Sep 28 2008
Researchers at the Center for Cancer Nanotechnology Excellence Focused on Therapy Response (CCNE-TR), based at Stanford University, have found a new way to target cancer cells while leaving healthy cells untouched.
The solution involves using single-walled carbon nanotubes as delivery vehicles. The new method has enabled the researchers to get a higher proportion of a given dose of medication into the tumor cells than is possible with the "free" drug-that is, the one not bound to nanotubes-thus reducing the amount of medication needed to be injected into a subject to achieve the desired therapeutic effect.
"That means you will also have less drug reaching the normal tissue," said Hongjie Dai, Ph.D., who leads a research team that is developing carbon nanotubes as drug and imaging agent delivery vehicles. He and his colleagues detail their latest results in the journal Cancer Research.
Dr. Dai and his colleagues worked with paclitaxel, a widely used cancer chemotherapy drug, which they employed against tumors cells of a type of breast cancer that were implanted under the skin of mice. They found that they were able to get up to 10 times as much paclitaxel into the tumor cells via the nanotubes as when the standard formulation of the drug, called Taxol®, was injected into the mice. The tumor cells were allowed to proliferate for about 2 weeks prior to being treated. After 22 days of treatment, tumors in the mice treated with the paclitaxel-bearing nanotubes were on average less than half the size of those in mice treated with Taxol®.
Critical to achieving those results were the size and surface structure of the nanotubes, which governed how they interacted with the walls of the blood vessels through which they circulated after being injected. Although a leaky blood vessel is rarely a good thing, in this instance, the relatively leaky walls of blood vessels in the tumor tissue provided openings that the nanotubes needed to slip into the tumor cells.
The researchers used nanotubes that they had coated with poly(ethylene glycol) (PEG). The PEG used was a form with three small branches sprouting from a central trunk. Stuffing the trunks into the linked hexagonal rings that make up the nanotubes created a visual effect that Dr. Dai described as looking like rolled-up chicken wire with feathers sticking out all over. The homespun-sounding appearance notwithstanding, the nanotubes proved to be highly effective delivery vehicles when the researchers attached the paclitaxel to the tips of the branches.
All blood vessel walls are slightly porous, but in healthy vessels, the pores are relatively small. By tinkering with the length of the nanotubes, the researchers were able to tailor the nanotubes so that they were too large to get through the holes in the walls of normal blood vessels but still small enough to easily slip through the larger holes in the relatively leaky blood vessels in the tumor tissue. That enabled the nanotubes to deliver their medicinal payload with tremendous efficiency.
Dr. Dai said that the technique holds potential for delivering a range of medications and that it may also be possible to develop ways to channel the nanotubes to their target even more precisely. "Right now, what we are doing is so-called 'passive targeting,' which is using the leaky vasculature of the tumor," he said. "But a more active targeting would be attaching a peptide or antibody to the nanotube drug, one that will bind more specifically to the tumor, which should further enhance the treatment efficacy."
In the meantime, fellow Stanford researcher Sanjiv Gambhir, M.D., Ph.D., also a member of the CCNE-TR, is using Dr. Dai's carbon nanotubes in conjunction with a relatively new type of tumor imaging agent. This work, which uses photoacoustic molecular imaging to spot the nanotubes, appears in the journal Nature Nanotechnology.
The researchers used "smart" targeted carbon nanotubes to home in on cancer cells in living mice. Once the nanotubes zeroed in, laser scans of the animals were conducted. The nanotubes absorbed the laser energy and released ultrasound waves that pinpointed tumor cell locations.
Photoacoustic molecular imaging is faster and less expensive than magnetic resonance imaging, the researchers said and, unlike a positron emission tomography-computerized tomography scan, requires no ionizing radiation. It can peer into the body to a depth of about 2 inches, which is useful for seeing in the breast or prostate. It also can be adapted to endoscopes to view internal organs and can pick up tiny early tumors not seen by any other way.
Photoacoustic imaging has been in development for 10 years but has been hard to harness for medical applications because it does not distinguish well between healthy tissue and tissue with early-stage disease. The study used carbon nanotubes coated with a peptide that recognizes a specific protein associated with tumors. Once these targeted nanotubes reach the tumor, their carbon cores show up in the photoacoustic molecular imaging scans since carbon nanotubes absorb light and convert it into sound.
Both of these studies were supported by the NCI Alliance for Nanotechnology in Cancer, a comprehensive initiative designed to accelerate the application of nanotechnology to the prevention, diagnosis, and treatment of cancer.
The drug delivery work is detailed in the paper "Drug Delivery With Carbon Nanotubes for In Vivo Cancer Treatment." An abstract of this paper is available through PubMed. View abstract
The work on photoacoustic imaging is detailed in the paper "Carbon Nanotubes as Photoacoustic Molecular Imaging Agents in Living Mice." An abstract of this paper is available through PubMed. View abstract.
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