【作者】 盘登科；

【导师】 张慧；

【作者基本信息】 北京化工大学 ， 化学， 2010， 博士

【摘要】 研制性能优良的磁靶向载药粒子是当前磁靶向药物传输领域的研究热点。无机层状材料水滑石(LDH)作为近年来倍受关注的分子储库和药物传输基质,已经成为磁靶向载药粒子的优选药物载体。本论文以LDH材料为药物载体,采用共沉淀自组装法和焙烧复原法制备了一系列LDH型核壳结构磁性纳米载药粒子。用XRD、FT-IR、ICP、CHN、TG-DTA、SEM、TEM/HRTEM、XPS、VSM及UV-Vis等表征方法研究了磁性载药粒子的晶体结构、组成、热稳定性、形貌、磁性和体外释放性能。探讨了LDH型核壳结构磁性载药粒子的形成机理。揭示了包覆层药物插层水滑石的晶粒尺寸、磁性载药粒子的包覆层厚度与磁性、外加磁场强度和施加方式与LDH型核壳结构磁性载药粒子的释放行为的内在联系,实现了药物的可控释放。模拟人体环境循环介质中磁靶向定位药物释放实验表明,LDH型核壳结构磁性载药粒子具有较好的磁靶向定位性能和药物缓控释性能,在磁靶向药物传输系统中具有潜在的应用价值。论文主要结果如下：(1)生物相容性磁性纳米粒的制备。采用LDH层状前体法制备了粒径均匀的镁铁氧体纳米粒子,其粒径约为50 nm。采用溶剂热法制备了四氧化三铁(Fe3O4)纳米粒子,其粒径可在100-430 nm范围内调控。(2)采用一步共沉淀法在镁铁氧体纳米粒子表面包覆双氯酚酸插层水滑石(DIC-LDH)组装得到了MgFe2O4@DIC-LDH磁性载药粒子。MgFe2O4@DIC-LDH具有清晰的核壳结构,粒子大小为90-180 nm,其壳层厚度为20-50 nm,核大小为50-120 nm。壳层DIC-LDH相不再具有单纯DIC-LDH的层片状形貌,其粒径变小并以密堆的形式包覆在镁铁氧体纳米粒子的表面。ICP和CHN表明其载药量为43.9 wt%,磁核含量为6.34wt%。MgFe2O4@DIC-LDH的比饱和磁化强度为5.54 emu/g。体外释放研究发现MgFe2O4@DIC-LDH具有明显的缓释性能。在无外加磁场时,其释放速率比单纯DIC-LDH快,归因于其具有较小的微晶尺寸(D110：14.4 nm)；施加1500 G磁场后,其释放速率急剧下降,归因于磁性载药粒子磁致团聚引起药物扩散路径变长、扩散阻力变大。动力学拟合发现MgFe2O4@DIC-LDH的释放行为符合modified Freundlich模型,其释放机理是基于离子交换的多相扩散。结合释放过程样品形貌的变化,其释放过程包括药物在LDH层间的层间粒内扩散、药物在包覆层LDH微晶粒子间的粒间扩散和药物在团聚的磁性载药粒子间的粒间扩散。(3)通过调变镁铁氧体的含量,采用共沉淀法在镁铁氧体纳米粒子表面包覆布洛芬插层水滑石(IBU-LDH)成功组装了系列具有不同磁核含量的磁性纳米载药粒子MgFe204@IBU-LDH。MgFe2O4@IBU-LDH粒径为90-180 nm,具有清晰的核壳结构和较强的磁性(4.52-8.30 emu/g)。随着磁核含量的增大(6.61-18.69 wt%),,磁性载药粒子包覆层中的IBU-LDH的层间距和载药量均减小,归因于LDH层板电荷密度的减小和磁核含量的增大。同时,包覆层IBU-LDH的微晶尺寸和包覆层厚度逐渐减小,说明磁核的加入对LDH微晶的生长具有抑制作用。基于上述结果,结合磁性载药粒子的XPS Ar+溅射和镁铁氧体纳米粒子的Zeta电位分析,发现MgFe2O4@IBU-LDH的形成涉及到Al(OH)3、Mg(OH)2和LDH在镁铁氧体纳米粒子表面的沉淀-溶解-沉淀-扩散机制,LDH的层板可能与磁核以Al-O-Fe的形式相互连接,最终籍LDH纳米晶粒子-粒子间的相互作用聚集而形成完好的核-壳结构。该机理可拓展到多种相似药物的LDH型磁性载药粒子体系,具有一定的普适性。体外释放研究发现MgFe2O4@IBU-LDH磁性纳米载药粒子具有明显的缓释性能。无外加磁场时,MgFe2O4@IBU-LDH的药物释放速率随着磁核含量的增大而增大,归因于包覆层粒子微晶尺寸和包覆层厚度的减小；施加外加磁场时,MgFe2O4@IBU-LDH的药物释放速率随着磁核含量的增大和磁场强度的增强而减小,归因于其磁致团聚程度增大而导致的药物释放路径的变长和扩散阻力的变大。动力学拟合结果表明MgFe2O4@IBU-LDH的药物释放机理是基于离子交换的多相扩散。可见,通过调变磁核含量调控磁性纳米载药粒子壳层LDH的微晶尺寸、包覆层厚度和磁性大小,能够实现调控磁性纳米载药粒子药物释放速率的目的。同时,调变外加磁场强度也是LDH型磁性纳米载药粒子药物释放速率的方便调控因素。(4)根据LDH的结构记忆效应,首先在溶剂热法制备的Fe3O4纳米粒子表面包覆硝酸根插层LDH,焙烧得到核壳结构的磁性纳米复合氧化物,然后采用复原法将去氧氟尿苷(DFUR)引入到磁性粒子中,在Fe3O4表面包覆去氧氟尿苷插层LDH (DFUR-LDH),从而组装得到Fe3O4@DFUR-LDH磁性纳米载药粒子。Fe3O4@DFUR-LDH具有规整的核壳结构和较强的磁性,其粒径约为300 nm,核层是粒径为200 nm的Fe304,壳层是堆积较为松散的约为50 nm厚的DFUR-LDH相,明显区别于单纯DFUR-LDH的层片粒子紧密交联的形貌特征。Fe3O4@DFUR-LDH的载药量为9.73 wt%,磁核含量为44.1 wt%。比饱和磁化强度为17.4emu/g,具有较好的磁响应性能。体外释放研究发现,Fe3O4@DFUR-LDH具有明显的缓释性能。在无外加磁场时,其释放速率比纯相DFUR-LDH快,归因于包覆层DFUR-LDH纳米粒子松散堆积形貌所引起相对较小的药物扩散阻力；施加1500 G磁场后,其释放速率急剧下降,这是由于磁性载药粒子磁致团聚引起的药物扩散路径变长、扩散阻力变大所致。动力学拟合表明,Fe3O4@DFUR-LDH的释放行为符合First-order和modified Freundlich模型,其释放机理涉及溶蚀和基于离子交换的多相扩散过程。(5)通过施加间歇性外加磁场,实现了LDH型核壳结构磁性纳米载药粒子的准脉冲释放。模拟人体环境循环介质中磁靶向药物定位释放研究表明,Fe3O4@DFUR-LDH磁性纳米载药粒子可在外加磁场的引导下定位聚集到指定部位,并能够缓慢释放出药物。外加磁场强度越大,其磁滞留量越高；释放介质的流速越大,距磁场距离越远,其磁致滞留量越小,药物释放速率越快。这些结果表明LDH型核壳结构磁性纳米载药粒子在磁靶向药物传输系统中具有潜在的应用前景。更多还原

【Abstract】 The preparation of magnetic targeting drug-carried nanoparticles is the most important research area in magnetic drug targeting delivery system. As recently pointed materials used for molecular container and drug delivery, the layered double hydroxides (LDH) is considered as a novel candidate in magnetic targeting drug carriers. In the present study, a series of core-shell structural magnetic nanoparticles (MFe2O4@drug-LDH) based on drug-intercalated LDH coated on MgFe2O4 or Fe3O4 nanoparticles are fabricated via a one-step coprecipitation and a calcination-reconstruction method. The crystal structure, composition, thermal property, morphology, magnetic properties and in vitro drug release behaviors are systematically investigated by using XRD, FT-IR, ICP, CHN, TG-DTA, SEM, TEM, XPS, VSM and UV-vis analyses. The formation mechanism of the MFe2O4@drug-LDH nanoparticles fabricated by a one-step coprecipitation method was revealed. The inherent interrelation between the release behavior of MFe2O4@drug-LDH nanoparticles and its magnetism, the crystallite size and the thickness of the coated drug-LDH crystallites, and the external magnetic field has been studied in detail. The drug release rate of the MFe2O4@drug-LDH nanoparticles can be controlled by tuning the crystallite size and thickness of the coated drug-LDH, the content of the magnetic core and the external magnetic field strength. The simulated magnetic drug targeting results show that the MFe2O4@drug-LDH nanoparticles possessing sustained release properties can be easily guided to a desired site, indicating the potential application of MFe2O4@drug-LDH nanoparticles in magnetic drug targeting delivery system. The detailed results are shown as follows.(1) Biocompatible magnetic nanoparticles:The MgFe2O4 magnetic nanoparticles with diameter of-50 nm were synthesized by the LDH layered precursor method. The monodispersed Fe3O4 nanoparticles were prepared by the solvothermal method and their particle sizes can be tuning in the range of 100-430 nm.(2) The MgFe2O4@DIC-LDH magnetic nanoparticles were synthesized by coating the Diclofenac (DIC) intercalated MgAl-LDH (DIC-LDH) on the surface of the MgFe2O4 nanoparticles via a one step coprecipitation method. The MgFe2O4@DIC-LDH nanoparticles possess clear core-shell structure with particle size of 90-180 nm and the core of 50-120 nm, while the shell of 20-50 nm. The densely coated DIC-LDH has no typical platelet-like morphology with much smaller particle size than that of the pure DIC-LDH synthesized by the same method. The MgFe2O4@DIC-LDH possesses a drug loading of 43.9%, MgFe2O4 content of 6.34%, and the measured saturation magnetization intensity of 5.54 emu/g.Under no external magnetic field (MF), the MgFe2O4@DIC-LDH nanoparticles present much faster drug release rate than that of the pure DIC-LDH, mainly due to the smaller particle size of the coated DIC-LDH crystallites. While under the MF of 1500 G, the drug release rate of MgFe2O4@DIC-LDH nanoparticles is reduced greatly due to much longer diffusion path and higher diffusion resistance originated from the aggregation of the particles induced by the MF strength. The release profile of MgFe2O4@DIC-LDH can be well-described by the modified Freundlich equation, indicating that the drug release mechanism involves heterogeneous particle diffusion based on ion-exchange, consisting of the intraparticle diffusion of the DIC-LDH crystalline particles, the interparticle diffusion between the DIC-LDH particles in coating layers and interparticle diffusion between the magnetically triggered aggregated MgFe2O4@DIC-LDH nanoparticles.(3) By tuning the contents of MgFe2O4, a series of MgFe2O4@IBU-LDH magnetic nanoparticles were fabricated by a one step coprecipitation method. The obtained MgFe2O4@IBU-LDH nanoparticles exhibit well-defined core-shell structure, homogeneous particle size distribution in the range 90-180 nm and superior magnetic responsive behavior (4.52-8.30 emu/g). The layered charge density, the interlayer spacing d003 and the thickness of the coated IBU-LDH crystallites are decreased gradually with increasing MgFe2O4 contents. Meantime, the crystalline sizes of the coated IBU-LDH are also decreased gradually due to the increasing MgFe2O4 content, revealing the inhibiting effect of the MgFe2O4 on the growth of the IBU-LDH crystallites.The interaction between the MgFe2O4 core and the coated IBU-LDH determined by using XPS Ar+ sputting and Zeta potential analysis reveals that the formation mechanism of MgFe2O4@IBU-LDH involves the deposition-dissolution-deposition-diffusion of Al(OH)3, Mg(OH)2 and drug-LDH species on the surface of the MgFe2O4 nanoparticles. The drug-LDH and MgFe2O4 were connected via the Al-O-Fe linkages. At the same time, the The drug-LDH particles formed in the solution were also adsorbed on the surface of MgFe2O4 because of the particle-particle interaction of the LDH nanocrystallites, resulting in the final MgFe2O4@IBU-LDH with well-defined core-shell structure. Owing to the ion-exchange property of the LDH materials, this formation mechanism can be extended for other analogue drug-LDH system, implying a broad utility range of the present study.Under no MF, due to the decreasing particle sizes and the thickness of the coated IBU-LDH mcirostallites, the MgFe2O4@IBU-LDH nanoparticles present increasing drug release rate with increasing MgFe2O4 contents, but a reverse trend was observed under the MF of 1500 G, due to increasing diffusion path and diffusion resistance originated from the increasing aggregation extend of the mangnetic nanoparticles induced by the external MF. The inhibition of the drug release rate can also be achieved by increasing the MF strength. The drug release mechanism of MgFe2O4@IBU-LDH nanoparticles is heterogeneous particle diffusion based on ion-exchange, and the drug release rate can be controlled by tuning the crystalline sizes and thickness of the coated drug-LDH crystallites, the content of the magnetic core and the external magnetic field strength.(4) By choosing an anticancer agent doxifluridine (DFUR) as model drug, monodispersed Fe3O4@DFUR-LDH nanoparticles were firstly prepared via the coprecipitation-calcination-reconstruction of the LDH materials over the surface of Fe3O4 spherical nanoparticles. The obtained Fe3O4@DFUR-LDH nanoparticles present well-defined core-shell structure with diameter of ca. 300 nm. The Fe3O4core is ca.200 nm, and the DIC-LDH shell is ca.50 nm with loosely aggregated morphology, different to the worm-like morphology with interconnected particles of the pure DFUR-LDH. The Fe3O4@DFUR-LDH possesses a drug loading of 9.73%, Fe3O4 content of 44.1%, the measured saturation magnetization intensity of 17.4 emu/g.Under no external MF, due to the loosely aggregated morphology of the coated DFUR-LDH, the Fe3O4@DFUR-LDH presents much faster drug release rate than that of the pure DFUR-LDH. While under the MF of 1500 G, the drug release rate of Fe3O4@DFUR-LDH is reduced greatly due to much longer diffusion path and higher diffusion resistance originated from the aggregation of the magnetic particles induced by the MF. The release profile of Fe3O4@DFUR-LDH can be well described by the First-order equation and modified Freundlich model, indicating that its drug release mechanism involve dissolution and heterogenous particle diffusion upon ion-exchange process.(5) The non-contact magnetically controlled drug pulsatile release of MFe2O4@drug-LDH upon a consecutive MF On-Off operation was also achieved based on the reversible aggregation-redispersion ability of the present magnetic MFe2O4@drug-LDH nanoparticles.The simulated magnetic drug targeting in a fluid release medium shows that the Fe3O4@DFUR-LDH magnetic nanoparticles can be easily retained at a desired site and its drug release rate can be adjusted by changing the velocity of the fluid. The retension of the Fe3O4@DFUR-LDH magnetic nanoparticles is inversely proportional to the velocity of the fluidis and the distance of the permanent magnet. The faster release of DFUR from Fe3O4@DFUR-LDH magnetic nanoparticles is proportional to the velocity of the fluid. The present results indicate the potential application of Fe3O4@DFUR-LDH in magnetic drug targeting delivery system.更多还原