Radiologist Moritz Kircher, who joined Memorial Sloan Kettering in 2010, is a physician-scientist with formal training in both clinical radiology and molecular imaging research. In the laboratory, his research is focused on the development of innovative nano-size materials that can be used to study detailed activities of cells. Specifically, he is developing nanoprobes, tiny particles of approximately 100 nanometers in size that can help image and treat tumors.
Last year, Dr. Kircher was awarded a three-year brain and immuno-imaging grant by the Dana Foundation to support his research and was also named a Dana Neuroscience Scholar.
In this interview, Dr. Kircher discusses his research involving molecular imaging and nanoparticles.
How did you get interested in the field of imaging?
I realized in medical school that imaging might be the best way of diagnosing disease. This is because you don’t have to try to detect disease in an indirect way, such as with a lab test or a stethoscope, but rather actually look inside the patient. You can see exactly where the disease is and what its extent is. This allows you to treat in a more focused manner. That’s why I went into radiology.Back to top
What’s the difference between traditional imaging and molecular imaging?
Molecular imaging is a new discipline within radiology. In contrast to the existing imaging
techniques that we currently have in the clinic — like CT, ultrasound, and routine MRI — the goal of molecular imaging is to be able to look at what is happening within individual cells noninvasively from outside the patient.
This way you can assess not just gross anatomy and tumor size, but also get much more specific information on cellular and subcellular metabolic processes. This allows us to diagnose disease in a more sensitive and precise way.Back to top
How might molecular imaging benefit patients?
As molecular imaging techniques enter the clinic, they will allow for more-sensitive and earlier disease detection and also for more-individualized treatment. For example, there can be many different genetic alterations in the same tumor type. Patients may respond better to a particular treatment depending on the underlying molecular etiology of their tumors. An accurate molecular imaging technique would be a way to determine the molecular subtype of a patient’s tumor. Hopefully, this would eventually help us to avoid surgical biopsies, which are not straightforward to perform in patients with brain tumors.
Molecular imaging agents could also allow us to see the extent of tumors and to hopefully detect them at such an early stage that the tumors can be completely removed and patients cured with surgery alone. In later-stage disease, currently it is very hard to find small metastases, such as peritoneal implants, and intraoperative molecular imaging techniques will be needed for complete tumor removal.
If we can combine molecular imaging with minimally invasive interventional radiology techniques, such as cryoablation and radiofrequency ablation, it may help us to avoid major surgeries altogether in the future.Back to top
Explain the research you’re doing in your lab. What are nanoparticles?
In my lab we are developing new multimodal nanoparticles, also called nanoprobes. These are very sophisticated contrast agents that have multiple capabilities built into them. They can also have targeting ligands on them — which may be peptides or antibodies — that help them seek out the tumors.
Multimodal means you can see the same nanoparticle with different imaging techniques. For example, we are currently working on refining a nanoparticle that can be seen with MRI, Raman imaging, and photoacoustic imaging. The idea is that this particle can be seen before surgery with MRI, which gives a whole-body image of the patient and the tumor to allow for correct staging and optimal surgical planning. Then, during surgery, the same nanoprobes can be seen with Raman and photoacoustic imaging technologies.
These are both new modalities that currently are being used in experimental clinical settings. The advantage of Raman imaging is based on the fact that it is possible, by creating a particular nanoparticle structure and dye composition, to enhance the signal originating from those
nanoparticles more than a billionfold. This means that Raman imaging can be more sensitive than other techniques, allowing us to detect a very small number of nanoparticles in living organisms. At the same tim,e the Raman signal is unique (a spectral fingerprint), so when you get the signal, you know you are detecting the nanoprobe and nothing else.
Photoacoustic imaging is a mixture of optical imaging and ultrasound. It combines the high sensitivity of optical imaging with the better depth penetration and the three-dimensional capabilities of ultrasound. Because it can reach several centimeters into the tumor, it can give the surgeon a road map on how to perform the tumor removal. Raman imaging can then be used for surgery at the tumor margin, or the edge of the tumor.Back to top
Does this research have particular applications for the treatment of brain tumors?
One reason brain tumor surgery is so difficult compared with surgery on other organs is that you cannot remove any healthy brain tissue around the tumor margin without risking impairment in the patient.
Because a “wide excision” — removal of the tumor along with with a margin of normal tissue—cannot be performed, there are usually small tumor deposits left behind that can cause recurrence. In addition, the margins of brain tumors are often diffuse and infiltrative, with small tumor protrusions extending into the normal brain that cannot be seen with the naked eye.
Our nanoparticles have been shown to enable visualization of such microscopic tumor tissue in mouse models, and we hope this will eventually work in humans. We envision using a handheld Raman imaging device during surgery so that the neurosurgeon can do complete excisions without harming any normal, crucial neurological structures. Ultimately this principle could be applied to many other areas of the body, but right now we are focusing on the brain to establish a proof of principle.Back to top
What needs to be done before this work can move from the laboratory into a clinical setting?
We have now started to test the nanoparticle imaging method in the most advanced brain tumor mouse models available, which were developed by Brain Tumor Center Director Eric Holland. His models closely resemble human brain tumors in the way the tumors grow and form very infiltrative margins.
If the technique works well in these models, this is a very good sign it will work in humans. However we will also need to test it in larger animals before human trials. If all the laboratory studies go well and we don’t see cytotoxic effects, then we can think about clinical trials. We believe these nanoparticles have a decent chance of being successful because they’re based on gold, and that’s an inert, nontoxic material that is already used in medical applications.Back to top