In a recent issue of the journal Science and Translational Medicine, researchers Michelle S. Bradbury, MD, PhD, and Ulrich Wiesner, PhD, and their teams, published the results of a proof-of-concept study of a novel cancer detection technology using ultrasmall, inorganic hybrid nanoparticles called C dots (Cornell dots). The trial was the first to be conducted in humans with this innovative technology, collecting promising safety and pharmacokinetic data that suggested C dots will have broad implications for the future of both cancer imaging and treatment.
Dr. Bradbury, a clinician-scientist who is a board-certified neuroradiologist at Memorial Sloan-Kettering Hospital, holding a joint appointment at Sloan Kettering Institute, and an Associate Professor of Radiology at Weill Medical College, was searching for a new agent to image cancerous tumors about eight years ago when she became aware of the work of Dr. Wiesner, the Spencer T. Olin Professor of Materials Science and Engineering at Cornell University-Ithaca, who had been developing the C dot nanotechnology. “I was looking for a better targeting agent than what was currently available,” she explained.
Dr. Bradbury hopes the very small C dots, which are hybrid core-shell silica nanoparticles approximately six to seven nanometers (a nanometer is a billionth of a meter) in diameter, will provide clinicians with a more potent, accurate tool to visualize cancers, improving their ability to target and treat disease and individualize patient care.
In this clinical trial, Dr. Bradbury and colleagues examined whole-body uptake, distributions, and renal clearance of C dots, in addition to gathering information essential for determining the safety of any new product to be used in humans. They labeled the C dots with radioactive iodine to create a multimodal imaging platform, then injected a single tracer dose of these labelled particles into five patients with metastatic melanoma. Using Positron Emission Tomography-Computed Tomography (PET-CT), they evaluated the organ uptake and clearance profiles at 2 to 4, 24, and 72 hours after injection and reported the following observations:
- Whole-body clearance half-times (that is, the time for the injection’s activity to fall to half of its beginning value) ranged from 13 to 21 hours.
- >90% of the administered particle activity was eliminated through the urinary system; particle stability was maintained.
- There was no appreciable C dot activity remaining after 72 hours.
- For the five patients recruited, the data suggested that this intravenously-injected particle was safe and well-tolerated.
While the current study was not intended or optimized to detect cancer, the investigators noted that the radiolabeled C dots preferentially accumulated within lesions seen in two of the five participants.
These positive safety and pharmacokinetic findings open the door to future investigations of C dots that hold enormous potential to improve patient care. Alternative cancer imaging modalities, such as CT or magnetic resonance imaging (MRI), are valuable; however, they would not provide the level of sensitivity or quantitation needed to conduct this type of study. The majority of nanoparticles that are under development are typically larger than C dots (i.e., > 10 nm) resulting in a substantially different pharmacokinetic profile from that seen in the present study, including a greater degree of non-specific uptake by the liver, spleen, and bone marrow, and slower clearance from the body.
The emerging medical area known as theranostics seeks to foster technologies like C dots that have the potential of combining multiple functionalities, such as diagnostic and therapeutic capabilities, on a single platform. While translating such multifunctional C dots to the clinic may be several years away, one exciting application that is currently in progress involves the use of C dots and a handheld portable fluorescence camera system in the operating room that would permit surgeons to directly visualize cancerous tissues in real-time, such as metastatic lymph nodes, for selective resection, while enabling them to preserve as much of a patient’s healthy tissue as possible. Dr. Bradbury also believes that this nimble and highly versatile platform could be tailored to eventually provide physicians with an array of real-time biological information about tumors while allowing them to deliver tumor-targeted treatments in the same setting (a “one-stop shop”).
She credited her collaborator Dr. Wiesner for developing a platform that has proved perfect for this research and noted the importance of this ongoing collaboration. “With C dots, Dr. Wiesner offered a modular, infinitely customizable, and clinically-translatable imaging platform which can be adapted to address key clinical questions in different settings,” she observed. “If we didn’t have the expertise of this multidisciplinary, interinstitutional team, there would have been no way to have gotten as far as we have.”
The support of the CTSC’s seed-funding initiative was also critical. “Often a barrier to getting funding for a new research idea is a lack of early data to show potential grantors,” she said. “The CTSC seed-funding grant allowed us to collect the early data so that we could submit an Investigational New Drug proposal to the Food and Drug Administration (FDA) and apply for more funding opportunities.”
“We are thrilled to have helped these researchers launch this idea,” Julianne Imperato-McGinley, MD, Director of the CTSC and Associate Dean for Translational Research for Weill Cornell, noted. “The success of Dr. Bradbury and Dr. Wiesner is an exemplar of what the CTSC’s seed-funding program hopes to achieve in terms of building cross-institutional, multidisciplinary, translational collaborations.”
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