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Posted: Feb 11, 2008

Nanoparticle self-lighting photodynamic therapy for deep cancer treatment

(Nanowerk Spotlight) Photodynamic therapy (PDT) is a cancer treatment that combines a chemical compound, called a photosensitizer, with a particular type of light to kill cancer cells. The treatment works like this: the photosensitizing agent is injected into the bloodstream. The agent is absorbed by cells all over the body, but stays in cancer cells longer than it does in normal cells. One to three days after injection, when most of the agent has left normal cells but remains in cancer cells, the tumor is exposed to light. The photosensitizer in the tumor absorbs the light and produces an active form of oxygen (singlet oxygen) that destroys nearby cancer cells. PDT has been used for the past 30 years and is a treatment that works. PDT takes very little time, is often done as an outpatient, can be accurately targeted to the affected area, can be repeated, and has no long-term side effects. It also isn't as expensive or invasive as some other cancer treatment options. The limitation of this form of cancer treatment is that the light needed to activate most photosensitizers cannot pass through more than one centimeter of tissue. For this reason, PDT is usually used to treat tumors on or just under the skin or on the lining of internal organs or cavities. PDT is also less effective in treating large or deep tumors, because the light cannot pass far into these tumors. Researchers have now proposed a new PDT system in which the light is generated by x-ray scintillation nanoparticles with attached photosensitizers. When the nanoparticle-photosensitizer conjugates are targeted to tumors and stimulated by x-rays during radiotherapy, the particles generate visible light that can activate the photosensitizers for photodynamic therapy. Therefore, the radiation and photodynamic therapies are combined and occur simultaneously, and the tumor destruction can be more efficient. More importantly, it can be used for deep tumor treatment as x-rays can penetrate through tissue.
"I have been working on nanotechnologies for 15 years" Dr. Wei Chen tells Nanowerk. "My original work was trying to use quantum dots for in vivo imaging. I was facing the challenge of light penetration. I also have experience with the design and synthesis scintillation nanoparticles. I knew light delivery was also a challenging issue for PDT, just like in vivo optical imaging. Then, I came up with the idea to combine photodynamic therapy with radiation therapy through scintillation nanoparticles for deep cancer treatment."
Chen, an assistant professor of Nano-Bio Physics at the University of Texas at Arlington, points out that photodynamic therapy is not new, and radiation therapy is not new; but the combination of both through scintillation nanoparticles is new and potentially important for deep cancer treatment. He introduced the concept in a paper in the Journal of Nanoscience and Nanotechnology in April 2006 ("Using Nanoparticles to Enable Simultaneous Radiation and Photodynamic Therapies for Cancer Treatment").
nanoparticle–porphyrin conjugates for X-ray stimulated photodynamic therapy for cancer treatment
A schematic illustration of nanoparticle–porphyrin conjugates for X-ray stimulated photodynamic therapy for cancer treatment. Annexin V is a molecule that can target some specific antigens at tumor cells. (Image: Dr. Chen, University of Texas at Arlington)
Although PDT has been widely used for skin cancer treatment, its application for deep cancer treatment is still a challenging issue because the light for PDT activation cannot penetrate deep into the tissue. To solve this problem, Chen and his collaborators propose a new PDT system in which the light is generated by scintillation luminescence nanoparticles (such as X-ray luminescence nanoparticles) with the attached photosensitizers.
Chen explains that, when the nanoparticle-photosensitizer conjugates are targeted to a tumor and stimulated by X-ray or other radiation sources during radiation therapy, the particles will generate light (energy) to activate the photosensitizers. With this novel therapeutic approach, no external light is necessary to activate the photosensitizing agent within tumors. Tissue thickness therefore would no longer be a limiting issue for PDT.
"Effectively, the radiation and photodynamic therapies are combined and occur simultaneously, and the tumor destruction will be more effective" he says. "More importantly, it can be used for deep tumor treatment as X-ray can penetrate deep into the tissue. No external light is necessary to deliver to the tumor and only an extremely low dose of radiation is needed for the treatment. Therefore, this provides a simple but more efficient modality for cancer treatment. We called this new modality Nanoparticle Self-Lighting Photodynamic Therapy."
Working with Chen's group are Dr. Shaopeng Wang and Dr. Yuanfang Liu, senior research scientists at ICx/Nomadics Inc.; Dr. Alan G. Joly, an optical physicist and a senior scientist at Pacific Northwest National Laboratory; and Dr. Carey Pope, Regents Professor And Head Sitlington Chair In Toxicology at the Center for Veterinary Health Sciences, Oklahoma State University.
The researchers reported their findings in a recent paper published in the January 29, 2008 online edition of Applied Physics Letters ("Investigation of water-soluble x-ray luminescence nanoparticles for photodynamic activation").
Their pilot studies indicate that water-soluble scintillation nanoparticles (the particle size in the study was about 15 nm) can potentially be used to activate photodynamic therapy as a promising deep cancer treatment modality.
For practical applications, the nanoparticle-porphyrin conjugates must be delivered to the tumor cells in vehicles such as antibodies, peptides, liposomes or other functional molecules. In designing the delivery vehicles one needs to consider how they will affect the quantum yield of singlet oxygen. Chen and his team used folic acid to target folate receptors at tumor cells. Their results indicate that folic acid has no effect on the quantum yield of singlet oxygen production in the nanoparticle conjugates, making this system practical for photodynamic activation applications.
Initial results of the studies have been promising. But before Nanoparticle Self-Lighting Photodynamic Therapy becomes a clinical reality, the researchers must overcome two main challenges: 1) they need to develop a class of water-soluble scintillation nanoparticles with very high quantum efficiencies of X-ray luminescence, and 2) they need to improve the targeting capabilities of the nanoparticle- photosensitizer compound – but this is a challenge for all drug-based cancer treatments.
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