Anthrax is a potentially fatal infection caused by the toxigenic bacterium Bacillus anthracis. The spores formed by this organism are easily spread and deadly when inhaled, which is why anthrax has been used as a weapon in biological warfare in the past and today it is still recognized as a serious bioterrorism threat.
Sounds like the perfect thing to be sticking inside cancer patients, right? Well, terrorism aside, the toxin produced by this organism actually has some inherent properties that make it attractive as a potential anticancer agent. Part of the reason it is such an efficient killer is because it is a pro at getting bulky, toxic molecules inside cells. MIT scientists therefore wondered whether they could tweak it so that it shuttles anticancer molecules inside cells, delivering them where they’re needed. And they managed it, successfully shuttling therapeutic antibodies inside cancer cells in the lab. The researchers hope that with further development, the system could be used to deliver a variety of different drugs inside cells, not just cancer drugs. The work has been published in ChemBioChem.
Antibodies are protective proteins produced by the immune system that recognize and bind to harmful substances. Because antibodies can be engineered to stick to virtually anything, they have become an invaluable tool in the treatment of a variety of diseases. For example, many cancer cells overexpress certain receptors, meaning that researchers can target these cells with designer antibodies. This is how the breast cancer therapy Herceptin works, by binding to the HER2 receptor that is overexpressed in certain breast tumors. HER2 signaling stimulates cell division, so blocking it prevents the cell from dividing uncontrollably.
While antibody therapy sounds wonderful, it is limited when the proteins are required inside the cell to work. Antibodies are bulky and struggle to cross the cell membrane, and currently there is no universal delivery technology for them. Armed with the knowledge that the anthrax toxin is efficient at getting things inside cells, MIT researchers set out to convert it into a drug delivery system.
Anthrax toxin is composed of three proteins that are nontoxic on their own. One of them, protective antigen (PA), attaches to cell surface receptors and then forms a pore in the cell membrane. This pore facilitates the entry of the other proteins, lethal factor (LF) and edema factor (EF), which disturb cellular processes once inside.
The researchers rendered LF and EF nontoxic by lopping off part of them and replacing these missing bits with antibody mimics to target proteins. Antibody mimics are similar to antibodies but are slightly smaller.
This modification led to the efficient shuttling of several therapeutic proteins inside cancer cells in the lab, including antibodies that targeted a protein called Bcr-Abl which plays a central role in the development of chronic myeloid leukemia. Tumor cells in which this protein was delivered rapidly underwent programmed cell death.
These results look promising, but before the system can be useful the researchers need to work out how to target specific cell types as the anthrax toxin uses a receptor found on many different cells. If they can achieve this, their novel system could represent a significant advance in the drug-delivery field.
