10 July 2018 Chromatin decompaction augments the effect of chemotherapy

STORM images of chromatin on untreated cells (left) and after treatment with silver nanoclusters (right). Scalebars: 2*m.

Super-resolution microscopy provides evidence of the significance of targeting chromatin compaction to increase the therapeutic index of chemotherapy.

Chemotherapy is one of the most common treatments for cancer. Targeting DNA using cytotoxic drugs has been proven to cause potent and selective destruction of tumor cells. However, a major factor in the resistance of chemotherapy is the insufficient accessibility of the drug to the DNA. Using super-resolution microscopy, K. Borgman from the Single Molecule Biophotonics group now provides evidence that chromatin compaction is a major barrier that limits the access of the drug to the DNA. Silver nanoclusters that have the property of decompact chromatin increase the therapeutic index of chemotherapy and reduces tumor burden. This work has been published in Advanced Materials.

DNA-binding cytotoxic drugs are the first choice in the treatment of many cancers. Unfortunately, the efficacy of this type of chemotherapy treatment is limited by the insufficient amount of drug that reaches the DNA. In collaboration with the groups of Lopez-Quintela and F. Dominguez at the Universidad de Santiago de Compostela, Kyra Borgman from the single molecule Biophotonics group led by ICREA Professor at ICFO Maria Garcia-Parajo now demonstrates that chromatin compaction is a main determinant that restricts the accessibility of the drug to DNA.

The Galician groups have long expertise on the synthesis of silver nanoclusters composed of only three atoms and have already explored their potential as pharmacological agents owing to their very small size and to their properties that can be precisely tuned with minor modifications to their size. In the collaboration with the ICFO group, the researchers now visualized by super-resolution STORM microscopy the ultrafine structure of chromatin on proliferating human lung carcinoma cells. STORM images showed a striking decompaction of chromatin upon addition of silver nanoclusters. Further experiments showed that co-administration of silver nanoclusters increased the cytotoxic effect of DNA-acting drugs in these cancer cells. Moreover, in mice with orthotopic lung tumors, the co-administration of silver nanoclusters increased the amount of the chemotherapeutic drug cisplatin bound to the tumor DNA by fivefold without modifying the cisplatin levels in normal tissues. As a result, cispla tin co-administered with silver nanoclusters strongly reduced the tumor burden.

Our results underscore the importance of targeting chromatin compaction to increase the efficacy of chemotherapeutic drugs. The work also shows the enormous power of super-resolution microscopy to reveal ultrafine structures in the nuclei of intact cells. Together, our findings establish the groundwork for exploring the potential therapeutic properties of nanoclusters, a goal that mainly depends on the development of efficient synthetic procedures capable of providing precise size control at the lowest scale of nanomaterials.