May 12, 2008
The Evolution of a Tumor Engineer
Needham's synthetic fat globules smuggle drugs into a tumor
By Monte Basgall
David Needham was still a university undergraduate in 1973, majoring in industrial chemistry in Nottingham, England, when he got the jolting news that his mother Audrey had breast cancer.
Rushing to a small hospital near his home town of Oldham near Manchester, UK, the future Pratt School of Engineering professor joined his father and brother to wait for his “mum” to have a total mastectomy.
Afterwards, jarring memories of how cancer treatment had affected her haunted him as he went through a Ph.D. program in physical chemistry at the University of Nottingham.
Needham had planned to work in the chemical industry, but he also began attending lectures on how tumors start. Thus began an odyssey that transformed him into a materials scientist and engineer who draws his inspiration from biology.
This marriage of engineering and biology has helped Needham design and perfect an artificial capsule much smaller than a cell that can carry loads of a powerful anticancer drug through the bloodstream, then dump the drug directly on tumor tissues and their supporting blood vessels. They are known as “liposomes,” drug-filled spheres that mimic natural fatty structures within cells. (See Sidebar)
Though it has been a longer road than he might have expected at age 20, Needham's search for a better cancer therapy has entered the clinical trial phase. Celsion Corp., of Columbia, MD has acquired the rights from Duke to market Needham's liposome in drug preparations and has begun clinical tests in human breast and liver cancers.
Coming to Duke from the University of Cambridge, UK and the University of British Columbia in Vancouver Needham has been collaborating on liposomes with Mark Dewhirst, a Duke Medical Center professor of radiation oncology and pathology.
Together they've sought to make liposomes into nano-scale Trojan horses to destroy tumor cells very specifically. Only one hundredth a red blood cell's size, these capsules would be small enough to reach tumor sites by cruising through blood vessels.
To kill tumors selectively, liposomes must be able to dodge destruction by a patient’s own immune system and be accepted by the body, even “invited in”. They also must respond to some sort of cue to release their life-saving drugs in exactly the right spots, rather than leaking them prematurely. (See a Windows Media video animation created by Celsion Corp. )
When Needham came to Duke, liposomes were already a hot idea in the scientific world but far from delivering their promise despite thousands of research papers, several start-up companies and millions of investment dollars. “People started to put drugs into them in 1972, but they never got the drugs back out in sufficient quantities at the disease sites,” Needham recalls.
Dewhirst, who heads a program at Duke that uses focused microwave and radiowave energy to gently heat tumor sites for enhancing the effects of conventional chemotherapy and radiotherapy, proposed using heat as an appropriate trigger. The technique is called hyperthermia. (Duke Hyperthermia Treatment Program)
Working with Dewhirst's group, Needham set about developing a liposome that would evade the body's immune defenses and then quickly dump all its cargo upon entering the hyperthermic zone.
David Needham, standing, and Mark Dewhirst. (Duke Photography)A March, 2000 paper in the journal Cancer Research co-authored by Needham and Dewhirst reported that malignant human tumors implanted into mice regressed completely within about 12 days when treated with a new experimental liposome carrying the anti-cancer drug doxorubicin. Moreover, most of those tumors did not re-grow during the 60 days of that trial.
"It's pretty unusual to see something work that well," Dewhirst said at the time. Needham’s liposome design received its first patent in 2001.
Pratt School biomedical engineering associate professor Fan Yuan has been a key collaborator on the project by painstakingly tracing the movements of drugs and liposomes in the heated tumors of rodents.
Because the liposomes' diameters are too small to see with an optical microscope, Yuan has to "tag" the tiny capsules with a special dye to make them glow in ultraviolet light.
"We cannot actually see them, but wherever we see the glow we know a liposome is there," Yuan says. "It's just like not being able to actually 'see' a star but still seeing the light from that star."
Yuan has found that while the sudden drug deluge affects all cells in the vicinity, cells lining the blood vessels that supply the tumors receive the greatest impact. "The drugs killed all the cells that formed the blood vessels, and that shut down the blood flow," Yuan says.
"Once the drug shuts down the blood flow, then the nutrient supply to the tumor stops," he adds. "So the tumor shrinks."
Even as he continues engineering new heat-triggered liposomes for testing on other forms of cancer, Needham has taken on another mission: showing undergraduates and graduate students the value of using biology as a model for engineering useful innovations.
And his mother Audrey? She's 77 and doing just fine now. "In fact she has been busy knitting chickens and selling them for £1:50 to help raise money to build Europe's first breast cancer prevention center in Manchester," he beams proudly.
Monte Basgall is senior science writer in Duke's Office Of News And Communication.