Primary treatment of most solid tumors includes surgical excision or radiation therapy, both of which require precise anatomic localization of the tumor as well as surrounding tissue and organs. If the targeting is too broad, unnecessary morbidity may occur to nearby structures, along with the possibility of poor outcomes. To shed light on new techniques in intraoperative-guided imaging, The ASCO Post recently spoke with Michelle S. Bradbury, MD, PhD, Director of Intraoperative Imaging, Radiology, at Memorial Sloan Kettering Cancer Center, New York.
Michelle S. Bradbury, MD, PhD
Optical Imaging in Cancer Surgery
In a nutshell, what is the current state of optical imaging in cancer surgery, and for what type of procedure is this technique used?
One of the primary indications for optical imaging has to do with detecting lymph nodes, sentinel lymph node mapping to be specific. It’s important to note that most of the optical tools used today do not specifically detect cancer, rather they simply target macrophages within the tumor microenvironment. Using both optical and positron-emission tomography (PET) imaging, we can sensitively track very small fluorescent silica nanoparticles (C dots) in real time, as they rapidly go to the nodes. Using a handheld fluorescent camera system, surgeons can trace the fluorescence signal from the site of injection to lymph nodes that contain metastatic disease. Another device that detects counts from the radioactive standard-of-care agent can confirm the results. Armed with these data, physicians then can select treatment options.
Another indication is surgical margin mapping. One can inject these fluorescent probes via an intravenous line and see a clear pattern by which to remove the tumor and look for residual disease. Also, a number of groups have tried to use this new technology to visualize adjacent nerves. So, in addition to mapping the disease, you could, at the same time, map the vital surrounding structures and give the surgeon a far better target.
Silica Nanoparticles
Nanotechnology still has a futuristic ring. Please tell the readers about your work with silica nanoparticles and where you are in their development.
We have been working to develop cancer-targeting silica C-dot particle for a range of diagnostic and therapeutic applications for at least 12 years. C dots are nanoparticles about 6 nm in diameter, which is about the diameter of a small protein. C dots can be administered into humans because they are made of a type of silica that poses no known danger to living things. The dye they enclose, which makes them light up, as well as the drugs decorating the C-dot surface can improve cancer imaging and drug delivery, because they can be used to target a specific tumor in a specific place.
However, it’s important to note the thing that makes all nanoparticles different from a targeting moiety such as a peptide on the cell surface is their multivalency. In other words, how many copies of this nanoparticle can we attach to the particle surface to create a good target? It’s not that we need loads of peptides or an antibody fragment. The idea with attaching these nanomoieties is to better deliver the contrast agent and contain it at the site.
We like to have targeted particle probes to better deliver therapeutics. Does that mean you need a targeting moiety on every single cancer? Well, that’s a question under discussion for a long time now, and we’ve found that it really depends on the tumor type, how many receptors are expressed, and whether that particular target needs to penetrate the cell, or it can be effective just by binding to the surface.
Melanoma: First-in-Human Phase I Studies (Now in Phase II)
Did you begin working with a specific cancer?
When we began working with this ultrasmall platform, we performed a first-in-human phase I imaging study in patients with melanoma, where we were trying to assess the safety of very small doses (microdoses) of the C dot and its behavior in the body, including its ability to target solid tumors such as melanoma and its metastatic disease spread to lymph nodes. I was targeting integrins, a marker overexpressed by many solid tumors, and which has been used for many years. I started in melanoma because it’s a good example of a tumor, similar to breast cancer, that obeys the ‘sentinel’ lymph node concept, that is, the first node to receive tumor cells from the primary lesion via the lymphatics. This is unlike other cancers such as prostate cancer or gynecologic malignancies, in which the drainage is not localized to a ‘sentinel’ node.
“Our targeted optical imaging allows the surgeon to see the disease in a specific way that leads to better treatment decisions. This is the Holy Grail of what’s needed in surgery.”— Michelle S. Bradbury, MD, PhD
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We’ve attached different targeting moieties to the nanoparticle surface depending on the cancer type. And because cancers are so heterogeneous, we’ve expanded those targets, and are able to perform real-time, fluorescence-based multiplexing for detecting more than one target in living systems; currently this is done ex vivo in pathology. However, we’ve simultaneously detected these cancer targets in a melanoma mini-swine model using intraoperative optical imaging guidance. We were able to pick up two targets on the metastatic lymph nodes, using the optical signals of each illuminated moiety; so, a surgeon can look at the display and see whether the nodes express more than one target.
Challenges and Advantages
New approaches are always challenged. What are the best properties in this platform to address questions that might arise about C dots and their ability to target and identify cancer?
In our case, we have an encapsulated silica dye in the core of the particle that permits deeper target tissue penetration, as it is extremely bright and photostable. As opposed to free dyes, which interact with the surrounding environment, the encapsulated dye captures most of the energy that excites the dye’s usable light, so there is much less loss of energy to heat. In short, it’s a more efficient process, and it displays up to about 1,000% brighter than the free dye itself.
What are the specific advantages of your platform for surgeons?
By targeting the cancer in nodes or even at sites of residual disease, we can obviously localize and treat it better by doing more of a precision surgical technique. And this is built on something surgeons are beginning to acknowledge. Surgeons do not want to go in and inject a therapy into an area that does not have a specific location and margin. Currently, most surgeons simply use white light, the naked eye, and feel for abnormal morphology, which is fairly primitive. But our targeted optical imaging technologies allow the surgeon to see the disease in a specific way that leads to better treatment decisions. This is the Holy Grail of what’s needed in surgery. We’re evolving these tools, but they are not mature yet.
What is the advantage of using optical probes on the nanometer scale?
For one, these small particles have been found to exhibit high biostability, a lack of toxicity, and an efficient clearance profile, given their small size. They are coated with a polyethylene glycol surface, which facilitates clearance through the kidneys and reduces their uptake in the liver, spleen, lymph nodes, and bone marrow. So, simply from a safety profile, their size is advantageous.
“This technology is going to inform and change the management of intraoperative care. [It] would give the surgeon a multilayered view to see disease sites in relation to the surrounding anatomic structures that may not be visible to the naked eye.”— Michelle S. Bradbury, MD, PhD
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Clinical Value of C Dots
Please drill down a bit into the function and clinical value of the C dot.
Each C dot is a shell of silica-encapsulating dye molecules that emit long-wavelength light, which easily penetrates tissues. The shell enhances the brightness and stability of these molecules and, as I mentioned, is also what contributes to product safety.
Our idea is to use PET imaging to map whole-body disease before an operation, followed by optical imaging and C dots to map disease localized to nodes during the operation. So, if the surgeon is looking at the tissue, especially in lumpy tissue, there is generally not enough contrast to discriminate and locate all disease within these structures. However, as fluorescent C dots are particles targeted to locate the cancer, they can be used to provide visual cues to guide the surgery, allowing the surgeon to do more precise excision and less damage to healthy tissue.
Our findings also suggest that C dots can also be modified to serve as targeted therapeutic agents. Our laboratory is in the process of translating drug-delivery systems to the clinic that we expect will provide targeted delivery of cancer therapeutic agents with reduced toxicity due to the significantly lower doses needed.
Closing Thoughts
Please share some closing thoughts on this exciting new technology.
I think this technology is going to truly inform and change the surgical management of patients with cancer, especially when we incorporate small-molecule drugs, machine learning, and augmented reality to project three-dimensional volumetric images onto the patient in real time in the operating room; this approach would give the surgeon a multilayered view to see disease sites in relation to the surrounding anatomic structures that may not be visible to the naked eye, which can improve surgical management. Moreover, this technology can continue to improve and expand our applications, as collaboration between the medical and technology sectors accelerates. It’s very exciting work. ■
DISCLOSURE: Dr. Bradbury reported no conflicts of interest.
