I am a clinician-scientist with experience in the application of a wide range of molecular imaging tools in both preclinical and clinical settings. At Memorial Sloan-Kettering, I direct a laboratory that focuses on the development, characterization, and evaluation of translational silica nanomaterials for cancer applications. We use these materials in conjunction with imaging tools (including PET and optical devices) to individualize patient care. In addition, my team explores the biological and chemical interactions of these materials at multiple spatial scales — from the cellular/molecular level to that of organs and tissues. We then link these findings to sites of disease using whole-body imaging studies of small animal models and humans.
Cancer Imaging Using C Dots
One goal of our work is to develop more-accurate intraoperative visualization/detection tools that could improve cancer staging, tumor burden assessment, and, in the future, therapeutic treatment strategies. To do so, we use a nanotechnology called C dots. About one-thousandth the size of a red blood cell, these particles have a radius tunable down to about 3.5 nanometers. C dots are small enough to be transported in the blood across the body’s tissues and are excreted efficiently through the urine. Each C dot is a shell of silica-encapsulating molecules that emit near-infrared (NIR) light, which easily penetrates a few millimeters into tissue. The shell, essentially glass, enhances the brightness and stability of these molecules, and is also what makes the C dot biologically safe. C dots were developed and optimized for biomedical use by Dr. Ulrich Wiesner, a professor in the Materials Science and Engineering Department at Cornell University, along with a small nanoparticle company, Hybrid Silica Technologies, Inc. (HST).
In vivo imaging of spectrally demixed Cy5 particle fluorescence (false spectrum) overlaid on visible light imaging of nude mice injected with either bare silica particles showing particle accumulation in the liver and bladder (left) or PEG-coated Cy5 silica particles showing particle accumulation in bladder (right).
To translate this technology to the clinic for evaluating tumors, our lab co-developed a new generation of non-porous, multimodal (PET-optical) C-dots-bearing peptides that bind with various classes of receptors commonly overexpressed on the surfaces of tumor cells and/or aberrant intracellular targets. These 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 (PEG) surface that reduces their uptake in the liver, spleen, lymph nodes, and bone marrow, and permits the attachment of ligands and/or contrast-producing agents; in the latter case, a radiolabel was added for PET imaging studies.
In small animal studies, we have demonstrated, using PET and optical imaging methods, that peptide-bound C dots accumulate to a much greater extent in melanoma cells bearing specific receptors than on those cells that do not. This renders tumor cells, the tumor’s blood vessels, lymph node spread, and distant metastases more clearly visible.
Our research has resulted in the first inorganic (silica) nanoparticle technology of its type and properties to receive U.S. Food and Drug Administration Investigational New Drug (IND) approval for use in first-in-human clinical trials. I am presently leading a phase 0 clinical trial in five metastatic melanoma patients at Memorial Sloan-Kettering to assess particle safety, whole-body particle distribution, and localization of particles within tumors using PET imaging. On the basis of these results, we plan to extend this clinical study to investigate the specific targeting of one or more tumor types using serial PET imaging.
Applications of C Dots in Melanoma Staging
In collaboration with other investigators at Memorial Sloan-Kettering, as well as Dr. Wiesner and HST, our laboratory is pioneering the use of these nontoxic, multimodal, and tumor-selective particle probes for real-time detection in intraoperative applications. Our initial objective is to enhance the detection of cancer cells in lymph nodes of metastatic melanoma patients, discriminate tumor burden, and ultimately detect the cancer at an earlier stage. Realizing this goal holds the potential to improve outcomes for patients with this highly lethal disease. This research may ultimately have application to other cancers as well, and this is currently being actively investigated.
Nodal mapping using multiscale NIR fluorescence imaging. (Top) Whole-body optical imaging of the tumor site (T) and draining inguinal (ILN) and axillary (ALN) nodes and communicating lymphatic channels (bar, LC) 1-hr p.i. in a surgicallyexposed living animal. (Bottom) Co-registered white-light and high-resolution fluorescence images (upper row) and fluorescence images only (lower row) revealing nodal infrastructure of local and distant nodes,
Following the initial clinical trial, we will perform a second clinical trial utilizing targeted multimodal C dots for sentinel lymph node (SLN) mapping, a technique that is routinely used during the staging of melanoma to identify the specific nodes that are at highest risk of tumor metastases.
For this trial, we will use multimodal C dots in conjunction with new optical and standard-of-care PET imaging tools to identify disease within nodes in the surgical setting after local administration for a primary lesion. We will perform pre-operative, whole-body PET scans to detect uptake at other disease sites, and potentially in other organs, and to determine how long the particles remain in the body. This clinical trial is an important step that we hope will ultimately lead to significant improvements in patient outcomes and prognoses for a number of different cancers.
This new hand-held optical device is manufactured by our collaborators, ArteMIS Molecular Imaging BV, and is the first-of-its-kind fluorescence camera system that provides real-time imaging guidance for open and minimally invasive surgical procedures. This camera will be used in conjunction with a clinically approved hand-held PET device, which detects radiolabeled agents. These newer-generation technologies may address limitations in the ability of current standard-of-care tools for cancer staging to identify unpredictable patterns of metastatic disease spread, difficult-to-detect nodes adjacent to tumors, and the difference between small nodes and vital structures during surgery.
Nanomaterials for Drug Delivery
We also co-develop porous silica nanomaterials, in conjunction with Dr. Wiesner’s laboratory, which can be used as drug-delivery vehicles to treat cancer. The particles exhibit a range of surface compositions to enable them to be adapted for specific types of therapeutics and the size can be tuned for renal clearance. In addition to silica-based agents, we have evaluated other nanomaterials (micelles, liposomes) as agents for solubilization, transport, and/or delivery of small-molecule therapeutics.
Our findings suggest that C dots can also be modified to serve as targeted therapeutic agents, and our laboratory is in the process of synthesizing a drug-delivery system that we expect will provide enhanced targeted delivery of a cancer therapeutic agent with reduced toxicity.
Awards and Funding
Our lab’s research was singled out in 2011 as a winner of the BioAccelerate NYC Prize, which provides critical funding for healthcare and biomedical projects that are expected to ultimately be brought to market. In addition to significant funding from the National Institutes of Health, National Cancer Institute, and other sources, our research has also been supported by Memorial Sloan-Kettering’s Technology Development Fund, which will support our SLN mapping clinical trial. Together these funds are aimed at addressing a strong unmet commercial need, and are enabling the team to extend the results of our preclinical studies to humans in the context of SLN mapping for several tumor types. A start-up company was recently created to support the further development of this technology.
About Michelle Bradbury
Michelle Bradbury is a member of Memorial Sloan-Kettering’s Department of Radiology and the Neuroradiology Service and holds a joint appointment in the Molecular Pharmacology and Chemistry Program in the Sloan-Kettering Institute.