Graphene quantum dots (GQDs) maintain the intrinsic layered structural motif of graphene but with smaller lateral size and abundant periphery carboxylic groups, and are more compatible with biological system, thus are promising nanomaterials for therapeutic applications. Here we show that GQDs have a superb ability in drug delivery and anti-cancer activity boost without any pre-modification due to their unique structural properties. They could efficiently deliver doxorubicin (DOX) to the nucleus through DOX/GQD conjugates, because the conjugates assume different cellular and nuclear internalization pathways comparing to free DOX. Also, the conjugates could enhance DNA cleavage activity of DOX markedly. This enhancement combining with efficient nuclear delivery improved cytotoxicity of DOX dramatically. Furthermore, the DOX/GQD conjugates could also increase the nuclear uptake and cytotoxicity of DOX to drug-resistant cancer cells indicating that the conjugates may be capable to increase chemotherapy efficacy of anti-cancer drugs that are suboptimal due to the drug resistance.

Well-defined graphene quantum dots (GQDs) are crucial for their biological applications and the construction of nanoscaled optoelectronic and electronic devices. However, as-synthesized GQDs reported in many works assume a very wide lateral size distribution; thus, their apparent properties cannot truthfully reflect intrinsic properties of the well-defined GQDs, and more importantly, the applications of GQDs will be affected and limited as well. In this work, we demonstrated that different sized GQDs with a narrow size distribution could be obtained via gel electrophoresis of the crude GQDs prepared through a photo-Fenton reaction of graphene oxide (GO). It is illustrated that the photoluminesce (PL) emissions of the well-defined GQDs originated mainly from the peripheral carboxylic groups and conjugated carbon backbone planes through fluorescence and UV-vis spectroscopies. More importantly, our findings challenge the notion that the excitation wavelength dependent PL property of the as-synthesized GQDs is the intrinsic property of the size-defined GQDs. Preliminary data at the cellular level indicated that the small sized GQDs exhibit weaker quenching DNA dye ability but higher toxicity to the cells compared to that of the as-synthesized GQDs. This discovery is essential to explore applications of the GQDs in pharmaceutics and to understand the origin of the optoelectronic properties of GQDs.

The enhancement of DNA affinity of small molecules usually ensures their high nuclease activities, and may also open a new scope of their applications in biology and medicine. In this work, we demonstrate that the nuclease activity and cytotoxicity of the small DNA intercalators can be dramatically enhanced by single atomic-layered graphene oxide (GO) sheets. Through π–π stacking interaction mainly between GO and the aromatic ligands of intercalators, the conjugates of GO and a small intercalator could be formed. Because of the large planar structure of the GO sheets, the coupling of GO with the small intercalators increased their affinity to DNA. Owing to the formation of conjugates with GO, the binding site of small intercalators to DNA was also changed from a minor groove to a major groove. Notably, GO and small intercalator conjugates exhibited higher cytotoxicity than that of the small intercalator alone. The results open up potential applications of GO for new chemotherapeutic agents that work through DNA intercalation.

We previously reported that graphene oxide could enhance nuclease activity of copper complex containing aromatic ligands, thus exhibit the potential for applications in anticancer therapy. However, the functional mechanism of graphene oxide is not well understood. In this work, using graphene quantum dots (GQDs), which have smaller lateral size, better biocompatibility, and a conjugate state higher than that of graphene oxide, we investigated systematically the mechanism of GQDs in enhancing nuclease activity of copper complexes. Through a variety of spectroscopic methods, we found that GQDs promote the reduction of copper ions and accelerate their reaction with O2, forming superoxide anions and copper-centered radicals. These active species then oxidize DNA molecules. The improvement in the reduction of copper complexes can be attributed to the coordination of the GQDs to the copper center of the complex, leading to an efficient electron-transfer from the electron-rich GQDs to the copper complexes. The fundamental understanding of the role of the GQDs in DNA cleavage by the transition complexes is promising for the discovery of anticancer therapeutics. More importantly, unique and rich three-dimensional structures of metal complexes also make it possible to prepare highly active DNA cleavage reagents with a high selectivity for DNA sequences and structures.