Medical Device Daily Contributing Writer

LONDON — Therapeutic genes wrapped in particles that automatically lodge inside tumors may offer a new generation of cancer therapies, a new study suggests.

Tests using mouse models of cancer showed that the genes contained in the particles, which were injected into the animals' blood vessels, were expressed solely in the animals' tumors.

In an earlier study, which used a different therapeutic gene but the same delivery system, tumors regressed completely in 80% of the animals.

Andreas Schatzlein, reader in cancer pharmacology at the School of Pharmacy of the University of London, told Medical Device Daily's sister publication, BioWorld International: "Our latest study shows that not only can gene therapy deliver genes to tumors at levels high enough to treat the tumors, but that this can be done in a highly specific way. Using these nanoparticles, we found we could get almost 100% of the therapeutic compound expressed in the tumor. This finding is quite unique."

Schatzlein and his colleagues, who were funded by Cancer Research UK, report their findings in a paper in the March 15 issue of Cancer Research titled: "Cancer-Specific Transgene Expression Mediated by Systemic Injection of Nanoparticles."

The group is now planning to begin Phase I trials in humans in a couple of years. The researchers hope that the treatment they are developing will be particularly helpful for people with cancers that cannot be removed surgically, because they are close to vital organs such as the brain or lungs.

Schatzlein's group has been working for many years on finding a way for gene therapy for cancer to fulfill its promise. "It is all about achieving the right balance between specificity and potency," he said. "If you use powerful genes but cannot control where they go, there is no improvement on current chemotherapy; but if you can control where the genes go, then you can use powerful molecules to kill the cancer cells, and avoid disturbing healthy cells."

Several years ago, they began to use a small star-shaped polymer called a dendrimer to enclose the therapeutic genes that they wanted to deliver to tumors. In 2005, they reported that they had fashioned dendrimer particles containing the gene for tumor necrosis factor alpha a powerful anti-cancer cytokine. When they injected these particles into a mouse model of cancer, all the animals responded and in 80 percent of them, the tumor completely regressed.

A subsequent study, where the scientists used the system to produce short interfering RNA molecules inside the cancer cells to treat the tumors, also had encouraging results.

The study reported in Cancer Research this month aimed to find out exactly where in the animals' bodies the genes were being expressed. For this investigation, Schatzlein and colleagues embarked on molecular imaging.

Instead of the genes they had used before, this time they used a reporter gene encoding a molecule called the human sodium/iodine symporter or NIS. The advantage of this gene is that, when it is expressed, it can accumulate a substrate, which may be, for example, radioactive iodine or technetium, which can be visualized.

"The striking observation from this study," Schatzlein said, "is that the expression only really occurs in the tumors, suggesting that the nanoparticles were highly selective for the tumors. We then went on to confirm this at the molecular level using real-time PCR."

It seems likely that this result is due to something called the enhanced permeability and retention (EPR) effect, whereby particles can pass through the blood vessels that supply tumors, which are more "leaky" than normal blood vessels, but not through normal veins and arteries.

Schatzlein added, "The EPR effect may be part of the explanation but I think we will have to dig deep in order to fully understand this phenomenon."

The team now wants to explore what might be the best genes to include in the dendrimer particles for clinical trials in humans. Although the NIS gene was used because it allowed the scientists to visualize where in the animals' bodies it was being expressed, this gene could also be used therapeutically: because it accumulates radioiodide, this in itself could act to kill the tumor.

(MDD Nanotechnology R&D Report 2009 reports on activity in the nanotechnology sector. For more information, call 800-688-2421 or 404-262-5476.)

No Comments