Water-soluble heparin–PTX conjugates for cancer targeting

Targeted drug delivery to cancer cells or tumor vasculature is an attractive approach to treating cancer. We here report the synthesis of an anticancer drug conjugate composed of paclitaxel (PTX) and polysaccharide heparin through the reaction of aminated PTX with the carboxyl group of heparin. The structure of the conjugates was identified by 1H NMR and FT-IR measurements. Heparin–PTX conjugates have high solubility in aqueous solutions. Unlike physically encapsulated drugs, heparin–PTX can self-assemble to form spherical nanoparticles in aqueous solution as characterized by Transmission Electron Microscopy (TEM). Size distribution of the nanoparticles as determined by Dynamic Light Scattering (DLS) was in the range of 200–400 nm depending on the coupling ratio of PTX to heparin molecules. The anticoagulant activity of heparin–PTX conjugates was decreased compared to that of heparin, thereby reducing hemorrhagic side effects. Cellular uptake of the nanoparticles was significantly enhanced compared to heparin as visualized by Confocal Laser Scanning Microscopy (CLSM). Furthermore, heparin–PTX conjugate nanoparticles exhibited higher cytotoxicity against KB cancer cells than did free PTX. The cytotoxicity of nanoparticles was found to depend on the amount of PTX conjugated to heparin as well as the conjugate concentration. Thus, conjugation of PTX to heparin may be useful for the solubilization and targeted delivery of PTX to solid tumors.