Melatonin and doxorubicin co-delivered via a functionalized graphene-dendrimeric system enhances apoptosis of osteosarcoma cells

Highlights: • The graphene-dendrimeric used for co-delivery. • It improves DOX efficacy in cancer treatment. • It reduces toxicity in normal cells. A functionalized graphene-dendrimeric system was designed via Fe₃O₄ nanoparticle (NP) as a magnetic nanocarrier for co-delivery of doxorubicin (DOX) and melatonin (MLT). Accordingly, β-Cyclodextrin (β-CD) was modified by creating amine functional groups. The modified β-CD was grafted with Graphene oxide (GO), and the resulting platform gain many functional groups, including the hydroxyl (-OH), carboxylic acid (-COOH), and amine functional groups (−NH2). Finally, magnetic NPs were synthesized on the prepared platform to efficiently controlling and targeting drugs to tumor sites. The human osteosarcoma cell lines including Saos-2 and MG-63, as well as Human Bone Marrow Mesenchymal Stem Cells (hBM-MSC) line, were used to determine the in vitro biological effects of the functionalized graphene-dendrimeric system. The magnetic nanocarrier has encapsulation efficiency (EE) values of 99.92% for DOX and 21.5% for MLT. The biocompatibility tests of the nanocarrier revealed that the magnetic nanocarrier was appropriate as a drug carrier. Co-delivery of DOX and MLT with an efficiently anticancer performance was also was confirmed by cellular uptake, 4′,6-diamidino-2-phenylindole (DAPI) staining, and apoptosis analysis in comparison with free DOX and MLT. Moreover, there was a synergy in the antitumor effect when MLT was combined with DOX, especially in the nano-formulation form, which may be due to the down-regulation of X-linked Inhibitor of Apoptosis (XIAP), survivin, and human telomerase catalytic subunit (hTERT) (p < 0.0001). Overall, the result of our study suggests that the designed carrier is a promising nanocarrier for targeted co-delivery of DOX and MLT with improved anticancer efficacy in cancer cells and thus reduced toxicity in normal cells.