A new nanoparticle formulated to deliver a drug directly to the growing blood vessels that feed tumors may help circumvent the crippling side effects associated with chemotherapy. The technology, developed by researchers at Washington University in Saint Louis, is the latest innovation in the burgeoning field of targeted drug delivery for cancer treatment.
Several nanoparticle-based drugs are already approved to fight cancer, and many more are currently moving through human clinical trials. But these so-called “first generation” strategies tend to rely on passive or naturally occurring mechanisms to find their way to tumors. Recent efforts have focused on designing sophisticated, multifunctional nanodelivery systems that can be adapted for use with multiple drugs and multiple targets.
The Washington University group focused on a fungal drug called fumagillin, which stops angiogenesis–the formation of new blood vessels, a critical factor in tumor development–by blocking the proliferation of endothelial cells that line blood vessel walls. Fumagillin is a powerful chemotherapeutic agent, but the dose needed to successfully suppress tumors causes intolerable neurotoxic side effects. This is a pervasive problem in chemotherapy: drugs strong enough to kill tumors are also strong enough to damage healthy tissue, often rendering the treatment as dangerous as the disease.
To target fumagillin directly at the blood vessels that feed a growing tumor, researchers adopted a nanoparticle platform they had previously developed for imaging growing blood vessels. The nanoparticles, about 250 nanometers in diameter, have inert liquid centers and an oily surface laced with two kinds of molecules–one for targeting and another for imaging. The targeting molecule is designed to latch onto a protein found in high concentrations on the endothelial cells that line walls of new blood vessels, while the imaging molecule is a metallic substance that shows up on an MRI. To adapt the system for cancer treatment, they added fumagillin to the nanoparticles’ oily coatings.
When injected into the bloodstream, the nanoparticles remain intact, protecting healthy tissues from absorbing their toxic payload. But when they reach the blood vessels feeding a tumor, their targeting molecules lock onto the surfaces of proliferating endothelial cells. Once attached, the particles’ lipid coats fuse with the cells’ lipid membranes and deliver the drug and the imaging molecule. “It basically becomes a vehicle to dump off a truckload of cargo,” says Joseph DeSimone, professor of chemistry and chemical engineering at the University of North Carolina at Chapel Hill, who was not involved in the work.”It’s sort of like a Trojan horse.”
As they describe in a recent paper inThe FASEB Journal, the researchers used MRI to image the tumors in rabbits both before treatment and three hours after. They then dissected the tumors to confirm their size. Rabbits given the fully loaded nanoparticles–containing the targeting molecule, the imaging molecule, and the drug–fared the best. After treatment, their tumors were drastically smaller than those of rabbits given nanoparticles either without the targeting molecule or without fumagillin.
“I think it’s a very significant finding,” says Jolanta Kukowska-Latallo, research assistant professor of internal medicine at the University of Michigan and member of the Michigan Nanotechnology Institute for Medicine and Biological Sciences, who was not involved in the work.
By delivering their cargo directly to the tumor site, the nanoparticles allowed the researchers to lower the required dose of fumagillin by a factor of 1,000. None of the rabbits displayed any detectable neurotoxic side effects.
The tumors of treated rabbits were also permeated with more immune cells than those of the control rabbits. Patrick Winter, research assistant professor of medicine and biomedical engineering at Washington University and lead author of the study, says this may mean the body’s ability to recognize a tumor as foreign and mount an attack is somehow amplified by the treatment.
Because the formation of new blood vessels is an essential component of tumor growth, Winter believes his team’s approach will be highly adaptable. “A method to block angiogenesis should be very effective in a wide range of cancers,” he says.
By including an imaging molecule, the researchers were able to noninvasively create detailed three-dimensional maps of the tumors’ vasculature, a feat never before achieved. They hope this will allow them to track how tumor-feeding blood vessels respond to various treatments, and to better understand tumor vasculature in general.
In fact, nanoparticles strictly designed for imaging–loaded with the metallic compound but not with any drug—will be the first application of the new technology to be tested in humans. Winter anticipates human clinical trials will begin by the end of 2008. Clinical trials of drug-laden nanoparticles may be three to five years away.
The Washington University team is one of many groups investigating nanoparticle-based systems for treating and imaging cancer, which range from elaborate polymers to quantum dots and use a wide range of mechanisms to deliver their effects. While many of these second- generation nanoparticle approaches show great promise in animal models, none have yet progressed to human clinical trials. In many cases, the safety of the nanoparticles’ components has yet to be demonstrated. Winters believes his group’s approach may circumvent some of these safety concerns, as the liquid core of the new nanoparticles has been previously used in artificial blood. “The toxicology and distribution and elimination of these agents is already very well known,” he says. “And these agents have already been used in large-scale manufacturing processes.”
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