层状双金属氢氧化物作为药物载体及其释放性能研究
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摘要
药物载体材料的开发是当今新型药物传递系统研究领域的重要研究方向,理想的药物载体应具有良好的生物相容性、生物可降解性、生物稳定性、极低的毒性以及较高的载药量等。近几年来,层状双金属氢氧化物(layered doublehydroxides,LDHs)作为药物载体材料的研究日渐兴起。由于LDHs具有层状结构,层片带结构正电荷,层间存在可交换的阴离子,层间空间可调,因此,可以将药物分子插入层间形成药物-LDHs纳米杂化物。因药物与层板间存在着静电作用、氢键作用以及空间位阻效应等可实现药物的有效控释,因此药物/LDHs纳米杂化物被认为是一类极具应用前景的新型药物输送控释体系。阴离子型药物的插层比较容易,而非离子特别是水难溶性药物的插层比较困难。如何实现非离子水难溶性药物的有效插层,制备具有理想载药量的药物/LDHs纳米杂化物是目前的重要研究课题。
本文选用具有较高抗肿瘤活性的非离子、难溶性药物喜树碱(Camptothecin,CPT)作为客体药物分子,以Mg-Al型层状双金属氢氧化物作为载体,分别采用二次组装法和结构重建法成功地制备出了喜树碱-LDHs纳米杂化物,考察了合成条件对杂化物载药量的影响,并采用XRD、TEM、SEM、FT-IR等测试手段对所得产物进行了表征,对纳米杂化物中喜树碱药物的释放行为进行了研究。
主要工作及结论:
1、Mg-Al LDHs的制备及表征
目的是为药物-LDHs纳米杂化物的制备准备主体材料。
采用非稳态共沉淀法合成了不同金属元素配比的Mg-Al LDHs,考察了原料配比对产物中镁铝摩尔比、晶体结构等的影响。研究结果表明,制备的Mg-Al LDHs样品中Mg的含量均比原料中的低,这可能是由于Mg(OH)_2的溶度积比Al(OH)_3小所致。
所合成样品的x值在0.19～0.36之间,晶胞参数α值在0.304～0.308 nm之间,c值在2.306～2.4 nm之间,层间距在0.767～0.799 nm之间,层间通道的高度约为0.30 nm。合成样品的颗粒均为较规则的六边形。通过TEM照片测量计算得到的颗粒粒径以及通过激光粒度分布仪测得的平均粒径均在100nm左右。
2、CPT-LDHs-SDS纳米杂化物的制备与表征
(1)采用二次组装法制备了CPT-LDHs-SDS纳米杂化物,考察了初始CPT浓度、反应时间、溶剂极性等因素对杂化物载药量(A_(in))的影响。以Mg_3AlLDHs作为载体,在喜树碱浓度为4000μg/ml的二甲基亚砜溶液中40℃下经30 h插层反应,得到最大载药量为5.2%(w/w)的CPT-LDHs纳米杂化物。
(2)在模拟人体内条件,即37℃、pH值分别为4.8和7.2的环境中,考察了药物释放行为,表明杂化物具有明显的缓释效果,释放数据符合准一级动力学方程。在pH=7.2的中性介质中的释放速率明显低于在pH=4.8的酸性介质中的释放速率,这是因为释放机理不同所致。在pH=7.2的中性介质中,LDHs层板稳定,CPT的释放靠扩散过程,即CPT在层间的扩散过程为释放过程的控制步骤;而在pH=4.8的酸性介质中,除扩散释放药物外,LDHs层板的酸溶解也可释放药物,且后者的作用更大。
3、CPT-LDHs纳米杂化物的制备与表征
(1)采用结构重建法在CPT的乙醇-水溶液中成功地制备了CPT-LDHs纳米杂化物,考察了乙醇/水的体积比(R_v)、初始CPT浓度、反应时间和反应温度等对杂化物载药量(A_(in))的影响。在60℃,R_v=7:3,经过24 h插层反应后,得到载药量高达14%(w/w)的纳米杂化物,比文献中所报道的结果有了明显提高。
(2)依据XRD分析结果和CPT分子的大小,推断CPT分子以长轴平行于层板的方式在LDHs层间呈单层排列。
(3)在模拟人体内条件,即37℃、pH值分别为4.8和7.2的环境中,考察了药物释放行为,表明杂化物具有明显的缓释效果,释放数据符合准二级动力学方程。在pH=7.2的中性介质中的释放速率明显低于在pH=4.8的酸性介质中的释放速率,这是因为释放机理不同所致。在pH=7.2的中性介质中,LDHs层板稳定,CPT的释放靠扩散过程,即CPT在层间的扩散过程为释放过程的控制步骤;而在pH=4.8的酸性介质中,除扩散释放药物外,LDHs层板的酸溶解也可释放药物,且后者的作用更大。
(4)选用二琥珀酰亚胺基碳酸酯(DSC)作为生物功能分子,对所合成的Mg-AlLDHs进行了表面功能化实验,经UV-VIS及FT-IR表征手段进行表征后,证明DSC成功地连接到了LDHs的表面,这可为提高LDHs作为药物载体时的生物相容性和靶向性奠定基础。
Nowadays one of the important research content in the research field of drug delivery system is research and development of the drug delivery materials.The perfect drug carrier should have advantages in the aspects of its bioavailability,biodegradability, biostability,reduced toxicity and the high drug loading.Recently,layered double hydroxides(LDHs)have been reported as a new delivery system for many anionic drugs via ion-exchange and some poorly water-soluble drug molecules via methods of coprecipitation,assemblage and reconstruction.Therefore in order for poorly water-soluble drug therapy to be more effective,the research on the property of LDHs as drug delivery material is very important.
Among those poorly water-soluble drugs,camptothecin(CPT)is a typical antitumor model.We chose CPT as the guest molecule and Mg-Al LDHs as the host material to synthesize CPT-LDHs nanocompounds via methods of assemblage and reconstruction. The effect of reaction conditions on the drug loading were examined.Powder X-ray diffraction(PXRD),TEM,SEM and FT-IR spectroscopy were used to characterize the achieved products.Release mechanism and kinetics of CPT from nanohybrids were investigated as well.
Main contents and conclusions:
1.Synthesis and characterisation of Mg-Al LDHs
The purpose of this part is to synthesize the pristine material LDHs.
The pristine Mg-Al LDHs was prepared by coprecipitation method from mixed solution of Magnesium and Aluminum chloride hexahydrates,The effects of the molar ratio of MgCl_26H_2O/AlCl_36H_2O on M~(3+)/[M~(2+)+ M~(3+)]molar ratio x and the lattice parameter were investigated.The results show that Mg/Al molar ratio of the syntheized product was lower than that of the raw mixed salt solution,the reason for which was that the solubility product of Mg(OH)_2 is lower than that of Al(OH)_3.
x is between 0.19～0.36,a is between 0.304～0.308nm,c is between 2.306～2.4nm,d is between 0.767～0.799nm,the interlayer space is about 0.30nm.The achieved product consisted of the typical thin,hexagonal plate-like crystals with～100 nm in size.
2.Synthesis and charaterisation of CPT-LDHs-SDS nanohybrids
(1)The method of assemblage was used to syntesize the nanohybrids.During the process the Mg/Al ratio x of Mg_xAl/DS LDHs,the polarity of the solvents,initial CPT concentration(C_(CPT))and contact time in the intercalation process were studied to investigate their effects on the amount of CPT loaded into CPT-Mg_xAl LDHs-SDS nanohybrids(A_(in)).The most effective uptake of CPT occurred in DMSO media by Mg_3Al LDHs-SDS.The maximum A_(in)value reached about 5.2%(w/w)under studied conditions.
(2)The release rate of CPT from the nanohybrid at pH 7.2 is remarkably lower than that at pH 4.8,this is due to a possible difference in the release mechanism.For the pH 7.2 release,the mechanism is primarily through diffusion of drug molecules;while for the pH 4.8 release,that is through both the dissolution of LDH layers and diffusion of drug molecules among which the former one is dominating.The release kinetics of CPT from the nanohybrids obeyed the pseudo-first order kinetic model.
3.Synthesis and charaterisation of CPT-LDHs nanohybrids
(1)The method of reconstruction was used to syntesize the nanohybrids in ethanol-water mixed solution.During the process the volume ratio(R_v)of ethanol/water, initial CPT concentration(C_(CPT)),the reaction temperature and contact time in the intercalation process were studied to investigate their effects on the amount of CPT loaded into CPT-LDHs nanohybrids(A_(in)).The maximum A_(in)value reached about 14% (w/w)when R_v=7:3 after 24h reconstruction under 60℃.
(2)According to the size of CPT molecule and the gallery height of the nanohybrid,a probably arrangement of CPT molecules in CPT-LDHs nanohybrid may be proposed, i.e.,CPT molecules arrange as monolayer with their long axes parallel to the LDHs layers.
(3)The release rate of CPT from the nanohybrid at pH 7.2 is remarkably lower than that at pH 4.8,this is due to a possible difference in the release mechanism.For the pH 7.2 release,the mechanism is primarily through diffusion of drug molecules;while for the pH 4.8 release,that is through both the dissolution of LDH layers and diffusion of drug molecules among which the former one is dominating.The release kinetics of CPT from the nanohybrids obeyed the pseudo-second order kinetic model.
(4)we successfully attached disuccinimidyl carbonate(DSC)to the LDHs surface and achieved the surface functionalization of LDHs.
本文选用具有较高抗肿瘤活性的非离子、难溶性药物喜树碱(Camptothecin,CPT)作为客体药物分子,以Mg-Al型层状双金属氢氧化物作为载体,分别采用二次组装法和结构重建法成功地制备出了喜树碱-LDHs纳米杂化物,考察了合成条件对杂化物载药量的影响,并采用XRD、TEM、SEM、FT-IR等测试手段对所得产物进行了表征,对纳米杂化物中喜树碱药物的释放行为进行了研究。
主要工作及结论:
1、Mg-Al LDHs的制备及表征
目的是为药物-LDHs纳米杂化物的制备准备主体材料。
采用非稳态共沉淀法合成了不同金属元素配比的Mg-Al LDHs,考察了原料配比对产物中镁铝摩尔比、晶体结构等的影响。研究结果表明,制备的Mg-Al LDHs样品中Mg的含量均比原料中的低,这可能是由于Mg(OH)_2的溶度积比Al(OH)_3小所致。
所合成样品的x值在0.19～0.36之间,晶胞参数α值在0.304～0.308 nm之间,c值在2.306～2.4 nm之间,层间距在0.767～0.799 nm之间,层间通道的高度约为0.30 nm。合成样品的颗粒均为较规则的六边形。通过TEM照片测量计算得到的颗粒粒径以及通过激光粒度分布仪测得的平均粒径均在100nm左右。
2、CPT-LDHs-SDS纳米杂化物的制备与表征
(1)采用二次组装法制备了CPT-LDHs-SDS纳米杂化物,考察了初始CPT浓度、反应时间、溶剂极性等因素对杂化物载药量(A_(in))的影响。以Mg_3AlLDHs作为载体,在喜树碱浓度为4000μg/ml的二甲基亚砜溶液中40℃下经30 h插层反应,得到最大载药量为5.2%(w/w)的CPT-LDHs纳米杂化物。
(2)在模拟人体内条件,即37℃、pH值分别为4.8和7.2的环境中,考察了药物释放行为,表明杂化物具有明显的缓释效果,释放数据符合准一级动力学方程。在pH=7.2的中性介质中的释放速率明显低于在pH=4.8的酸性介质中的释放速率,这是因为释放机理不同所致。在pH=7.2的中性介质中,LDHs层板稳定,CPT的释放靠扩散过程,即CPT在层间的扩散过程为释放过程的控制步骤;而在pH=4.8的酸性介质中,除扩散释放药物外,LDHs层板的酸溶解也可释放药物,且后者的作用更大。
3、CPT-LDHs纳米杂化物的制备与表征
(1)采用结构重建法在CPT的乙醇-水溶液中成功地制备了CPT-LDHs纳米杂化物,考察了乙醇/水的体积比(R_v)、初始CPT浓度、反应时间和反应温度等对杂化物载药量(A_(in))的影响。在60℃,R_v=7:3,经过24 h插层反应后,得到载药量高达14%(w/w)的纳米杂化物,比文献中所报道的结果有了明显提高。
(2)依据XRD分析结果和CPT分子的大小,推断CPT分子以长轴平行于层板的方式在LDHs层间呈单层排列。
(3)在模拟人体内条件,即37℃、pH值分别为4.8和7.2的环境中,考察了药物释放行为,表明杂化物具有明显的缓释效果,释放数据符合准二级动力学方程。在pH=7.2的中性介质中的释放速率明显低于在pH=4.8的酸性介质中的释放速率,这是因为释放机理不同所致。在pH=7.2的中性介质中,LDHs层板稳定,CPT的释放靠扩散过程,即CPT在层间的扩散过程为释放过程的控制步骤;而在pH=4.8的酸性介质中,除扩散释放药物外,LDHs层板的酸溶解也可释放药物,且后者的作用更大。
(4)选用二琥珀酰亚胺基碳酸酯(DSC)作为生物功能分子,对所合成的Mg-AlLDHs进行了表面功能化实验,经UV-VIS及FT-IR表征手段进行表征后,证明DSC成功地连接到了LDHs的表面,这可为提高LDHs作为药物载体时的生物相容性和靶向性奠定基础。
Nowadays one of the important research content in the research field of drug delivery system is research and development of the drug delivery materials.The perfect drug carrier should have advantages in the aspects of its bioavailability,biodegradability, biostability,reduced toxicity and the high drug loading.Recently,layered double hydroxides(LDHs)have been reported as a new delivery system for many anionic drugs via ion-exchange and some poorly water-soluble drug molecules via methods of coprecipitation,assemblage and reconstruction.Therefore in order for poorly water-soluble drug therapy to be more effective,the research on the property of LDHs as drug delivery material is very important.
Among those poorly water-soluble drugs,camptothecin(CPT)is a typical antitumor model.We chose CPT as the guest molecule and Mg-Al LDHs as the host material to synthesize CPT-LDHs nanocompounds via methods of assemblage and reconstruction. The effect of reaction conditions on the drug loading were examined.Powder X-ray diffraction(PXRD),TEM,SEM and FT-IR spectroscopy were used to characterize the achieved products.Release mechanism and kinetics of CPT from nanohybrids were investigated as well.
Main contents and conclusions:
1.Synthesis and characterisation of Mg-Al LDHs
The purpose of this part is to synthesize the pristine material LDHs.
The pristine Mg-Al LDHs was prepared by coprecipitation method from mixed solution of Magnesium and Aluminum chloride hexahydrates,The effects of the molar ratio of MgCl_26H_2O/AlCl_36H_2O on M~(3+)/[M~(2+)+ M~(3+)]molar ratio x and the lattice parameter were investigated.The results show that Mg/Al molar ratio of the syntheized product was lower than that of the raw mixed salt solution,the reason for which was that the solubility product of Mg(OH)_2 is lower than that of Al(OH)_3.
x is between 0.19～0.36,a is between 0.304～0.308nm,c is between 2.306～2.4nm,d is between 0.767～0.799nm,the interlayer space is about 0.30nm.The achieved product consisted of the typical thin,hexagonal plate-like crystals with～100 nm in size.
2.Synthesis and charaterisation of CPT-LDHs-SDS nanohybrids
(1)The method of assemblage was used to syntesize the nanohybrids.During the process the Mg/Al ratio x of Mg_xAl/DS LDHs,the polarity of the solvents,initial CPT concentration(C_(CPT))and contact time in the intercalation process were studied to investigate their effects on the amount of CPT loaded into CPT-Mg_xAl LDHs-SDS nanohybrids(A_(in)).The most effective uptake of CPT occurred in DMSO media by Mg_3Al LDHs-SDS.The maximum A_(in)value reached about 5.2%(w/w)under studied conditions.
(2)The release rate of CPT from the nanohybrid at pH 7.2 is remarkably lower than that at pH 4.8,this is due to a possible difference in the release mechanism.For the pH 7.2 release,the mechanism is primarily through diffusion of drug molecules;while for the pH 4.8 release,that is through both the dissolution of LDH layers and diffusion of drug molecules among which the former one is dominating.The release kinetics of CPT from the nanohybrids obeyed the pseudo-first order kinetic model.
3.Synthesis and charaterisation of CPT-LDHs nanohybrids
(1)The method of reconstruction was used to syntesize the nanohybrids in ethanol-water mixed solution.During the process the volume ratio(R_v)of ethanol/water, initial CPT concentration(C_(CPT)),the reaction temperature and contact time in the intercalation process were studied to investigate their effects on the amount of CPT loaded into CPT-LDHs nanohybrids(A_(in)).The maximum A_(in)value reached about 14% (w/w)when R_v=7:3 after 24h reconstruction under 60℃.
(2)According to the size of CPT molecule and the gallery height of the nanohybrid,a probably arrangement of CPT molecules in CPT-LDHs nanohybrid may be proposed, i.e.,CPT molecules arrange as monolayer with their long axes parallel to the LDHs layers.
(3)The release rate of CPT from the nanohybrid at pH 7.2 is remarkably lower than that at pH 4.8,this is due to a possible difference in the release mechanism.For the pH 7.2 release,the mechanism is primarily through diffusion of drug molecules;while for the pH 4.8 release,that is through both the dissolution of LDH layers and diffusion of drug molecules among which the former one is dominating.The release kinetics of CPT from the nanohybrids obeyed the pseudo-second order kinetic model.
(4)we successfully attached disuccinimidyl carbonate(DSC)to the LDHs surface and achieved the surface functionalization of LDHs.
引文
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