Free oxygen radicals, also known as reactive oxygen species or just “free radicals”, are often thought of as dangerous chemicals that need to be neutralized by antioxidants to avoid harm to our cells. Usually this is spot on – reactive oxygen species are unstable oxygen-containing compounds that can react chemically with a variety of essential molecules within our bodies, including DNA, causing permanent damage. However, an exciting technology called photodynamic therapy can transform these reactive oxygen species into invaluable tools to treat a variety of conditions, from acne to psoriasis, and, within the last few decades, certain types of cancer.
Photodynamic therapy, or PDT, requires a light reactive molecule, called a photosensitizer, which uses the energy of light to start reactions that create reactive oxygen species. When a photosensitizer is introduced into a cancerous tumor and stimulated with light, the high concentrations of oxygen radicals produced wreak havoc on the diseased tissue, not only killing the cancer cells themselves but also making the tumor a clear target for the immune system. Cancer uses a variety of molecular tricks to avoid notice by immune cells, but by destroying some of the cancer cells, PDT can create inflammation within the tumor, which can in turn activate a cancer-specific immune response and help the body to clear out the remaining cancerous cells.
Unfortunately, current PDT technology is far from perfect for cancer treatment. Many photosensitizers are either not efficient at generating reactive oxygen species, or are themselves toxic to surrounding tissues. In a series of papers published in the Journal of the American Chemical Society, Wenbin Lin, PhD, professor of chemistry, and his lab have demonstrated that using photosensitizers as building blocks for intricate nanoscale structures improves PDT in both head and neck and colon cancer mouse models. These structures, known as metal organic frameworks (MOFs), are composed of organic molecules and metal atoms arranged in repeating units to create a lattice. MOFs have a variety of applications within chemistry laboratories, most commonly gas storage, but the Lin group is pioneering in generating nanoscale MOFs as PDT reagents.
“MOFs are molecular materials that you can fine tune any way you want. For use in medicine, you have to be able to finesse the material for specific function and compatibility with a biological system,” Lin said.
Using frameworks with immunotherapy
In the latest paper, the group has taken that fine tuning even further by generating a MOF with particularly wide pores within the lattice. They then load these pores with a drug known as an IDO inhibitor that promotes the activation of the immune system. The IDO inhibitor is part of a treatment called checkpoint blockade therapy, which promotes an immune response to cancer cells by blocking the immunosuppressive signals present within the tumor. The Lin group found that by combining PDT and checkpoint blockade therapy, treated mice rejected not only the tumor that was targeted directly by PDT, but also an untreated tumor on the other side of the body.
“It is well known that PDT can create an inflammatory tumor environment, and that checkpoint blockade therapy works very well in an inflamed tumor environment; the two together can be immunogenic,” Lin said. “The thing is that the IDO inhibitor doesn’t work well by itself, but by putting it in a MOF it can be much more effective. And PDT alone doesn’t result in the rejection of distant tumors – it only works for the injected tumors.”
The destruction of an untreated tumor after localized treatment elsewhere in the body, known as the abscopal effect, is a rare but highly sought after phenomenon that is not entirely understood. It is thought to be related to immune activation, and the Lin group’s results align neatly with this hypothesis. By including an immune stimulatory drug, they see an abscopal effect not brought on by PDT alone.
When asked about this finding, Kuangda Lu, PhD, the first author on the paper, said, “We had actually planned for that effect. We couldn’t be one hundred percent sure that we would see it, but we had expected to see it based on the way we designed the treatment. Although we did expect it, it was very exciting to see it work.”
Lu, whose work as a graduate student was instrumental in all three papers and wrote his dissertation on this project, plans to continue working with Lin on further improving the MOFs for PDT cancer treatment. In fact, he and others in the Lin group just submitted another paper detailing the next step for this technology overcoming one of the biggest flaws in PDT: the limited penetration of visible light into tissue. For this reason, PDT as it is now can only be used for tumors very close to the surface of the skin. By using higher energy radiation that can pass much further through tissue, such as X-rays, to target cancer deeper within the body, the Lin group hopes to eventually use MOF mediated PDT to treat a wide range of solid tumors. Lin hopes to begin clinical trials by next year.
The Lin group’s exploration of new cancer treatments is not limited to MOFs, however. In a recent paper published in Nature Communications, the group describes a related project that employs nanoparticles instead of MOFs as a delivery system for two compounds: a photosensitizer and oxaliplatin, a traditional chemotherapy drug. By adding a checkpoint blockade therapy drug into the mix, the group saw potent anti-tumor immune responses in both treated and untreated tumors and clearance of the cancerous cells. Taken together, the results of the MOF and nanoparticle studies demonstrate the power of combination therapy for combating cancer using two innovative drug delivery technologies.
Additional authors on the paper include Chunbai He, Nining Guo, Christina Chan, Kaiyuan Ni, and Ralph Weichselbaum.