Molecular bioengineer K. Dane Wittrup is designing cancer-fighting drugs that he hopes will annihilate enemy cells like guided missiles.
Wittrup, C. P. Dubbs Professor of Chemical Engineering and Biological Engineering, is developing a class of drugs inspired by the immune system’s own disease-fighting antigens that target colon, lung, and breast cancers. He wants to make molecules that bind to cancer cells with as much precision as those made by the body that latch on to viruses, bacteria, and other enemy invaders.
When Nobel Prize-winning immunologist Paul Ehrlich first proposed “magic bullets” at the beginning of the 20th century, he pictured a drug carrier injected into the body that transports itself to a target such as a tumor or pathogen and destroys it while leaving healthy cells unscathed. This dream has recently been pursued by attempting to target tiny nanotech devices for delivery of drugs to tumor cells with bulls-eye precision.
“I wish it were so simple,” says Wittrup, associate director of the Koch Institute for Integrative Cancer Research. Wittrup has become convinced that antibody-like drugs and nanodevices are often more like sea mines than guided missiles. They float through the bloodstream, wiping out enemy cells only if they manage to survive the body’s natural defense system against particles and then passively wash up against their target.
“If the analogy is that nanoparticles are like little bombs, they can be equipped with a proximity fuse, but not a guidance system,” he says. “It’s not that nanoparticles don’t work — it’s that they don’t necessarily work in the way we hoped they might.”
Five years ago, Wittrup set out to understand why some engineered antibody fragments were not localizing into tumors in mice as well as expected. He turned to mathematical models to help quantify how magic bullet drugs could be designed to fulfill their creators’ — and Ehrlich’s — futuristic vision.
KEY DETERMINANT
Wittrup, who discovers new biopharmaceuticals through protein-engineering technology, designed a freely available Web-based tool that helps researchers determine how efficiently their drug- or poison-toting nanoparticles will deliver their payloads to target cells. He has found that size is a key determinant of success.
Wittrup started his career as a chemical engineer, manipulating cells to churn out pharmaceuticals more effectively. He eventually launched his own drug-development lab and was recruited in 1999 by MIT, where he joined bioengineers, nanotechnologists, mechanical engineers, and biologists working to identify the most promising drug targets, the most promising materials for nanoparticles — and, his own holy grail — what drives how many molecules or particles end up inside cells to play their “magic bullet” roles.
The convoluted, leaky blood vessels feeding many types of tumors are a perfect means for nanoparticles and antibodies to diffuse out of the bloodstream and reach cancer cells. They bind to a tumor’s surface and destroy it through three possible mechanisms: signaling the body’s immune system that this cell is an enemy target; interrupting an inappropriate growth signal on the cell surface; or delivering a poison drug or a tiny dose of radiation to the outside of the cell. Ideally, two or more of these tactics would come into play at once.
Wittrup’s model, based on published measurements of the transport of nanoparticles and molecules of varying sizes, predicts that nanoparticles smaller than 50 nanometers — 100,000 times smaller than the period at the end of this sentence — will accumulate specifically in tumors if you attach a binding site to them. For larger nanoparticles, simply floating randomly in the bloodstream and occasionally hitting a target is the modus operandi.
This knowledge may influence how researchers design improved nanotherapies, he says, leading to more effective drugs in early-stage experiments to human clinical trials.
ARSENIC DRUG
Wittrup finds it ironic that Ehrlich’s best-known magic bullet was a drug made of poisonous arsenic. Arsphenamine, the first effective treatment for syphilis, had toxic side effects and was alleged to have killed 275 patients. Wittrup hopes his work will lead to failsafe drugs that annihilate cancerous tumors while minimizing side effects.
Understanding how drugs work inside the body, Wittrup says, may make them less “magic” and more predictably effective. Thanks to such developments, Wittrup says, “I have no doubt that 20 years from now, cancer will be a manageable disease rather than a death sentence.”