Functionalized Graphene Oxide Nanoparticles For Controlled Drug Release And Tumor Therapy

With the limit of short effective half-life, antitumor drugs need to be frequently administered for chemotherapy. The inhibition effect of antitumor drugs on tumor growth can be improved by frequent dosing, whereas the plasma concentration would increased exponentially, leading to serious systemic side effects and susceptibility of drug resistance. Therefore, in order to lower the damage to normal tissues and the possibility of drug resistance, it is warranted to develop novel delivery systems to deliver antitumor drugs, regulate drug release ratio and maintain the lowest effective concentration as long as required. Herein the study, we combine graphene oxide(GO) nanoparticles and β- cyclodextrin in order to fabricate an intelligent controlled release system to deliver doxorubicin(DOX) and topotecan(TPT).Combination chemotherapy has been widely employed for clinical applications, but it’s rare to evaluate the efficiency of the combination of DOX and TPT. In this work, the synergistic effects of DOX and TPT on He La cell proliferation was carried out, and the value of coefficient of drug interaction(CDI) illustrated that the drug combination showed a synergistic effect in a wide range of concentrations. However, when the concentrations of drugs in the combination were increased beyond a critical levels(80% inhibition for each drug), an antagonism between drugs was noticed. This investigation provided a basis for the rational design of novel release devices.As a nanometer material, GO possesses large drug loading capacity and easy modificability and some other remarkable properties. β-Cyclodextrin(β-CD) is a p H-sensitive and non-toxic "cavity" macrocyclic molecule, possesses good biocompatibility and molecular recognition. Based on the optimized drug combination between DOX and TPT, a novel controlled release system was fabricated. Briefly, DOX was bonded to adamantanecarboxylic acid(AD-COOH) through covalent linkage to form AD-DOX, while GO was modified by β-cyclodextrin(β-CD) to form GO-CD, then GO-CD was assembled with as-produced AD-DOX via host-guest interaction. Different to the conjugation of DOX via covalent linkage, TPT was loaded onto GO through π-π stacking interaction. Then the intermediate gained during program of producing TPT/GO-CD/AD-DOX carriers were characterized by FT-IR, UV-vis, Zeta potential and particle size distribution. And cell culture experiments in vitro were performed to evaluate their killing activity. It was found that TPT/GO-CD/AD-DOX nanoparticle synchronized the delivery of DOX and TPT, and p H value played a critical role in determining the release profiles of dual drugs. Moreover, in vitro cellular investigations proved that TPT/GO-CD/AD-DOX was superior to free drugs and single-drug loaded nanoparticles in inhibiting the growth of Hela cells.