Synthesis,Modification,and Properties Of Camptothecin Intercalated LDH Nanohybrids

Layered double hydroxides (LDHs), also called anionic clays or hydrotalcite-like compounds, are an important class of layered inorganic materials. The brucite-like LDH layers possess structural positive charges due to the isomorphous substitution, which are counterbalanced by interlayer hydrated anions. LDHs are widely studied as drug delivery system. The drug can be intercalated into the gallery of LDHs to form the drug-LDH nanohybrids, which are considered as potential drug delivery and controlled-release system because of the host-guest interaction and steric-hinerance effect.There have been many reports on the synthesis of drug-LDH nanohybrids, mainly including co-precipitation, ion exchange, reconstruction and hydrothermal methods. Nevertheless, these conventional methods are most suitable for the intercalation of anionic water-soluble drugs. It is difficult for the water-insoluble or neutral charge drugs to be intercalated into the interlayer of LDHs due to the lack of driving force. Thus, the secondary intercalation or drug-modification ion exchange methods were raised to prepare the water-insoluble drug intercalated LDH nanohybrids. Recently, the delamination of LDHs attracts much attention because the nanosheets can be used as positive charged building block to prepare nanohybrid materials. And the delamination-reassembly is widely studied to synthesis organic-LDH ultrathin film and macromolecule-LDH nanohybrids thanks to their facile process and mild conditions. But to the best of our knowledge, the delamination/reassembling process has not been reported to prepare the drug-LDHs nanohybrids. Therefore, it is important to explore the feasibility and characteristics of delamination/reassembling method to synthesis the drug-LDHs nanohybrids for the targeted drug delivery-controlled release systems.In addition, the clinical application is limited for the poor water dispersion and serious aggregation. In order to solve these problems, liposome has been introduced into related study. Liposome is an artificially prepared spherical vesicle composed of a lipid bilayer with an aqueous interior, which is widely studied as drug delivery system. Herein, we make an assumption that liposome is used as a modification material for the coating of drug-LDH nanohybrids to improve the water dispersion of nanohybrids owing to steric-hinerance effect. Accordingly, the drug-LDHs@liposome nanocomposites have the potential to be a new targeted drug controlled-release system for the biocompatibility and surface modification.Camptothecin (CPT) is a kind of efficient clinical anticancer drug. But its application has been limited by the poor solubility, toxicity, side effect and short effective reaction time. So it is of great importance to develop the new delivery system for improving the solubility, stability and controlling the release of CPT.In this work, we take the water-insoluble and charge-neutral anticancer drug, CPT, as model drug to explore the preparation of CPT-LDH nanohybrids via delamination-reassembling method. The CPT-LDH@liposome nanocomposites were also synthesized by reverse evaporation method. In order to reach better understanding of drug-LDHs system, the drug loading amounts, crystal structure, morphology of CPT-LDH nanohybrids and CPT-LDH@liposome nanocomposites were characterized by XRD, TEM, UV-vis, Zeta potential, particle size and so on. Besides, the drug release and dispersibility were studied as well.Main contents and conclusions:(1) We chose the biocompatible surfactant deoxycholate as the guest molecule and Mg3Al-NO3LDH as the host material to synthesis DC-LDH nanohybrids via the delamination/reassembling method. The so-synthesized nanohybrids were characterized by XRD, TEM, FT-IR, elemental analyses and TG-DSC. The DC anions arrange as a slight tilted bilayer with the long axis perpendicular to the brucite-like layer. The feasibility and characteristic of delamination/reassembling method were investigated. It was proved that this strategy exhibited the advantages of short reaction time and mild experimental conditions and the loading amount of DC in the nanohybrids could be easily controlled by changing the ratio of DC to LDH. What’s more, a new system was built for the encapsulation of water-insoluble drugs.(2) We chose the water insoluble anticancer drug, CPT, as the guest molecule and Mg3Al-NO3LDH as the host material to synthesis CPT-LDH nanohybrids via the delamination/reassembling method. The so-synthesized nanohybrids were characterized by XRD, TEM, FT-IR, elemental analyses and UV-vis. For this route, CPT molecules were initially incorporated into the micelles of a biocompatible surfactant, such as sodium cholate (SCh) or sodium deoxycholate (SDC). The resulting negatively charged CPT-loaded micelles and the positively charged LDH nanosheets were then co-assembled together to form CPT-Sur-LDH nanohybrids. It revealed that the loading of CPT in the nanohybrids could reach as high as13.5%, indicating that this route could be used to achieve the effective intercalation of charge-neutral and poorly water-soluble drugs into the LDH gallery. The in vitro release of CPT from the nanohybrids had been examined, and the results showed that the release was a diffusion-controlled process and that the diffusion process through the LDH particles was the rate-limiting step. The parabolic diffusion equation effectively described the kinetic process associated with the release of CPT from the nanohybrids.(3) The nanocomposites of liposome coated CPT-LDHs were synthesized by the optimized reverse evaporation method. The morphology, mean diameter, stability, and redispersion were characterized. CPT-LDHs were successfully encapsulated in the aqueous interior of liposome. It indicated that the CPT-LDH@liposome nanocomposites have good dispersion stability and re-dispersibility in water. The coating of liposome outside the CPT-LDH nanohybrids is an effective method to solve the problem of poor dispersion stability. The in vitro release profiles of CPT from the nanocomposites were examined, indicating that the nanocomposite is a novel pH-responsive drug delivery system and the diffusion through the particles the rate limiting step.(4) Ananohybrid of CPT-graphene oxide (GO)-LDHs is synthesized by using the delamination-coassembling method. For the coassembly route, CPT molecules were initially loaded on the surface of GO nanosheets; the resulting negatively charged CPT-loaded GO nanosheets and the positively charged LDH nanosheets were then coassembled together into the layered CPT-GO-LDH nanohybrid, in which the GO nanosheets and the LDH nanosheets were alternatively stacked and the CPT molecules were located in its interlay er gallery. The so-obtained nanohybrid was characterized by XRD、TEM、FT-IR、UV-vis and TGA/DSC. The drug loading amount, only13.4mg/g (1.34%), is lower than the CPT-Sur-LDH nanohybrids, which would be addressed in the future work.