Assembly And In Vitro Release Properties Of Core-Shell Structural Magnetic Nanoparticles Based On Drug Intercalated Layered Double Hydroxides

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.