A new technique downregulates the genes responsible for drug resistance, via a tailored DNA nanoplatform that deploys chemotherapeutic drugs and RNA interference to a given multidrug-resistant tumor.
The journal Angewandte Chemie has reported that a team of Chinese scientists has developed a mix of gene-silencing elements and chemotherapeutic drugs that selectively kill cancer cells. The nanoplatform is designed using well-known DNA origami techniques. With the nanoplatform, scientists are able to deliver a desired RNA transcription template and chemotherapeutic components into the tumor.
This development is of a particular breakthrough given that multidrug-resistant cancer cells disrupt any treatment procedures by often removing powerful drugs from the tumor cell before their pharmacologic benefit is effective. Scientists have tried therefore to interfere with the gene expression level with RNAi (RNA interference) techniques in which small RNA interfering strands combine with a specific carcinogenic cell’s messenger RNA and inhibit transcription. The problem arises when RNA transcription templates need to be delivered within the cell's cytoplasm at a time when in parallel the active potent chemotherapeutic drug needs to be present to kill the cell.
Dr. Baoquan Ding, from the Beijing-based National Center for Nanoscience & Technology, and his colleagues, have been able to build a platform that can carry and deliver every all components needed (including the gene-silencing elements and the chemotherapy drugs) into the tumor cell. This is done through the creation of a nanosized DNA object constructed with specific components and the desired shape of a given simplicity or complexity.
One of the advantages of DNA origami lies in the structure's ability to self-assemble into a triangular nanoplatform that can bind multiple functional units. In this particular research, the DNA platform was able to carry the powerful anticarcinogenic drug doxorubicin, a particularly effective drug against malign tumors. This hydrophobic drug did not bind to the nanoplatform but was instead loaded onto it through a process of intercalation, the exact same process through which doxorubicin itself works: intercalating into DNA and inhibiting transcription in the cancer cell. In parallel, two linear hairpin RNA transcription templates were linked covalently to the nano platform and were in charge of gene therapy and RNA interference. Besides these, a disulfide linkage was also loaded to be cleaved by cellular glutathione and a cell-specific unit was tasked with recognition and insertion by the tumor cell.
The researchers monitored the nanoplatform in vitro on cell cultures and by administering it into mice hosting the multidrug-resistant tumors. A high and selective delivery and release rate of doxorubicin, a high release of RNA transcription templates, and a high and selective tumor-killing efficiency were confirmed. Adding to the success, the multifunctional nanoplatform was determined to not be of any harm to the mice while being effective and deadly to multidrug-resistant tumors.
This team of researchers has opened a new possible treatment path through a nanostructure that can specifically target cancer cells whilst dramatically reducing chemotherapy side effects. And of greater importance for this field of research to come, is the capacity of this DNA nanoplatform format to be adaptable to the specific drug components and delivery strategies that may be required in a given therapy.