Synthesis And Characterization Of Drug(Ciclosporin A,Cucurbitacine,5-fluorocytosine)-LDH Nanohybrids

The side effects of anticancer drug in clinical application are a challenge in pharmaceutics, which makes the development of novel and efficient controlled drug release system important.Layered double hydroxides (LDHs), also known as hydrotalcite-like compounds, are three-dimensional crystals formed by orderly arranged two-dimensional laminates in the longitudinal direction. The host layers are composed of two or more kinds of metal ions. The host layers possess positive charges because of isomorphous substitution, which are balanced by hydrated exchangeable anions located in the interlayer gallery. Some drug molecules can be intercalated into the gallery of LDHs to form drug-LDHs nanohybrids. For the interaction of ionic bonding, hydrogen bonding and van der Waals energy, the drug molecules combined with the host layers and drug-LDHs are promising controlled-release systems.Among the extensive reports on the synthesis of drug-LDHs, co-precipitation, ion exchange, reconstruction and hydrothermal methods are commonly used. However, as only anionic drugs can be strongly attracted to the positively charged layers, these conventional methods are mainly suitable for the intercalation of anionic drugs and are less effective for charge-neutral or water-insoluble drugs. For such drugs, secondary intercalation method and drug modification-ion exchange method are proposed. But these two methods are limited by the drawbacks of time-consuming and low drug loading amount.Recently, our group has proposed a delamination/reassembling method, i.e., LDHs are first delaminated to nanosheets and then reassembling with drugs to form drug-LDHs. This method can eliminate the intercalating resistance and make full use of the interlayer spaces. Compared with conventional methods, the method has the advantage of short reaction time, mild condition and high drug loading amount. Thus, it is promising for the preparation of hydrophobic drug LDHs nanohybrids.This work aims to evaluate the application of delamination/reassembling method for the preparation of drug-LDHs nanohybrids and offer references for the application of LDHs in drug delivery systems. Charge-neutral water-insoluble drugs ciclosporin A (CsA), cucurbitacine (CA) and charge-neutral water-soluble drug5-fluorocytosine (FC) are chosen as the guest species. Besides, the Zn2Al-NO3and Mg3Al-NO3LDHs are taken as the host layers. The delamination/reassembling method are adopted to intercalate the CsA, CA and FC into the interlayer of LDHs to prepare the drug-LDHs nanohybrids.Main contents and conclusions:(1) Preparation and characterization of CsA-LDH nanohybridCsA is chosen as the guest molecule and Zn2Al-NO3LDH is selected as the host material to synthesize the CsA-LDH nanohybrid via delamination/reassembling method. Firstly, CsA was encapsulated in the micelle of bio-compatible surfactant sodium cholate (Ch). After, CsA@Ch micelle was reassembled with the delaminated LDH nanosheets, generating CsA-Ch-LDH nanohybrid. The nanohybrid with high drug loading amount of20%was obtained according to the results of elemental analysis, demonstrating the efficient loading of the charge-neutral hydrophobic drug. Based on the gallery height of the nanohybrid and the sizes of CsA and Ch, it is predicted that the Ch anions are arranged as a bilayer with the long axis presenting an angle of70°with the brucite-like layer and the CsA molecules is encapsulated in the bilayer.(2) Preparation and characterization of CA-LDH nanohybridCA is chosen as the guest molecule and Zn2Al-NO3LDH is taken as the host material to synthesize the CA-LDH nanohybrid by delamination/reassembling method. Firstly, CA was encapsulated in the micelle of bio-compatible surfactant sodium cholate (Ch). After, CA@Ch micelle was reassembled with delaminated LDH nanosheets. The CA-Ch-LDH nanohybrid with a high drug loading of7.06%was achieved. The Ch and CA molecules exist in the LDHs with a similar structure as that in CA-Ch-LDH, i.e., Ch anions are arranged as a bilayer with the long axis approximately perpendicular to the brucite-like layer. The in vitro release examination indicates that the CA-Ch-LDH nanohybrid was a good drug controlled release system and its drug release process obeyed pseudo-second order kinetic model.(3) Preparation and characterization of FC-LDH nanohybridsFC is chosen as the guest molecule and Mg3Al-NO3LDH is taken as the host material to synthesize the FC-LDH nanohybrids by delamination/reassembling method. FC and the delaminated LDH nanosheets were reassembled in aqueous medium. The FC-LDH nanohybrids with a high drug loading of11%was achieved. Based on the gallery height of the nanohybrid and the size of FC, it is predicted that the FC molecules lie in the brucite-like layer with the long axis approximately parallel to the brucite-like layer. The result shows that the reassembling method is effective for the loading of non-ionic water-soluble drugs on the LDHs.