Nanoparticles for two-photon photodynamic therapy in living cells

Photodynamic therapy (PDT) uses a combination of ultraviolet or visible light and a light-sensitive chemical, or photosensitizer, to kill cancer cells using reactive oxygen.

PDT has become an important option for treating or relieving the symptoms of esophageal cancer and non-small cell lung cancer, but its wider use in cancer therapy is limited by a number of factors, including the toxicity of the photosensitizer dyes. But now, using a biocompatible polymer nanoparticle, researchers at the University of Michigan have developed a nontoxic photodynamic dye that appears to be particularly lethal to brain cancer cells.

The leader of the team that conducted this work, Raoul Kopelman, Ph.D., was one of the first investigators to study nanoparticles for use in cancer therapy as part of the National Cancer Institute's Unconventional Innovations Program. The success of this nanotechnology pilot program played an important role in the NCI's decision to establish the Alliance for Nanotechnology in Cancer. Kopelman and his colleagues published this latest work in the journal Nano Letters.

In creating their PDT nanoparticle, the Michigan investigators chose as the photosensitizer a commercially available dye that can simultaneously absorb two low-energy, near-infrared photons and use the combined energy to produce a highly reactive form of oxygen known as singlet oxygen. Singlet oxygen is exceedingly toxic to cells, so for PDT to be successful, investigators need to develop methods that limit exposure of healthy cells to the PDT dyes. Nanoparticles, it turns out, appear to be an ideal vehicle for doing just that.

The investigators constructed their nanoparticle using polyacrylamide, a widely used, inert and biocompatible polymer. Nanoparticles made of this polymer do not clump together and have the ability to shed proteins that stick to many other types of polymers. This polymer is also stable in biological fluids and tests showed that nanoparticles made with this polymer did not release any of the PDT dye into solution. In fact, cells exposed to massive levels of dye-loaded nanoparticles showed no toxic effects in the absence of light.

However, toxicity was readily apparent when glioma cells were exposed to the dye-loaded nanoparticles and then irradiated with near-infrared light for 30 seconds. Cellular damage was notable within 10 minutes of light exposure in the cells treated with PDT nanoparticles. Cells began dying within 30 minutes and most were dead within 120 minutes after treatment.

The researchers note that they are now developing a second generation PDT nanoparticle coated with tumor-targeting molecules.

This work, which was supported by the National Cancer Institute's Unconventional Innovations Program, is detailed in a paper titled, "Nanoparticles for two-photon photodynamic therapy in living cells." This paper was published online in advance of print publication. An abstract is available at the journal's website. View abstract.