Release Behavior of 5-Fluorouracil from Chitosan-Gel Microspheres Modified Chemically and Their Antitumor Activities

Abstract

In order to provide a device which releases 5-fluorouracil (5FU) in a controlled manner and has targetability to the specific organ cells, chitosan-gel microspheres immobilizing 5FU derivatives (aminopentyl-carbamoyl-5FU, aminopentyl-ester-methylene-5FU) coated with polysaccharides or lipid multilayers were prepared. The chitosan-gel micro-spheres cross-linked with glutaraldehyde (MS(CM)) were obtained by applying emulsion method using an ultrasonicator. The MS(CM)s were coated with polyanionic polysaccharides, such as CM-N-acetyl-a-1,4-polygalactosamine, CM-chitin and hyaluronic acid, by formation of polyelectrolyte complex membrane to give MS(CMG), MS(CMC) and MS(CMH), respectively. Moreover, MS(CML) was obtained by coating MS(CM) with dipalmitoyl phosphatidylcholine (DPPC) multilayer. The release rate of 5FU from the MS(CM) was depressed by immobilization of 5FU derivatives into MS(CM) via covalent bonds and by coating with polysaccharide or DPPC multilayer at 37°C. The temperature-sensitive release behavior of 5FU from MS(CM) was achieved between 37°C and 42°C by coating with DPPC multilayer. Moreover, MS(CML-CM-Poly(GalNAc)) and MS(CML-Lac), MS(CMG) immobilizing 5FU derivatives showed the cell specific cytotoxicities against SK-Hep-1 human hepatoma cells and HLE human hepatoma cells in vitro, respectively.