Cancer is one of the most common diseases in the world. Cancer cells divide abnormally and grow uncontrollably, resulting in the formation of malignant tumors, and invading human body. Cancer causes about 13 percent of the all human deaths worldwide (WHO 2007).
Chemotherapy is a popular medical treatments for the cancer, however, it often attacks normal cells in addition to the cancer cells, damaging normal tissue and organs, which cause severe side effects. According to the American cancer society, these side effects include pain, vomiting, limphedemia, sexual decline and various symptoms, which seriously decrease quality of life.
To improve cancer-specificity, drug delivery system (DDS) has developed, but it is difficult to optimize a delivery system for each drug.
Team Todai nanORFEVRE are trying to make cancer-specific drug which doesn’t need delivery system (DDS).
To achieve a cancer-cell-killing system with high specificity, we first took attention to a mechanism in the human immune system called membrane attack complex (MAC), which operates when bacteria infect our body. In the system of MAC, subunits penetrate the membrane, oligomerize, and form a pore into the bacteria membrane. Then the subunits disrupt the lipid bilayer, inducing targeted cells lysis and death. The point of this system is that the subunits show cytotoxity only after forming a pore. MAC do not kill the cell simply by penetration, as molecules on the surface of harmless cells prevent MAC from sticking in (and forming pores). Therefore, MAC will only show cytotoxity to foreign cells such as bacteria.
However, the target-recognition of MAC is far more complicated than referred above, in which a lot of molecules are related. So it is much difficult to mimic the whole system, leading us to take a simple synthetic biological approach.
In the previous study, Rausch et al. used peptides to develop pore-forming proteins like MAC ,but in that research they could not recognize the specific cells. To achieve the recognition system, we thought about using DNA. Recently, in situ computation by DNA was reported (Maria Rudchenko et al. (2013). In that study, DNA was used as logic circuits: using surface antigens as inputs and generating DNA strands as outputs. Rudchenko et al. said that it may be possible to use their logic circuit for other self-assembling systems and DNA machinery. We, therefore, thought that it might be possible to make cancer-recognition system using DNA. Inspired by cell recognizing molecular nano-robot study (Douglass et al. (2012), we used DNA aptamer to recognize cancer cells.
Our general idea is explained as follows. 1) Subunits stick in normal and cancer cells nonspecifically. 2) In case that cancer-specific proteins exist, OCKs get able to oligomerize. 3)Then subunits oligomerize and form a pore, and cytotoxicity is induced to the cancer cell. Overall, our subunits may oligomerize only on the cancer cells and kill only cancer cells.
DNA itself has information embedded in the sequence. Using DNA computation and DNA-protein hybrid system, in which multiple molecules coordinate, we believe that our “Oligomeric Cell Killer" has the potential to treat cancer and other diseases like infection.