“右旋糖酐—磁性LDH-Fu”转运模型磁靶向缓控释作用的大鼠实验研究
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摘要
1“右旋糖酐-磁性LDH-氟尿嘧啶”转运模型的体内磁靶向性研究
以“右旋糖酐-磁性LDH-氟尿嘧啶”超分子组装为磁靶向给药系统,研究三聚体模型在大鼠体内各组织中药物转运分布的磁靶向性。建立高效液相色谱内标法,用于测定给药后大鼠体内各组织的药物分布浓度;用紫外分光光度法、原子吸收法及等离子体发射光谱法测定给药后大鼠各组织中铁的浓度分布特征。方法学研究表明,高效液相色谱内标法回收率高、精密度好,适合模型运载和释放到动物组织中的氟尿嘧啶的定量检测;铁染色及定量分析方法能较好地评价载体铁的体内分布情况。经腹腔注射给药后,在不同部位给予磁场干预,实验结果显示,设立磁场的部位(背右侧及头部)药物浓度明显高于远离磁场部位的组织,验证了三级超分子药物转运模型的体内磁靶向性。在外磁场作用下“磁靶向LDH-氟尿嘧啶-右旋糖酐”三级复合物能在动物体特定部位浓集,表现良好的磁靶向特异性。
2“右旋糖酐-磁性LDH-氟尿嘧啶”转运模型的体内缓释性研究
建立给药后大鼠血浆5-Fu浓度测定的HPLC内标法,通过DAS2.0软件分析药动学实验数据,研究“右旋糖酐-磁性LDH-氟尿嘧啶”转运模型在大鼠体内的药物缓释效果。结果表明,原药组的药时曲线为单峰、二室模型,超分子转运模型组表现多峰、多房室模型过程,第一个药峰呈二室模型、其余各峰为一室模型;原药组的达峰时间为10分钟,而LDH组的首次达峰时间为6小时,是原药组的36倍;原药组5-Fu的消除半衰期为1.16小时,LDH组首峰的半衰期为3.53小时,是5-Fu原药的3.06倍。在“右旋糖酐-磁性LDH-氟尿嘧啶”转运模型下5-Fu的药代动力学行为改变,表现了良好的体内缓释作用效果。
1 Study on targeted-specificity of Dextran-Magnetic LDH-Fluorouracil model in vivo
With a supermolecule model of dextran-magnetic LDH-fluorouracil as magnetic targeted drug delivery system, the magnetic targeting drug bio-distribution of this transfering model in rats was studied. A HPLC internal labeling method had been established to determine the concentration of 5-Fu in tissues. Ultraviolet spectro-photometry, flame atomic absorption spectrometer and the inductively coupled plasma were used to detect the iron concentration in tissues, and Prussian blue iron staining was employed for observing the difference of iron bio-distribution in tissues. The results shown that the established HPLC internal standard method had good recovery rate and precision, after administration via peritoneal injection, the drug concentration were significant higher in both right back and head where the magnetic field had been set up, than in other parts which were far away from the magnetic field. Drug concentration distribution shown statistical significance, and proved that the ternary composite model had an ideal magnetic targeted transfering effect. The data reported here suggest that under the influence of an external magnetic field, the Dextran-Magnetic LDH-Fluorouracil can be significantly enriched in the target area, and show good magnetic targeted-specificity.
2 Study on intravital sustained-release effect of Dextran-Magnetic LDH- Fluorouracil model
With an objective to study the sustained-release function of the transfer model of Dextran-Magnetic LDH-Fluorouracil in rats, the HPLC internal standard method had been established to test the plasma concentrations of 5-Fu in rats after administration, and the pharmacokinetic experimental data were analysed with the software of DAS 2.0. The results demonstrated that the concentration-time curve of fluorouracil group shown single peak with a two-compartment model, but that of the LDH group shown multi-peak with a multi-compartment model, in which the 1st peak shown two-compartment model, while others shown single compartment model. The fluorouracil group presented drug peak at 10 minutes, but LDH group presented the 1st drug peak at 6h which was 36 times of that of fluorouracil group; the half time of fluorouracil group was 1.16h, but that of LDH group was 3.53h which was 3.06 times of that of fluorouracil group. The data reported here suggest that Dextran-Magnetic LDH-Fluorouracil transfer model can change pharmacokinetic action of 5-Fu after injection into animals, and will show good intravital sustained-release effect in vivo.
以“右旋糖酐-磁性LDH-氟尿嘧啶”超分子组装为磁靶向给药系统,研究三聚体模型在大鼠体内各组织中药物转运分布的磁靶向性。建立高效液相色谱内标法,用于测定给药后大鼠体内各组织的药物分布浓度;用紫外分光光度法、原子吸收法及等离子体发射光谱法测定给药后大鼠各组织中铁的浓度分布特征。方法学研究表明,高效液相色谱内标法回收率高、精密度好,适合模型运载和释放到动物组织中的氟尿嘧啶的定量检测;铁染色及定量分析方法能较好地评价载体铁的体内分布情况。经腹腔注射给药后,在不同部位给予磁场干预,实验结果显示,设立磁场的部位(背右侧及头部)药物浓度明显高于远离磁场部位的组织,验证了三级超分子药物转运模型的体内磁靶向性。在外磁场作用下“磁靶向LDH-氟尿嘧啶-右旋糖酐”三级复合物能在动物体特定部位浓集,表现良好的磁靶向特异性。
2“右旋糖酐-磁性LDH-氟尿嘧啶”转运模型的体内缓释性研究
建立给药后大鼠血浆5-Fu浓度测定的HPLC内标法,通过DAS2.0软件分析药动学实验数据,研究“右旋糖酐-磁性LDH-氟尿嘧啶”转运模型在大鼠体内的药物缓释效果。结果表明,原药组的药时曲线为单峰、二室模型,超分子转运模型组表现多峰、多房室模型过程,第一个药峰呈二室模型、其余各峰为一室模型;原药组的达峰时间为10分钟,而LDH组的首次达峰时间为6小时,是原药组的36倍;原药组5-Fu的消除半衰期为1.16小时,LDH组首峰的半衰期为3.53小时,是5-Fu原药的3.06倍。在“右旋糖酐-磁性LDH-氟尿嘧啶”转运模型下5-Fu的药代动力学行为改变,表现了良好的体内缓释作用效果。
1 Study on targeted-specificity of Dextran-Magnetic LDH-Fluorouracil model in vivo
With a supermolecule model of dextran-magnetic LDH-fluorouracil as magnetic targeted drug delivery system, the magnetic targeting drug bio-distribution of this transfering model in rats was studied. A HPLC internal labeling method had been established to determine the concentration of 5-Fu in tissues. Ultraviolet spectro-photometry, flame atomic absorption spectrometer and the inductively coupled plasma were used to detect the iron concentration in tissues, and Prussian blue iron staining was employed for observing the difference of iron bio-distribution in tissues. The results shown that the established HPLC internal standard method had good recovery rate and precision, after administration via peritoneal injection, the drug concentration were significant higher in both right back and head where the magnetic field had been set up, than in other parts which were far away from the magnetic field. Drug concentration distribution shown statistical significance, and proved that the ternary composite model had an ideal magnetic targeted transfering effect. The data reported here suggest that under the influence of an external magnetic field, the Dextran-Magnetic LDH-Fluorouracil can be significantly enriched in the target area, and show good magnetic targeted-specificity.
2 Study on intravital sustained-release effect of Dextran-Magnetic LDH- Fluorouracil model
With an objective to study the sustained-release function of the transfer model of Dextran-Magnetic LDH-Fluorouracil in rats, the HPLC internal standard method had been established to test the plasma concentrations of 5-Fu in rats after administration, and the pharmacokinetic experimental data were analysed with the software of DAS 2.0. The results demonstrated that the concentration-time curve of fluorouracil group shown single peak with a two-compartment model, but that of the LDH group shown multi-peak with a multi-compartment model, in which the 1st peak shown two-compartment model, while others shown single compartment model. The fluorouracil group presented drug peak at 10 minutes, but LDH group presented the 1st drug peak at 6h which was 36 times of that of fluorouracil group; the half time of fluorouracil group was 1.16h, but that of LDH group was 3.53h which was 3.06 times of that of fluorouracil group. The data reported here suggest that Dextran-Magnetic LDH-Fluorouracil transfer model can change pharmacokinetic action of 5-Fu after injection into animals, and will show good intravital sustained-release effect in vivo.
引文
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[1] Ambrogi V, Fardella G, Grandolini G, Perioli L. Intercalation compounds of hydrotalcite-like anionic clays with anti-inflammatory agents-I. Intercalation and in vitro release of ibuprofen [J]. International Journal of Pharmaceutics. 2001, 220: 23-32.
[2] Perioli L, Ambrogi V, Giovagnoli S, et al. Mucoadhesive Bilayered Tablets for Buccal Sustained Release of Flurbiprofen [J]. AAPS PharmSciTech, 2007, 8 (3): E1-E8.
[3] Aamir I K, Lixuei, Alexander J, Dermot O'Hare. Intercalation and controlled release of pharmaceutically active compounds from a layered double hydroxide [J]. Chem Commun, 2001, 22: 2342-2343.
[4] Hussein MZ, Zainal Z, Yahaya A. Controlled release of a plant growth regulator,α-napHthaleneacetate from the lamella of Zn-Al-layered double hydroxide nanocomposite [J]. Control Release, 2002, 82: 417-427.
[5] Choy J H, Kwak S Y, Park J S, Jeong Y J, Portier J. Intercalative nanohybrids of nucleoside monopHosohates and DNA in layered metal hydeoxide [J]. Am Chem Soc, 1999, 121: 1399-1340.
[6] Choy J H, Kwak S Y, Park J S, et al. Angew Chem Int Ed, 2000, 39(22) : 4042-4045.
[7] Chris G,Peter V C. Layered double hydroxide minerals as possible prebiotic information storage and transfer compounds [J]. Origins of Life and Evolution of Biospheres, 2006, 36: 13–37.
[8]李文卓,陆军,秦成刚,等. DNA和菲啶鎓复合物嵌入水滑石的研究[J].化学学报, 2004, 62( 22): 2239-2243.
[9]倪哲明,夏盛杰,王力耕,等.诺氟沙星插层镁铝水滑石新型药物-无机复合材料的超分子结构、热稳定性和缓释性能[J].高等学校化学学报, 2007, 28(7): 1214-1219.
[10]孙辉,张慧,段雪,等.磁性药物-无机纳米复合材料的结构设计与表征[J].科学通报, 2004, 49(24): 2525-2530.
[11]孟锦宏,张慧,段雪,等.新型层状农药缓/控释材料-草甘膦插层双金属氢氧化物的超分子结构与缓释性能[J].科学通报, 2005, 50(3): 208-214.
[12]孟锦宏,张慧,段雪,等.超分子结构草甘磷插层水滑石的组装及结构研究[J].高等学校化学学报,2003, 7: 1315-1319.
[13] Jian Ya LING, Jing YANG, Qin Zheng YANG. Study on Intercalative Nanohybrid of Cordycepin in Layered Double Hydroxide [J].中国化学快报(英文版), 2003, 14(10): 1097-1100.
[14]杨贞,郭子建.无机层状复合氢氧化物中顺铂-DNA模型分子的选择性插[J].无机化学学报, 2003, 19(7): 673-677.
[15]苟国敬,鲍凤娟,姚慧琴,等.镁铝复合氢氧化物结构与性能的关系[J].功能材料,2008, 39 (增刊):495-500.
[16]苟国敬,许红平,鲍凤娟.层状复合氢氧化物对硫酸钠的阴离子交换作用[J].盐湖研究,2008, 16(4): 9-14.
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