Mohamed E. El-Sayed, PHD - University of Michigan Postdoctoral-Multidisciplinary Award:

The Breast Cancer Research Program award that I got was a multi-disciplinary post-doctoral award. I received this during my time at the University of Washington in the Bioengineering Department. The focus of this particular research is sort of trying to develop new smart stimuli sensitive polymers that can be used for delivery of different fragile therapeutic molecules mostly nucleic acid drugs. With recent advances in molecular biology, people are becoming more and more aware of different genes that are upregulated in breast cancer cells and because of that these cancer cells become resistant to chemotherapy.

Our goal is to use nucleic acid molecules that can correct the angogenes(?) or the faulty genes within the breast cancer cells and deliver them using polymeric carriers from the systemic circulation into the breast cancer cells. One of the major barriers in this case is how to stabilize the nucleic acid drugs, how to make them taken up specifically by the cancer cells and more importantly how to go from outside the cell into the cytoplasma of the cell to produce the desired therapeutic activity. And, this is where we focus our efforts. We try to develop the proper carriers that can protect the nucleic acid drugs that can target the breast cancer cells and can deliver the therapeutic cargo, the nucleic acids, directly into the cytoplasma of the breast cancer cells. When this happens, it corrects the faulty genes within the cells and as a result the cells commit suicide. And, this is a significant treatment approach for breast cancer.

This is sort of a schematic drawing of how nucleic acid molecules are internalized within breast cancer cells. The yellow circle that we have here represents a breast cancer cell. If we have nucleic acid molecules by themselves without being carried or protected by any polymeric carriers, they enter the cell by a process called endocytosis. Think about it as the cell membrane (?) forming a pouch or a sack that will pick up the nucleic acid molecules into small vesicles known as the endosomes. These endosomes ultimately fuse with another set of vesicles that are know as lysosomes which have a very high content of enzymes. These enzymes will degrade the nucleic acid drugs and spread them outside the cell, which means you lose the therapeutic activity of the nucleic acid that you are trying to deliver into the breast cancer cell. What we are trying to do is, we take these nucleic acid drugs, complex them with a specific set of polymers knows as smart or stimuli sensitive polymers. They form smart particles that will be also taken up by endocytosis, but once they enter the endosome, they recognize a significant change in the local environment. The endosome is known to be acidic. The pH of the endosome drops gradually from 7.4 to as low as pH 5. What does that mean? It simply means this acidity of the endosome triggers these polymers that encapsulates the nucleic acid to switch the confirmation to be sort of stiff rods like this pen and the make holes or puncture holes into the endosome membrane (?) and escape into the cytoplasma. When they do that, the nucleic acid is still protected and slowly released into the cytoplasma. It acts on a specific target within the cytoplasma, corrects faulty genes, and actually, sort of switches back or normalizes the expression of cancer genes within the breast cancer cells makes the most sense to chemotherapy. And, this is one approach to improve the sensitivity of cancer cells to chemotherapeutic interventions.