CHEMISTS RECRUIT ANTHRAX TO DELIVER CANCER CELLS
Bacillus anthracis
bacteria have very efficient machinery for injecting toxic proteins into cells,
leading to the potentially deadly infection known as anthrax. A team of MIT
researchers has now hijacked that delivery system for a different purpose:
administering cancer drugs.
"Anthrax toxin is
a professional at delivering large enzymes into cells," says Bradley
Pentelute, the Pfizer-Laubauch Career Development Assistant Professor of
Chemistry at MIT. "We wondered if we could render anthrax toxin nontoxic,
and use it as a platform to deliver antibody drugs into cells."
In a paper appearing
in the journal ChemBioChem, Pentelute and colleagues showed that
they could use this disarmed version of the anthrax toxin to deliver two
proteins known as antibody mimics, which can kill cancer cells by disrupting
specific proteins inside the cells. This is the first demonstration of
effective delivery of antibody mimics into cells, which could allow researchers
to develop new drugs for cancer and many other diseases, says Pentelute, the
senior author of the paper.
Hitching a ride
Antibodies -- natural
proteins the body produces to bind to foreign invaders -- are a rapidly growing
area of pharmaceutical development. Inspired by natural protein interactions,
scientists have designed new antibodies that can disrupt proteins such as the
HER2 receptor, found on the surfaces of some cancer cells. The resulting drug,
Herceptin, has been successfully used to treat breast tumors that overexpress
the HER2 receptor.
Several antibody drugs
have been developed to target other receptors found on cancer-cell surfaces.
However, the potential usefulness of this approach has been limited by the fact
that it is very difficult to get proteins inside cells. This means that many
potential targets have been "undruggable," Pentelute says.
"Crossing the
cell membrane is really challenging," he says. "One of the major
bottlenecks in biotechnology is that there really doesn't exist a universal
technology to deliver antibodies into cells."
For inspiration to
solve this problem, Pentelute and his colleagues turned to nature. Scientists
have been working for decades to understand how anthrax toxins get into cells;
recently researchers have started exploring the possibility of mimicking this
system to deliver small protein molecules as vaccines.
The anthrax toxin has
three major components. One is a protein called protective antigen (PA), which
binds to receptors called TEM8 and CMG2 that are found on most mammalian cells.
Once PA attaches to the cell, it forms a docking site for two anthrax proteins
called lethal factor (LF) and edema factor (EF). These proteins are pumped into
the cell through a narrow pore and disrupt cellular processes, often resulting
in the cell's death.
However, this system
can be made harmless by removing the sections of the LF and EF proteins that
are responsible for their toxic activities, leaving behind the sections that
allow the proteins to penetrate cells. The MIT team then replaced the toxic
regions with antibody mimics, allowing these cargo proteins to catch a ride
into cells through the PA channel.
'A prominent advance'
The antibody mimics
are based on protein scaffolds that are smaller than antibodies but still
maintain structural diversity and can be designed to target different proteins
inside a cell. In this study, the researchers successfully targeted several
proteins, including Bcr-Abl, which causes chronic myeloid leukemia; cancer
cells in which that protein was disrupted underwent programmed cell suicide.
The researchers also successfully blocked hRaf-1, a protein that is overactive
in many cancers.
"This work
represents a prominent advance in the drug-delivery field," says Jennifer
Cochran, an associate professor of bioengineering at Stanford University.
"Given the efficient protein delivery Pentelute and colleagues achieved
with this technology compared to a traditional cell-penetrating peptide,
studies to translate these findings to in vivo disease models will be highly
anticipated."
The MIT team is now
testing this approach to treat tumors in mice and is also working on ways to
deliver the antibodies to specific types of cells.
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