Preparation of the porous ZIF-8 and the behaviors of loading ibuprofen
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摘要: 由于难溶性药物低的溶解度，严重限制了其口服生物利用度。对此，结合金属—有机框架材料(MOFs)具有疏水性和高比表面积的特点，以溶液共沉淀法制备的MOF多孔材料ZIF-8作为载药基底。通过改变Zn2+与2-甲基咪唑(2-Methylimidazole)的摩尔比，进而对ZIF-8的比表面积及孔径分布进行调控，然后对难溶性药物布洛芬(IBP)的负载性能进行研究。研究结果表明：当Zn2+与2-甲基咪唑的摩尔比为1∶8时，材料ZIF-8(8)具有最大的比表面积和孔体积，分别为1187 m2/g和1.183 cm3/g，其对难溶性药物布洛芬的负载量高达21.8%。且药物载体复合材料IBP-ZIF-8(8)表现出良好的体外溶出度，在pH为2.5和7.4的磷酸缓冲溶液中，其累积溶出度均为98%左右。ZIF-8(8)处理的RAW246.7细胞存活率均高达94%以上，表现出良好的生物安全性。Abstract: Oral bioavailability of poorly soluble drugs is severely limited due to their low solubility. In recent years, metal-organic framework materials (MOFs) have attracted much attention because of their hydrophobicity and high specific surface area. In this paper, the porous ZIF-8, one of MOF family materials, were prepared by solution co-precipitation method. The specific surface area and pore size distribution of ZIF-8 were optimized by changing the molar ratio of Zn2+ to 2-Methylimidazole. In addition, ZIF-8 were used as the carrier for ibuprofen (IBP), a poorly soluble drug, and its loading performance was studied in detail. The results showed that when the molar ratio of Zn2+ to 2-methylimidazole was 1∶8, ZIF-8(8) had the largest specific surface area (1187 m2/g) and pore volume (1.183 cm3/g). And the loading capacity of ZIF-8(8) on IBP was as high as 21.8%. The drug carrier composite (IBP-ZIF-8(8)) showed a well dissolution rate in vitro, and its cumulative dissolution rate was about 98% in phosphate buffer solution with pH of 2.5 and 7.4. The survival rate of RAW246.7 cells treated with IBP-ZIF-8(8) was over 94%, demonstrating satisfied biosafety. ZIF-8(8) with excellent specific surface area, pore volume, good loaded-IBP performance and biosafety has great potential applications in drug controlled-release system.
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Key words:
- metal-organic frameworks /
- ZIF-8 /
- ibuprofen /
- poorly soluble drugs /
- oral bioavailability
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图 1 不同ZIF-8材料的XRD衍射图(a) 和红外图谱(b)
Figure 1. XRD spectrum (a) and FTIR spectrum (b) of ZIF-8 materials
图 3 不同ZIF-8材料的N2吸脱附曲线(a)；DFT孔径曲线(b)；BJH孔径曲线(c)；HK孔径曲线(d)
Figure 3. N2 adsorption and desorption curves (a); DFT pore size curves (b); BJH pore size curves (c); HK pore size curves (d) of ZIF-8 materials
图 4 布洛芬在乙醇溶剂和不同pH下(pH=7.4；pH=2.5)的紫外吸收光谱
Figure 4. UV absorption spectra of ibuprofen in ethanol solvent and at different pH values (pH=7.4; pH=2.5)
图 5 布洛芬在在乙醇溶剂和不同pH下(pH=7.4; pH=2.5)的标准曲线
Figure 5. Standard curves of ibuprofen in ethanol solvent and at different pH values (pH=7.4; pH=2.5)
图 6 IBP与IBP-ZIF-8(8)的XRD衍射图谱(a)和IBP、IBP-ZIF-8(8)和ZIF-8(8)的TG图谱(b)
Figure 6. XRD specrum of IBP and IBP-ZIF-8(8) (a) and TG curves of IBP, IBP-ZIF-8(8) and ZIF-8(8) (b)
图 7 IBP-ZIF-8(8)在不同pH下的溶出曲线(a：pH=2.5; b：pH=7.4)
Figure 7. Dissolution curves of IBP-ZIF-8(8) at different pH values (a: pH=2.5; b: pH=7.4)
图 8 RAW246.7细胞与ZIF-8(8)共培养24 h后的细胞存活率
Figure 8. Survival rate of RAW246.7 cells co-cultured with ZIF-8(8) for 24 hours.
表 1 实验过程中使用的试剂
Table 1. Reagents used during the experiment
Name of reagents Purity Source Zinc nitrate hydrate AR Kelong Chemical Reagent Co. Ethanol AR Kelong Chemical Reagent Co. 2-Methylimidazole AR Zhenri Chemical Co. Ibuprofen (IBP) AR Solarbio Science & Technology Co. Phosphate solution AR Pricella Biotechnology Co. 
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表 2 不同ZIF-8材料的比表面积和孔径参数
Table 2. Specific surface area and pore size parameters of ZIF-8 materials
Samples SBET/
(m2·g−1)Vmesopore/
(cm3·g−1)Vmicropore/
(cm3·g−1)ZIF-8(4) 872.033 0.199 0.615 ZIF-8(8) 1186.919 0.305 0.878 ZIF-8(12) 1078.442 0.221 0.668 Notes: SBET: Specific surface area; Vmesopore: mesopore volume; Vmicropore: micropore volume
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表 3 不同ZIF-8材料对布洛芬的载药量
Table 3. Loading capacity of ZIF-8 material for ibuprofen
Samples Solvent Drug loading/% ZIF-8(4) ethanol 11.9 ZIF-8(8) ethanol 21.8 ZIF-8(12) ethanol 18.2
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