The story of cancer is almost as old as the story of humans. As far back into ancient times as the 15th century BCE in Egypt, physicians have struggled to offer their patients any sort of relief from slowly spreading tumors. If tumors were visible to the naked eye–on the skin, breasts, neck, etc–surgery was, as it is now, the best line of treatment. Short of that, there were changes in diet, bloodletting, and laxatives, none of which, unsurprisingly, worked very well. Things continued in this vein for the next few thousands of years, and cancer became more common following the Industrial Revolution and longer lives and sources of pollution that came with it.
However, as we get better at understanding what cancer is (a malignancy of uncontrolled cell growth) and what it is not (an imbalance in humor), we also get better at developing sophisticated treatments for it. We’ve told you about immunotherapies like CAR-T, checkpoint inhibitors, and cancer vaccines in the past that are approved or similar to approved therapies. We’ve discussed how doctors are constantly re-evaluating surgical intervention and chemotherapy to give their patients the best chance at survival. We’ve even discussed lifestyle changes that might help with cancer prevention. But this week, I’m going to tell you about something that’s much more theoretical, at this point. This particular treatment regimen is not in clinical trials, and if it does enter clinical trials, it would take approximately a decade to make it to the market, if it were approved. The approval rate for drugs that enter Phase 1 clinical trials is less than 10%. However, there is a reason to think that therapies like the one described today could be on the market one day, and every attempt at curing cancer helps us chip away a little more at the roadblocks ahead. So let’s go.
In a paper published in Nature at the end of May, researchers from Shanghai Jiao Tong University proposed using a nanoparticle that was capable of three-pronged anticancer activity for more efficient and robust treatment. Nanoparticles are ultra-small materials that are approximately 10,000-100,000x smaller than a single salt crystal. Some are made of metals like gold and silver, others are made of DNA, oils (lipids), or polymers. Their small size makes them attractive to scientists trying to get treatments to hard to reach places. Scientists can tune the size, shape, and electrical charge of nanoparticles and decorate them with molecules, called ligands, that are taken up by specific cells. These properties are designed so that nanoparticles injected into the body will accumulate in desired organs, or at sites of disease, like tumors. Drugs packaged as cargo within nanoparticles are delivered to the intended locations, with minimal exposure to the rest of the body. A few nanoparticle drugs are already being used to reduce side effects of toxic chemotherapy drugs. The scientists in this study added a new twist, making their particles triggered by light. These particular particles are made up of platinum (IV) and a large, ring-shaped molecule, called an upconversion nanoparticle, that absorbs low energy light and releases it as high energy light. This energy is used to power two cancer-killing mechanisms.
The first is the release of platinum (II), which is used to treat cancer right now in drugs like cisplatin, a common chemotherapy drug. When these particles interact with infrared light, the light converts the platinum (IV) to platinum (II), the cancer-killing kind. At the same time, the molecule holding the platinum to the upconversion nanoparticle, known simply as a linker, degrades to release oxygen into the tumor. This oxygen is necessary for the second main therapeutic action of these particles. While normal oxygen is not toxic, photosensitizing agents, like the upconversion nanoparticles, can transform wavelengths of light into energy that generates reactive oxygen species, which have cancer-killing properties. Using light to create reactive oxygen species is called photodynamic therapy.
Until this study, there has been one major problem with photodynamic therapy: tumors often lack oxygen, especially in their cores. Also known as hypoxia, low levels of oxygen occur when tumors outgrow the local blood supply. Low oxygen levels change the behavior of cancer cells and make them resistant to chemotherapies and photodynamic therapy. These nanoparticles circumvent that problem by producing oxygen themselves to feed the photodynamic therapy. In this way, these nanoparticles can attack cancer cells both with reactive oxygen and chemotherapy.
The biggest benefit of this particular type of therapy is that it requires targeted, specialized wavelengths of light for therapy to be activated. Because of this, the light beams can be aimed directly at the tumor, triggering the release of therapeutic agents only into the tumor, not into the rest of the body and systemic circulation. In this way, some side effects of current chemotherapeutic regimens can be avoided, as only the tumor is affected. Administering this therapy only three times to tumor-bearing mice resulted in tumor shrinkage and kept the tumors from recurring for nearly three weeks after the final treatment (remember, weeks are a much larger portion of a mouse’s life than a human’s!). This trend held strong in cervical cancer, triple negative breast cancer, melanoma, and colorectal cancer, although each of these tumors was formed just under the skin of the mouse, rather than in the sites they would be found in humans, so they are not the most accurate models. Photodynamic therapy has been done in more rigorous cancer models by other researchers though, so this is still an exciting result if it can be translated. Knowing that we can combine these therapies effectively is the first step to smarter, safer cancer treatment for the 21st century.
Xu, S., Zhu, X., Zhang, C., Huang, W., Zhou, Y., & Yan, D. (2018). Oxygen and Pt (II) self-generating conjugate for synergistic photo-chemo therapy of hypoxic tumor. Nature Communications, 9(1), 2053.
Featured Image: Photodynamic Therapy
Visible Light Spectrum. Modified from Wikipedia Commons image.
Tumor Hypoxia © NIH Image Gallery