聚烯丙基氯化铵调控下多孔羟基磷灰石微球的合成及作为药物载体的应用研究

doi:10.15541/jim20170041

摘要/Abstract

摘要：

选用聚烯丙基氯化铵(PAH)作为晶体生长调节剂, 在水热条件下成功制备了多孔羟基磷灰石(Hydroxyapatite, HAP)中空微球。详细研究了反应时间和添加剂浓度等因素的影响: 150℃水热反应12 h, 控制PAH 浓度0.3~0.5 g/L, 可合成尺寸均匀、孔径密集的HAP中空微球。微球生长经历早期前驱体微结构、异相成核、相转化等不同阶段, 聚合物在各阶段都起到重要的调节作用。以典型的布洛芬(ibuprofen, IBU)作为模型药物, 研究微球的药物负载和脱附能力。结果显示: 多孔微球具有良好的药物负载和释放能力, 吸附量较好, 可达到413.65 mg/g。且药物具有较好的pH响应释放行为, 可作为pH敏感靶向药物载体应用到生物医学等领域。

关键词: 羟基磷灰石, 聚烯丙基氯化铵, 多孔微球, 水热反应, 药物载体

Abstract:

Porous and hollow hydroxyapatite (HAP) microspheres were synthesized successfully in hydrothermal method utilizing poly(allylamine hydrochloride) (PAH) as the crystal growth regulator. Effects of reaction time and concentration of the polymer on the growth of final products were investigated. Uniform microspheres with dense pores can be synthesized by controlling the PAH concentration (0.3-0.5 g/L) after 12 h hydrothermal reaction at 150℃. Formation of hollow microspheres includes different stages of early precursor microstructures, heterogeneous nucleation and phase transformations. At different stages, the cationic polyelectrolyte PAH plays an important role in regulating growth of hollow microspheres. Ibuprofen (IBU) was chosen as a typical model drug to study the drug loading and the desorption ability. The results show that porous and hollow microspheres have relatively high drug loading capacity (413.65 mg/g). Drug release of the microspheres is favorably pH-responsive, which may have close relationship with the surface properties of HAP nanorods. Date from this study suggest that the porous microspheres will have potential application as the targeted-drug carrier in the biomedicine field.

Key words: hydroxyapatite, poly(allylamine hydrochloride), porous microspheres, hydrothermal method, drug carrier

中图分类号:

TQ174

马芳, 崔名芳, 朱建华, 李雅丽. 聚烯丙基氯化铵调控下多孔羟基磷灰石微球的合成及作为药物载体的应用研究[J]. 无机材料学报, 2017, 32(11): 1215-1222.

MA Fang, CUI Ming-Fang, ZHU Jian-Hua, LI Ya-Li. Porous Hydroxyapatite Microspheres Prepared by Using Poly (Allylamine Hydrochloride) and Its Application in Drug Delivery[J]. Journal of Inorganic Materials, 2017, 32(11): 1215-1222.

图/表 15

图1 PAH的结构式

Fig. 1 Structural formula of PAH

图2 0.42 g/L PAH和磷酸氢二钠溶液混合后形成的类“囊泡”结构

Fig. 2 Optical images of “vesicles” after addition of Na2HPO4 with PAH (0.42 g/L) (a) “Vesicles” before introduction of calcium ions; (b) Aggregations after addition of Ca2+; (c) Polarized image after adding Ca2+

图3 PAH和磷酸氢二钠复合物的粒径分布分析(a)和钙离子加入后, 纳米颗粒的粒径分布(b)

Fig. 3 Diameter distributions of "vesicles", which were synthesized by 0.42 g/L PAH and disodium hydrogen phosphate solution before adding calcium ions (a) and calcium phosphate "vesicle structure" after adding calcium ions (b)

图4 钙离子加入前(a)后(b), 溶液中颗粒的Zeta电位

Fig. 4 Zeta potential of "vesicles" before introduction of calcium ions (a); Zeta potential of nucleated particles after addition of calcium ions (b)([PAH]=0.42 g/L)

图5 不同反应时间得到的HAP的SEM照片

Fig. 5 SEM images of the HAP samples after reacting for different time (a) 0.5 h; (b) 1.5 h; (c) 8 h; (d) 12 h

图6 水热反应1.5 h产物的透射电镜(a)和高分辨率透射电镜(b)分析结果

Fig. 6 TEM (a) and HRTEM images (b) of samples after hydrothermally reacting for 1.5 h

图7 不同反应时间产物的XRD图谱

Fig. 7 XRD patterns of HAP samples after being reacted for various time (a) 0.5 h; (b) 1.5 h; (c) 8 h; (d) 12 h; (e) 0 h

图8 不同水热时间合成产物的FTIR图谱

Fig. 8 FTIR spectra of the products synthesized by hydrthermal method for different time (a) 0 h; (b) 0.5 h; (c) 1.5 h; (d) 8 h; (e) 12 h

图9 水热反应12 h产物的TEM照片(a, b)和HRTEM分析结果(c), (c)图中的插入图为选区电子衍射花样

Fig. 9 TEM (a, b) and HRTEM (c) images of HAP microspheres after reacting for 12 h. Inset in (c) shows the selected area diffraction (SAED) pattern([PAH]=0.42 g/L)

图10 不同PAH浓度下水热合成产物的SEM图片

Fig. 10 SEM images of the HAP samples synthesized by hydrothermal method with different PAH concentrations (a) 0 g/L; (b) 0.06 g/L; (c) 0.06 g/L; (d) 0.24 g/L; (e) 0.36 g/L; (f) 0.42 g/L

图11 不同PAH浓度条件下产物的XRD图谱

Fig. 11 XRD patterns of the HAP samples synthesized by hydrothermal method with different PAH concentrations (a) 0.06 g/L; (b) 0.24 g/L; (c) 0.36 g/L; (d) 0.42 g/L

图12 HAP多孔微球的形成机理示意图

Fig. 12 Illustration for the strategy of HAP porous microsphere

图13 HAP的N2吸脱附等温曲线及孔径分布图

Fig. 13 N2 adsorption-desorption isotherm and the pore size distribution of HAP porous microspheres prepared by a hydrothermal method at 150℃ for 12 h

图14 (a) IBU正己烷溶液和(b)IBU被HAP吸附后溶液的紫外-可见光谱; (c)IBU释放6 h后, PBS溶液中的紫外-可见光谱

Fig. 14 UV-Vis spectra of IBU before (a) and after (b) adsorption onto the surface of porous microspheres, UV-Vis spectrum of IBU in the PBS solution after releasing for 6 h (c)

图15 负载IBU的多孔HAP微球在pH=4.0、5.6和7.4的PBS溶液中的释放曲线, 37℃

Fig. 15 IBU release profiles of porous microspheres in PBS solution of pH at 4.0, 5.6 and 7.4, under 37℃

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