Every year, more than 18 million people around the world are told, “You have cancer.” In the U.S., nearly half of all men and more than one-third of women will develop some kind of cancer during their lifetimes, and 600,000-plus die from it annually. Despite the billions of dollars and countless new treatments that have been thrown at it since President Richard M. Nixon declared “war” on the disease in 1971, cancer refuses to be beaten.
Why does it remain such a formidable foe? After all, it’s been known since Nixon’s day that unrepaired genetic damage can cause cells to grow uncontrollably, which is viewed as cancer’s root cause. But this understanding has not pointed the way to an obvious treatment. Research into cancer biology has revealed it to be one of the most complex and insidious human diseases for a variety of reasons.
First, cancer can be caused by any number of factors, from viral infections to exposure to carcinogenic chemicals to simple bad genetic luck. One patient’s lung cancer might be caused by an entirely different constellation of mutations than another’s, and a drug that targets a certain mutational profile benefits only a subset of patients. Furthermore, cancer cells often spontaneously develop new mutations, limiting the effectiveness of genetically targeted drugs.
Second, cancer is caused by malfunction of the body’s own cells, so it is hard to design drugs that will target only cancerous cells while sparing healthy ones.
Third, while genetic mutations can drive cancer formation, cancers can stop growing and remain dormant for years, suggesting that there are more factors at play than gene mutation alone.
And finally, cancer has a number of different “tricks” that allow it to hide from the body’s highly vigilant immune system, letting it grow undetected and unchecked until, often, it is too late.
Cancer treatment regimens through the 19th and 20th centuries were largely limited to an aggressive triumvirate of surgery, radiation, and chemotherapy, all of which carry traumatic side effects and can bring patients to the brink of death in the name of saving their lives. As our knowledge of the disease has grown more nuanced over the decades, a paradigm shift has happened in the field, centered on the recognition that attacking a complex disease with blunt tools is not the most effective approach. A surge of new therapeutic strategies — including immunotherapy, nanotechnology, and personalized medicine — is giving hope to patients for whom traditional treatments have failed and offering the potential of long-lasting cures.
Scientists at the Wyss Institute for Biologically Inspired Engineering with expertise in fields ranging from molecular cell biology and immunology to materials science, chemical engineering, mechanobiology, and DNA origami are at the forefront of several of these novel approaches. Their research, united by the common principle of emulating nature, has the potential to make existing treatments better, create new ones, and even prevent cancer from starting in the first place.
Better drug delivery is in our blood
Chemotherapy has been the backbone of cancer treatment for the past half-century, because it infuses drugs into the bloodstream to kill rapidly dividing cancer cells all through the body. However, since chemotherapy systemically targets all fast-growing cells, it can also damage the intestines, bone marrow, skin, hair, and other parts of the body, and in some cases must be given at such a high dose that it nearly kills the patient in the course of treatment. Efforts to make chemotherapy drugs less toxic have included encapsulating them in nanoparticles that release them only when they reach their intended location, but less than 1 percent of nanoparticle-encapsulated drugs actually reach their targets, as the human liver and spleen aggressively filter them out of the blood.
Samir Mitragotri, a core faculty member at the Wyss Institute, decided to apply chemical engineering to the problem of keeping drugs in the bloodstream long enough to do their jobs. The first thing he faced was that red and white blood cells circulate through the blood several times a day, seemingly escaping detection and destruction by the liver and spleen.
“I thought, ‘If these cells are naturally not cleared from the bloodstream, maybe we can use them to help the nanoparticles stay there as well, rather than creating some new and expensive disguise to protect the nanoparticles,’” said Mitragotri, the Hiller Professor of Bioengineering and Hansjörg Wyss Professor of Biologically Inspired Engineering at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS).
Mitragotri’s lab found that nanoparticles attached to red blood cells are indeed ignored by the liver and spleen in mice, and the nanoparticles are sheared off and deposited into tissues when the blood cells make the particularly tight squeeze through the tiny capillaries that deliver blood to organs. By injecting blood-cell-bound nanoparticles into a blood vessel directly upstream of whole human lungs, the researchers were able to get 41 percent of them to accumulate in the lung tissue — a far cry above the usual 1 percent.
“Simply by changing which blood vessel we inject the nanoparticles into, we can deliver a much higher dose of a drug to its intended organ, and rely on the body’s natural clearing mechanism to get rid of any particles that don’t reach the target. We can even get some nanoparticles to target the brain,” Mitragotri said.
Despite its bad reputation, chemotherapy is unlikely to be going anywhere soon, as research has found that new therapies work best when given in combination with chemotherapy. But technologies such as blood-cell-bound nanoparticles could help reduce the dose that must be administered and increase chemotherapy’s efficacy, improving the quality of life for cancer patients worldwide.