-142: 677-682. 7. Oliver, S. A., Willey, R. 1., Oliveri, 0. et aI., Structure and magnetic properties of magnesium ferrite fine powders, Scripta Metall Mater., 1995,33: 1695-1705. 8. Chen, Q., Rondinone, A. 1., Chakoumakos, B. C. et aI., Synthesis of superparamagnetic MgFe204 nanoparticles by coprecipitation, 1. Magn. Magn. Mater., 1999, 194: 1-7. 9. Liu, 1. 1., Li, F., Evans, David 0. et aI., Stoichiometric synthesis of a pure ferrite from a tailored layered double hydroxide (hydrotalcite-like) precursor, Chern. Commun., 2003, 2: 542 - 543. 10. Zhang, H., Qi, Q., Evans, D. 0. et aI., Synthesis and characterization of a novel nano-scale magnetic solid base catalyst involving a layered double hydroxide supported on a ferrite core, Solid State Chern., 2004, 177: 772-780. II. Zhang, H., Xu, Y. H., Evans, D. 0. et aI., Synthesis, characterization and properties of a nano-scale magnetic solid base catalyst MgAI-OH-LDHs/MgFe204, Acta Chirn. Sinica (in Chinese), 2004, 8: 750-756. 12. Si, L. C., Wang, G., Cai, F. L. et aI., Polymerization reaction in restricted space of layered double hydroxides (LDHs), Chinese Science Bulletin, 2004, 49(23): 2459-2463. 13. Cavani, F., Trifiro, F., Vaccari, A., Hydrotalcite-type anionic clays: preparation, properties and applications, Catal. Today, 1991, II: 173-301. 14. Khan, A. I., Lei, L. x., O'Hare, D. et aI., Intercalation and controlled release of pharmaceutically active compounds from a layered double hydroxide, Chern. Commun., 2001, 2342-2343. 15. Li, M., Captopril application in non-cardiovascular disease, 1. Chin. Hosp. Pharm. (in Chinese), 1996,4: 467-468. 16. Selby, W., Pathogenesis and therapeutic aspects of Crohn's disease, Veterinary Microbiology, 2000, 77: 505-511. 17. Kong, X. L., Huang, Z. G., Preparation of delayed-release microcapsule and its investigation dissolution of captropril, 1. Guang Xi Med. Univ. (in Chinese), 1998, 15: 50-51. 18. Zhao, Y., Li, F., Evans, David 0. et aI., Preparation oflayered double-hydroxide nanomaterials with a uniform crystallite size using a new method involving separate nucleation and aging steps, Chern. Mater., 2002, 14: 4286-4291. 19. Duan, x., Jiao, Q. Z., Li, L., CN99II9358.7, 1999. 20. Blundell, S. 1., Magnetism in Condensed Matter, New York: Oxford University Press, 2001,131-136. 21. Norman, B. C., Lawrence, H. D., Stephen, E. w., Introduction to Infrared and Raman spectroscopy, New York and London: Academic press, 1964. 22. Dean, 1. A., Lange's handbook of chemistry, 13th ed., New York: McGraw-Hill Book Company, 1985. 5: 47. 23. Walls, 1. M. Methods of Surface Analysis, Cambridge: Cambridge University Press, 1989 (Received July 22, 2004; accepted September 17, 2004)

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