Medical Device Daily National Editor

Nanoparticles have long been considered a potential vehicle for drug therapy. Arm these little guerilla fighters with a drug and send them off into the body to do battle.

But of course, there are some major problems with this strategy, two in particular: getting them to the actual site of the battle, and then keeping them from delivering "friendly fire," you might say – killing the healthy cells, not just the evildoers.

Chun Li, PhD, and his collaborating researchers believe they have taken a big step in achieving both goals, and doing so in attacking a particularly difficult problem, the skin cancer known as melanoma.

Li, a professor at the University of Texas M.D. Anderson Cancer Center (Houston), told Medical Device Daily that a serious barrier for the use of developments nanoparticles in the body is that the immune system identifies these substances as foreign threats and sends them to the liver and spleen for destruction.

To solve this part of the problem, Li's collaborator, Jim Zhang, PhD, a professor in the department of chemistry at the University of California-Santa Cruz, developed an elegant targeting technique.

Zhang has created hollow gold nanoparticles 40 to 50 nanometers in diameter, capable of penetrating into the vasculature of a tumor. Li loads these with short-molecule peptides that are so engineered that they are "tuned" to the cells of a tumor and take the particles past the body's various physiological barriers to the tumor cite.

There, the researchers solve the second of the two targeting problems.

Li uses infrared light to heat the gold nanoparticles which are attached to the tumor cells, destroying only those cells, not the surrounding "friendlies," that is, the healthy cells.

"Active targeting of nanoparticles to tumors," Li said, "is the Holy Grail of therapeutic nanotechnology for cancer," adding that this research takes a step closer to that goal.

He told MDD that the approach in this research can be compared to phototherapy in which light is used to turn on the active ingredient of a prodrug.

In this case, by contrast, the infrared light heats the gold particles to perform what is called photothermal ablation.

Li, Zhang and colleagues used the treatment on live lab mice.

When they irradiated the mice with the near infrared light, those that had been injected with targeted nanospheres had nearly 66% of their tumors destroyed. This compared with only 7.9% tumor destruction in the mice that had only been injected with untargeted nanospheres.

The researchers were able to measure the tumors by using tagged glucose (F-18-labelled). This shows up on a PET scan. Tumors treated with targeted nanospheres did not light up very much, showing there was little metabolized tagged glucose in them.

The procedure involved injecting the nanosphere materials into the bloodstream, a systemic approach – which Li said is a different than the usual method of attempting to inject a therapeutic around the tumor itself.

"Our major contribution," Li said, "is to figure out what are the optimum properties or characteristics of this material to target the tumor site. There are many biological barriers, in addition to liver and spleen ... to be able to go through blood vessels.

He called the peptides loaded on to the gold particles "a short-chain version of a protein, much smaller than a protein," with the length of the protein being key to its ability to reach the target. These peptides would bind only to the melanocortin type 1 receptor, which is overly abundant in melanoma cells.

Using fluorescent tagging on the nanosphere particles, the researchers found that they were drawn right into the cells through the cell membrane while the untargeted gold particles were not.

In live mice, fluorescent tagging showed that the untargeted nanospheres gathered only near the tumor's blood vessels, whereas the targeted ones penetrated into the tumor and were found spread around inside it.

Then the infra-red light was used to irradiate and heat the gold nanospheres and thus literally "cooking" the tumor cells, Li said.

The researchers reported that the actively targeted gold nanospheres did more than eight times more damage to the melanoma tumors than the same nanospheres that were not actively targeted. He noted also that because the gold nanosphers provided a way to focus the infrared light, a much-reduced dose of light could be used, further sparing healthy tissues.

Irradiation with near-infrared light alone, or treatment with nanospheres alone without light, had no effect on the cells.

Li noted that melanomas are not easy to treat in this way because it is so difficult to get the targeted particles to differentiate between healthy and cancerous tissue.

Li told MDD that in this first use of the technique, it shows most promise for treatment of skin cancers and other topical and localized cancers. But he said that the research provides proof of principle for treating other cancers as well, for instance with the use of fiber-optic delivery of the infrared light to cancers within in the body.

He added: "Receptors common to other cancers can also be targeted by a peptide-guided hollow gold nanosphere. We've also shown that non-invasive PET can monitor early response to treatment." Li said that before "talking to the doctors" about the method, the research will next determine safety, and look for potential toxicities.

The study – appearing in the Feb. 1 issue of Clinical Cancer Research – was financed by the National Cancer Institute's Alliance for Nanotechnology in Cancer, the John S. Dunn Foundation (Houston), and the U.S. Department of Defense.

No Comments