image: This is an MRI image (left) of a tumor shows nanoparticle accumulation in color. At the cellular level, tumor cells (blue), ferumoxytol (green) and a therapeutic nanomedicine (magenta) can be seen. view more
Credit: Miller M et al., Massachusetts General Hospital and Brigham and Women's Hospital
Many nanotherapeutics are currently being tested in clinical trials and several have already been clinically approved to treat cancers. But the ability to predict which patients will be most responsive to these treatments has remained elusive. Now, a collaboration between investigators at Massachusetts General Hospital (MGH) and Brigham and Women's Hospital (BWH) has led to a new approach that uses an FDA-approved, magnetic nanoparticle and magnetic resonance imaging (MRI) to identify tumors most likely to respond to drugs delivered via nanoparticles. The team's preclinical results are published in Science Translational Medicine November 18.
"Just as genetics is used in some cases to predict an individual's response to a drug, we wanted to develop a companion diagnostic that can predict response based on physiological differences," said Miles Miller, PhD, a postdoctoral fellow at the MGH Center for Systems Biology. "We hypothesized that ferumoxytol - a product that has been approved for the treatment of anemia - could be used to identify tumors that are more likely to respond to a nanomedicine."
"Our goal is to develop new nanotherapeutics that can be safely and effectively delivered to cancer patients," said Omid Farokhzad, MD, director of the Laboratory of Nanomedicine and Biomaterials at BWH. "One of the key translational challenges has been to better match patients to new nanotherapeutics based on patients' physiology. Our work takes a precision medicine approach to nanotherapeutics: using this technique, we can predict how well drug-loaded nanoparticles will accumulate in a particular tumor."
Farokhzad -- who has founded three companies, all of which have nanomedicines in the clinic or fast-approaching clinical trials -- teamed up with Ralph Weissleder, MD, PhD, Director of the MGH Center for Systems Biology and an expert in high-resolution in vivo imaging. The researchers hypothesized that the accumulation of nanoparticles may vary from patient to patient based on an individual's unique physiology. For instance, some patients may harbor tumors with more "leaky" vasculature or other physiological conditions that allow nanoparticles to accumulate faster at tumor sites. This accumulation of nanoparticles within tumors is known as the enhanced permeability and retention (EPR) effect. To determine if it would be possible to predict which tumors have high or low EPR, the investigators used ferumoxytol in mouse models of solid tumor cancers. Because it is magnetic, ferumoxytol can be imaged using MRI.
"Clinical impact is the ultimate goal of our work. Therefore, we tested an imaging technology, MRI, commonly used in the clinic and a diagnostic nanoparticle, ferumoxytol, that is already FDA-approved for other indications," said Weissleder, who is also an Attending Clinician in Interventional Radiology at MGH.
In addition to using MRI, the team labeled the magnetic nanoparticles with a fluorescent dye, allowing them to see the accumulation of particles on a single-cell level by microscopy.They categorized each tumor as having "low," "medium" or "high" EPR and then treated each tumor with a chemotherapeutic drug delivered via nanoparticles.
The researchers report that in preclinical models, their MR imaging strategy accurately predicted how much drug would reach the tumors (with more drug being delivered to tumors with higher EPR) and therefore how well the tumors would respond to the drug-loaded nanoparticles.
"This work represents a major stepping stone toward translating new discoveries of nanotherapeutics into clinical impact and selecting patients for nanotherapeutic trials," said Farokhzad.
To continue moving this work closer to clinical validation, the team intends to perform similar studies in patients. Studies of different forms of cancer may also help the team to identify which cancer types will be most responsive to nanotherapeutics.
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This work was supported in part by the NIH (R01CA164448, U54-CA151884, 5P50CA086355, and HL084312, T32 CA79443) and the David H. Koch-Prostate Cancer Foundation Award in Nanotherapeutics. Farokhzad discloses his financial interest in BIND Therapeutics, Selecta Biosciences and Blend Therapeutics, which develop nanoparticle medical technologies but did not support this study.
Brigham and Women's Hospital (BWH) is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare. BWH has more than 4.2 million annual patient visits, nearly 46,000 inpatient stays and employs nearly 16,000 people. The Brigham's medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in patient care, quality improvement and patient safety initiatives, and its dedication to research, innovation, community engagement and educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Brigham Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, more than 1,000 physician-investigators and renowned biomedical scientists and faculty supported by nearly $600 million in funding. For the last 25 years, BWH ranked second in research funding from the National Institutes of Health (NIH) among independent hospitals. BWH continually pushes the boundaries of medicine, including building on its legacy in transplantation by performing a partial face transplant in 2009 and the nation's first full face transplant in 2011. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative as well as the TIMI Study Group, one of the premier cardiovascular clinical trials groups. For more information, resources and to follow us on social media, please visit BWH's online newsroom.
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $800 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine. In July 2015, MGH returned into the number one spot on the 2015-16 U.S. News & World Report list of "America's Best Hospitals."
Journal
Science Translational Medicine