Photodynamic therapy (PDT) is not a new innovation in the medical space. Early forms of the technique have been in use since the early 20th century to treat skin carcinoma and other dermatological conditions, having been developed by early pioneers such as Hermann von Tappeiner and Niels Ryberg Finsen.
In modern oncology, PDT has been used for more than a decade to treat certain cases of oesophageal cancer and non-small cell lung cancer.
Photodynamic therapy: the past and present
In cancer therapy, PDT uses photosensitising agents such as porfimer sodium, which when injected into the blood stream are absorbed by cells. As the agents tend to remain in cancer cells longer than they do in healthy cells, they can have enough specificity to target tumours while leaving unaffected tissue largely unscathed.
Photosensitisers are activated by different wavelengths of light depending on their type, so once tumour cells have absorbed the agent, they are exposed to light of the corresponding wavelength. This creates a biochemical reaction in the photosensitising agents, which then produce an active form of oxygen that kills nearby cancer cells. As well as its direct cytotoxic effects, PDT has been shown to damage tumour blood vessels to effectively starve cancer cells, as well as potentially signalling the immune system to attack in the right area.
PDT marks an interesting crossover point between pharmaceutical intervention and medical technology, as the photosensitising drugs and the devices delivering light to the target areas rely on each other to be effective.
This type of therapy might not be new, but as the research community’s understanding of photobiology deepens, new and refined approaches to PDT and other light-based therapies are emerging, and look set to expand the role of various light wavelengths in modern medical treatment. Data from Persistence Market Research (PMR) suggests the PDT market will reach a value of $1.2bn in 2019, and projects that the market will grow with a compound annual growth rate of 6.2% up to 2029.
“The growing availability of FDA-approved photosensitizer drugs and laser systems is contributing to the increased adoption of novel and innovative technologies to treat various conditions of dermatology, ophthalmology, and oncology,” PMR noted in a recent press release.
“This is an area that does not receive a lot of attention but has a lot of potential, particularly for infectious disease and cancer therapies,” says Dr Jordan Feld, University of Toronto associate professor of medicine and senior scientist at the Toronto General Hospital Research Institute (TGRI).
Shedding new light on lung transplants
Feld and a research team, including University of Toronto surgical colleagues Dr Marcos Galasso and Dr Marcelo Cypel, represent one of the research centres expanding the applications of PDT and other light-based approaches. Their project, the results of which were recently published in Nature Communications, made use of PDT and another therapy based on ultraviolet C (UVC) to sterilise lungs infected with hepatitis C virus (HVC) during ex-vivo lung perfusion, potentially adding hundreds of safe lungs to a donor pool that urgently needs them.
Ex-vivo lung perfusion (EVLP) is a relatively new method of preserving donor lungs. The technique involves connecting lungs to a pump outside the body and perfusing them with oxygenated solution to keep them alive and healthy. One of the benefits of this technique is the opportunity it affords to intervene and improve their quality before transplant. The Toronto team’s light-based experimental therapies are a sophisticated method of doing just that.
“We added ultraviolet C (UVC) light to the perfusion circuit so that as the virus passed through the circuit, it was exposed to UVC light for the full six hours of perfusion,” says Feld. “In our model system, this makes the virus completely non-infectious and entirely prevents transmission.”
To conduct the research, the team built a customised light device (patent pending) designed to integrate with the EVLP circuitry. An inner hollow quartz tube houses the light source – either a UVC lamp or custom LED light – and an outer PVC tube seals the device and prevents light leakage.
While UVC exposure has proven effective at preventing sterilising the hepatitis C virus that it can reach, one issue – and it’s a common problem for light-based therapies – was that the UVC light could not penetrate into the lungs, potentially leaving residual HVC that has not been exposed to the light.
“This unexposed virus may still be infectious,” Feld says. “As a result, the second approach we evaluated was using photodynamic therapy with [photosensitising agent] methylene blue. Methylene blue is activated by red light, which damages the virus and also makes it non-infectious. The advantage of methylene blue is that it permeates the entire organ – turning it a nice blue colour – during the ex-vivo perfusion. As a result, it is likely more effective at inactivating all of the HCV, both in and outside of the lungs. However, because it goes into the organ, we have had to do additional safety studies to make sure that exposure to activated methylene blue is not harmful to the lungs.”
The team is already running an early clinical trial of the UVC device, and Feld says the results look “promising”. With some additional safety data, Feld and his colleagues are also aiming to trial the methylene blue PDT method soon. The technique could be applied to other organs, and the team has run experiments on light-based treatment of kidneys during cold perfusion, and is considering others. But in the donor lung space alone, the ability to make use of sterilised HCV-infected lungs for transplants could have an impressive impact on organ availability.
“Our estimates suggest that using HCV-infected donors could increase the number of lung donors by 1,000 every year across North America,” says Feld.
Solving the light delivery challenge
As the PDT and light-based therapy market matures and expands to different in vivo indications, the prevailing challenge that is emerging is delivering light to the right part of the body with sufficient strength and specificity to achieve the intended therapeutic effect on the target while sparing surrounding tissues.
“We have focused on EVLP precisely to get around the issue of delivering the light into the body,” says Feld. “However, for some light-based therapies, novel delivery systems will be required to deliver adequate and appropriate light inside the body and to do so in a focused manner to avoid causing off-target toxicity.”
This is a particular issue in the treatment of cancerous tumours in internal organs with PDT, especially the lungs, oesophagus and other organs that tend to move and are more difficult to expose to consistent light. Innovations in devices are helping to address this problem, as demonstrated last year by a pioneering piece of research in Japan.
Researchers at Waseda University, led by associate professor of biomedical engineering Dr Toshinori Fujie (who has since moved to the Tokyo Institute of Technology), developed a novel wirelessly-powered light-emitting device that could greatly improve the specificity of light-based cancer therapy, especially when targeting delicate organs.
The device can be stably fixed to the inner surface of a tissue between layers of bioadhesive and elastic nanosheets, the latter of which were inspired by the proteins used by mussels to clamp on to objects. This allows the wirelessly-powered LED chips in the device to concentrate steady, localised light on the tumour. The system has been tested on tumour-bearing mice, with exposure to green light proving particularly damaging to tumours.
“This device may facilitate treatment for hard-to-detect microtumours and deeply located lesions that are hard to reach with standard phototherapy, without having to worry about the risk of damaging healthy tissues by overheating,” Fujie said. “Furthermore, because the device does not require surgical suturing, it is suitable for treating cancer near major nerves and blood vessels, as well as for organs that are fragile, that change their shape, or that actively move, such as the brain, liver, and pancreas.”
It’s clear that the therapeutic journey of PDT and other light-based therapies is only just beginning, despite their long history in clinical practice. Innovations in device design and biomechanical engineering are helping to develop PDT applications in oncology, infectious disease, ophthalmology, dermatology and more. A great deal of research and clinical testing lies ahead, but it may not be too much longer before some of the toughest-to-treat medical conditions are tackled by putting them under the spotlight.