Preparation And Property Of An Isoniazid Phospholipid Prodrug Liposome

Liposomes are microscopic vesicles composed of membrane-like lipid bilayers surrounding aqueous compartments. Liposome was discovered by Bangham in 1960s which has become the versatile tool in biology, biochemistry and medicine today. Low trapping efficiency is one of the difficulties in liposome's research and application. In this dissertation, a novel prodrug liposome was prepared for getting high trapping efficiency. A phospholipid prodrug was designed and synthesized, and the liposome was prepared by the amphiphilic phospholipid prodrug. In this way the liposome not only gets a high trapping efficiency (nearly 100%), but also results in lower leakage percentage.Isonicotinyl hydrazide (INH) was chosen as a model drug. Isonicotinyl hydrazide phospholipid prodrug liposome was prepared and the drug release property was investigated. Firstly,4-(2-isonicotinoylhydrazino)-4-oxobutanoic acid (PINH) was synthesized, then PINH reacted with thionyl chloride and got active acyl chloride (PINHCl). After that, sn-glycero-3-phosphocholine (GPC) reacted with acyl chloride (PINHCl) under the catalyzation of 4-dimethylamiopyridine (DMAP), and got isonicotinyl hydrazide phospholipid prodrug (INHPC). INHPC liposomes were prepared by thin-film hydration with sonication method. The liposomal dispersions were analyzed by transmission electron microscope (TEM) and Dynamic light scattering (DLS). The size of liposome decreased from 1553.0±118.1 nm to 450.0±113.6 nm with increasing sonication time. When the liposomal dispersion was diluted, the size decreased rapidly with dilution, and then reaching to 594.0±77.2 nm until diluted by a thousand times.In vitro drug release experiments were carried out in a dialysis bag and then dialyzed with 40 mL of phosphate buffer solution (pH 7.4). The drug amount in the release medium was determined by ultraviolet (UV) spectrum analysis and cyclic voltammogram (CV). PINH was released out by the liposome because ester bond was easier hydrolyzed than amide linkage. Isonicotinyl hydrazide phospholipid prodrug liposome shows a remarkable controlled drug release when compared with no liposome trapping PINH.Covalently bonding a prodrug with liposome forming molecule, not only enhances the trapping efficiency (nearly 100%) of liposome, but also decreases decomposition of the prodrug. This novel method provides a new way for trapping drugs especially for hydrophilic drugs into liposome.