Synthesis And Properties Of Layered Double Hydroxides And Drug Intercalated Layered Double Hydroxides

The toxic and side effects of drugs, especially the anticancer drugs have had been obsessing the patients and doctors, so the development of targeting and controlled release drug delivery system with high efficacy and little side effects has become an extremely important task in the field of medicine.Layered double hydroxides (LDHs), or the so-called Hydrotalcite-like compounds (HTlc), are a family of layered solids with structurally positively charged layers and interlayer balancing anions which can be replaced by the desired anions. The drugs can be intercalated into LDHs to obtained drug/LDHs nanohybrids. The process of controlled-release of drugs is governed by the host-guest interaction involving both electrostatic attraction and hydrogen bonding and the guest-guest interaction within the two-dimensional interlayer gallery, and this indicates that the nanohybrid can be used as a potential drug delivery system.In the paper, with LDHs chosen as host material and anticancer drugs as guest species, 5-Fluorocytosine (5-FC) and Camptothecin (CPT) have been successfully intercalated into LDHs using coprecipitation methods to obtain 5-FC/LDHs and CPT/LDHs nanohybrids. The synthesis strategy and the properties of nanohybrid, released behavior, released mechanism and the relationship between structures and released behavior of nanohybrids were systematically studies.The main contents of this paper are as follows.Section 1 Synthesis of LDHs with Uniform SizeMgAl-LDHs was synthesized by co-precipitation method, and the effects of temperature (T), aging time (t), total metal ion concentration (c) and mixing method on the size and size distribution of LDHs were investigated by orthogonal design method. It was found that the primary factor affecting the size of MgAl-LDHs was aging time while that affecting the size distribution of MgAl- LDHs was mixing method. The optimal synthesis method and conditions of MgAl- LDHs with uniform size were obtained: decreasing pH method, T= 25℃, c = 0.50 M and t = 0.75 h. For LDHs prepared with the optimal conditions, the mean size was 62.8 nm and the width of size distribution was 28.2 nm.Section 2 Synthesis of LDHs with novel morphologies(1) MgAl-LDHs with novel morphologies can be controlled synthesized using simple traditional coprecipitation method with organic molecule as templates to engineer of the growth orientation of LDHs(2) Ring-like, belt-like and sphere-like particles were obtained with sodium dodecylsulfate together with Na2-edta, sodium stearate and sodium tartrate as templates, and the obtained samples were denoted as SDS-EDTA/LDHs, St/LDHs and Tar/LDHs, respectively.(3) The XRD and FT-IR analysis indicated that the templates were intercalated into the gallery of LDHs. For SDS-EDTA/LDHs, SDS and edta^2-- anions were adsorbed on two neighbouring surfaces of the LDHs hydroxide basal layers, respectively and for Tar/LDHs, the tartrate anions orientated vertically to the layers. For St/LDHs, the stearate molecules formed a bilayer in the interlayer space. The hydrophobicity and the ordered orientation structure of the stearate molecules bilayer in the gallery were verified by steady-state fluorescence method and polarization microscope observation.Section 3 Synthesis and Characterization of 5-fluorocytosine/LDHs nanohybrid and surface functionalization of LDHs(1) The intercalation of 5-fluorocytosine (5-FC) into the interlayer of LDHs, has been carried out using coprecipitation method to obtain 5-FC/LDHs nanohybrid. With the increment of the molar ratio (R_F/M) of 5-FC to metal ions in the raw material, the intercalated amount of 5-FC (A_in) increased.(2) The morphology of 5-FC molecules in 5-FC/LDHs nanohybrid is dependent on A_in. At lower A_in value, 5-FC molecules are intercalated into the gallery of LDHs with a horizontal orientation, and 5-FC molecules and NO3^- anions coexist in the interlayer region of LDHs. At higher A_in value, parts of 5-FC molecules are intercalated into the gallery of LDHs with a horizontal orientation, and parts of 5-FC molecules with a vertical-arranging monolayer.(3) The in vitro drug release from the nanohybrids is remarkably lower than that from the corresponding physical mixture and pristine 5-FC at either pH 4.8 or pH 7.5. In addition, the release rate of 5-FC from the nanohybrid at pH 7.5 is remarkably lower than that at pH 4.8, which is possibly due to a difference in the release mechanism. The release mechanism in neutral aqueous solution is an ion-exchange process between the interlayer 5-FC and inorganic anions in the release media, and the diffusion process of 5-FC in the interstices and interlayers of nanohybrid is the rate-limiting step. On the other hand, the 5-FC release of nanohybrid in acidic aqueous solution is essentially controlled by the dissolution process of the host layers.(4) The outside surface of the nanobiohybrid may be functionalized with targeting biomolecules for site direction. The surface of LDHs was successfully functionalized by disuccinimidyl carbonate (DSC), and then bovine serum albumin (BSA) is able to be attached to the LDHs complex through binding of primary amine groups. It has established the foundation to further study the active targeting of drug/LDHs nanohybrid.Section 4 Synthesis and Characterization of Camptothecin/LDHs nanohybrid(1) The intercalation of Camptothecin (CPT) into the interlayer of LDHs has been carried out using coprecipitation method to obtain CPT/MgAl-LDHs nanohybrid and CPT/ZnAl-LDHs nanohybrid. With the increment of the molar ratio (R_C/M) of CPT to metal ions in raw materials, the intercalated amount of CPT (A_in) increased. (2) The morphology of CPT molecules in CPT/LDHs nanohybrid was horizontal-arranging monolayer and vertical-arranging bilayer. It was interestingly found that the gallery height of the CPT-LDH nanohybrids decreased remarkably with the increase of A_in value, which maybe arises from theπ-πinteractions of aromatic rings among CPT molecules.(3) The in vitro drug release behavior from the nanohybrid is obviously different from the corresponding physical mixtures with rapid release in the initial step, followed by a more sustained release of the remaining CPT. The release kinetics of CPT from the nanohybrid obeyed the pseudo-first order kinetic model. The release mechanism in neutral aqueous solution is an ion-exchange process between the interlayer CPT and inorganic anions in the release media, and the diffusion process of CPT in the interstices and interlayers of nanohybrid is the rate-limiting step.