Specific targeting of tumor tissue is essential for tumor imaging and therapy, but remains challenging. Here, we report an unprecedented method using synthetic sulfonic acid-graphene quantum dots (sulfonic acid-GQDs) to accurately target cancer cell nuclei in vivo, without any modification of biological ligands, and without the need for intervention in normal tissue cells. A key factor in this selectivity is the high interstitial fluid pressure (IFP) in tumor tissue, which allows sulfonated GQDs to penetrate the plasma membrane of tumor cells. In vitro, the repulsive force between negatively charged sulfonate GQD and cell membrane results in low distribution of sulfonate GQD in normal tissues in vivo. However, because sulfonic acid GQDs are attached to cell membranes, incubation of cells in ultrathin film medium can activate the plasma membrane penetration process. Molecular dynamics simulations show that once through the plasma membrane, the negatively charged functional groups of these GQDs will keep the membrane small enough to perform the self-cleaning function of penetrating the nuclear membrane into the nucleus. Our study demonstrates that IFP is a previously unknown tumor nucleus-specific targeting mechanism, suggesting that sulfonated GQDs may be developed as a new tool for tumor specific imaging and therapy.

https://pubs.acs.org/doi/10.1021/acs.bioconjchem.7b00466