Glioblastoma is the most aggressive brain cancer and the hardest to treat, as it spreads and invades healthy brain tissue in a diffuse, microscopic way. Surgical treatment calls for a fine balance between excising all cancerous tissues and removing as little healthy brain tissue as possible. To help neurosurgeons more accurately remove glioblastoma, an international research collaboration has developed an optical imaging probe that identifies microscopic cancer cells in the margins of tumour-resected cavities in the brain.
The imaging probe works by exploiting the significantly increased fatty acid (FA) metabolism exhibited by glioblastoma cells. FA metabolism plays a key role in tumour progression and proliferation and is central to cancer immunity. To enable real-time, non-invasive imaging of FA absorption, the researchers – from Erasmus University Medical Center (Erasmus MC) in The Netherlands and the University of Missouri in the USA – covalently linked a long-chain saturated FA with the clinically approved near-infrared (NIR) dye indocyanine green (ICG).
ICG has intrinsic low autofluorescence, enables deep tissue imaging and exhibits a high signal-to-noise ratio compared with visible fluorophores. The team hypothesized that a probe combining ICG with a FA might specifically accumulate in tumours and enable efficient intraoperative visualization of tumour margins. Importantly, the spectral characteristics of ICG make it compatible with many existing intraoperative cameras and surgical microscopes.
The researchers initially investigated the uptake of the FA-ICG probe in living cells, confirming that the dye’s physiological uptake resembles that of natural FAs. They then used fluorescence imaging to assess FA-ICG uptake in mice with implanted glioblastoma, observing high accumulation in the brain tumours.
Comparing the fluorescence signal from mice administered with equivalent doses of FA-ICG and ICG revealed that the average radiance from FA-ICG was approximately 2.2 times higher than that from IGC. At 12 and 24 h post-injection, retention of the probe in the brain was approximately two to three times higher in the tumour-bearing than the non-tumour-bearing hemisphere.
Next, lead authors Meedie Ali and Pavlo Khodakivskyi and their colleagues investigated the application of FA-ICG as a preclinical imaging agent in a patient-derived model of glioblastoma. They showed that the probe could successfully image tumour growth at different time points in several mice.
“This finding is of importance for preclinical research since patient-derived xenograph models of glioblastoma are characterized by an unpredictable growth pattern and low tumour implantation rates,” explains principal investigator Elena Goun from the University of Missouri. “Thus, monitoring of tumour status by sensitive, non-invasive in vivo fluorescence imaging would be of high value as the introduction of optical imaging of reporter genes [an alternative monitoring approach] is known to result in tumour phenotypic alterations.”
Fluorescence-guided surgery
The researchers also demonstrated the feasibility of FA-ICG as a contrast agent for NIR image-guided cancer surgery, performing surgery on tumour-bearing mice using a standard NIR camera approved for use in surgical suites. Not only did the FA-ICG probe successfully image glioblastoma in the animals’ brains, but the brains also exhibited a considerably higher fluorescence signal than seen from similar mice injected with an ICG-only dye.
Subsequently, the team employed the probe during surgical resection of veterinarian-diagnosed symptomatic canine mastocytoma (a skin cancer) in a pet dog. Ten hours after injection with FA-ICG, the dog underwent surgery, with image-guided surgery performed successfully using an open-air NIR surgical camera.
If the probe transitions to routine clinical use, it could prove be of great benefit to neurosurgeons. If they can identify cancer cells, which are microscopic and resemble healthy brain tissue, outside the surgical margins, follow-up chemotherapy and radiation treatments should be more effective and cancer recurrence may be delayed. The probe also offers the practical features of a workable surgical procedure, an appropriate half-life and fluorescence that can be seen under normal operating room lights.
“Our results demonstrate that FA metabolism represents an excellent target for tumour imaging, leading to significantly enhanced uptake of the FA-ICG probe in tumours,” the researchers write. “[The probe] represents a promising candidate for a wide range of applications in the fields of metabolic imaging, drug development and most notably for translation in image-guided surgery.”
The researchers are now planning a Phase I clinical trial to examine the safety and efficacy of the probe. Specifically, they aim to determine how well patients tolerate the probe, what side effects may occur at an effective dose, and how the probe’s performance compares to existing optical imaging surgical tools.
“The upside of fluorescence-guided surgery is that you can make little remnants much more visible using the light emitting properties of these tumour cells when you give them a dye,” says Rutger Balvers, a neurosurgeon at Erasmus MC who is expected to lead the human clinical trials, in a press statement. “And we think that the upside of FA-ICG compared to what we have now is that it’s more select in targeting tumour cells. The visual properties of the probe are better than what we’ve used before.”
The study is described in npj Imaging.
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