Graphene oxide nanocells for impairing topoisomerase and DNA in cancer cells

Abstract

DNA topoisomerases and nuclear DNA are important targets for cancer therapy. However, DNA topoisomerase inhibitors and DNA damaging drugs demonstrate a large window of side effects in the clinic. Graphene oxide based biocompatible and biodegradable nano-scale materials have the potential to overcome this complication. However, encompassing different topoisomerase inhibitors along with DNA damaging drugs into 2D-graphene oxide remains a main challenge. To address this, in this manuscript, we have engineered self-assembled spherical 3D-graphene oxide nanoparticles coated with lipid (GO-nanocells) which can concomitantly load and release multiple topoisomerase inhibitors (topotecan and doxorubicin) and DNA damaging drug (cisplatin) in a controlled manner. Fluorescence confocal microscopy confirmed that these GO-nanocells were taken up by HeLa cervical cancer cells and transported into lysosomes temporally over 6 h. A combination of confocal microscopy, gel electrophoresis, and flow cytometry studies revealed that these GO-nanocells damaged nuclear DNA along with topoisomerase inhibition leading to induction of apoptosis through cell cycle arrest in the G2-M phase. These GO-nanocells killed HeLa cancer cells with remarkably greater efficacy compared to a free drug cocktail at 48 h post-incubation. These self-assembled GO-nanocells can serve as a nanoscale tool to perturb multiple therapeutically important sub-cellular targets simultaneously for improved efficacy in future cancer chemotherapy.