Folate-conjugated Dendrimer-Curcumin Prodrug For Targeted Anticancer Drug Delivery

It has been shown that curcumin has a wide range of pharmacological activity,such as anti-inflammatory, anti-oxidation, anti-tumor, inhibition of thrombosis,prevention of myocardial infarction. Clinical studies have found that there arenon-toxic side effects at high doses (12g/day) by the oral. However, lowbioavailability of curcumin limits its application in the clinical setting. To solve thisproblem, the subject combined dendrimer features and prodrug concept to develop anactive targeting prodrug dendrimer carrier, expecting to improve the bioavailability ofcurcumin.A tumor-targeted prodrug dendrimer (FA-PEG-PAMAM-Tris-Cur) was designedand synthesized. The hydrophobic drug curcumin (Cur) and the targeting moleculefolic acid (FA) were conjugated to the surface of the polyamine (PAMAM-Tris) viathe amidation reaction. In addition, the prodrug carrier PAMAM-Tris-Cur and a seriesof carrier PAMAM-Cur, FA-PEG-PAMAM-Cur with amino terminal weresynthesized as the contrasts.The dendrimer conjugates were characterized in terms of structure using protonnuclear magnetic resonance spectroscopy. About3.0curcumin molecules and2.8folicacid molecules were conjugated with each dendrimer PAMAM on the surface, whileeach PAMAM-Tris surface was bonded with about9.0curcumin molecules and6.0folic acid molecules. The size and morphology was characterized by Zeta nanoparticlesize analyzer and transmission electron microscopy, respectively. The modifieddendrimer showed a size within50nm with excellent monodispersity. Furthermore,the prodrug dendrimer FA-PEG-PAMAM-Tris-Cur showed no hemolysis indicatingthe good biocompatibility.The drug loading of the dendrimers (FA-PEG-PAMAM-Cur andFA-PEG-PAMAM-Tris-Cur) was also investigated. The drug loading ofFA-PEG-PAMAM-Tris-Cur was reached to23.1±1.5%, which was a dramaticincrease compared to that of FA-PEG-PAMAM-Cur (11.8±1.2%). Also the drugloading of FA-PEG-PAMAM-Tris-Cur/Cur was10%more than that ofFA-PEG-PAMAM-Cur/Cur.The targeting capability of these conjugates was analyzed in the humanhepatocellular carcinoma cell line (HepG2). The cellular uptake ofFA-PEG-PAMAM-Cur and FA-PEG-PAMAM-Tris-Cur was found to be greatly enhanced because of the folate-receptor-mediated endocytosis, indicating superiortargeting ability.In conclusion, FA-PEG-PAMAM-Tris-Cur exhibited enhanced curcumin loading,good biocompatibility and superior targeting ability, which would be potentialcurcumin delivery system available.