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Science Highlight: June 5, 2017

Advanced quantum dots shed bright light on biological processes

Short wave infrared quantum dots provide real-time whole body, brain tumor imaging in mice

Fluorescent quantum dots are valuable tools used to tag and image biological processes in live animals. However, precise fluorescent imaging at the cellular and molecular levels has not been possible because of non-specific fluorescence and light scattering by surrounding tissues. Now researchers have created short wave infrared (SWIR) quantum dots that resolve many of these problems. The system was used in live mice to image working organs, take metabolic measurements, and track microvascular blood flow in normal brain and brain tumors.

“Quantum dots are small (nanoscale) particles that can be engineered to emit light at different wavelengths,” explains Behrouz Shabestari, Ph.D., director of the Optical Imaging Program at NIH’s National Institute of Biomedical Imaging and Bioengineering, which co-funded the research. “When they are injected into a live animal, the emitted fluorescent light can be seen with special cameras. By engineering the dots to bind to specific tissues of interest, researchers can use them to study biological processes in real-time.” 
Quantum dot imaging of mouse brain tumor

The top outlines the experimental set-up with composite SWIR quantum dots injected into the circulation and then imaged through a cranial window in the mouse brain. The bottom shows the resulting fluorescent image with healthy arteries in red, veins in blue, and the disorganized blood vessels of a brain tumor in green.1

An international group of investigators led by Moungi G. Bawendi, Ph.D., the Lester Wolfe Professor in Chemistry at the Massachusetts Institute of Technology, collaborated to create what Bawendi calls the “next-generation,” of quantum dots. Said Bawendi, “We took advantage of the special qualities of short wave infrared light, which is essentially the ability to give a clear bright signal emitted from the tissue of interest that is not blocked or scattered by the surrounding tissues. The system allows us to view biological processes in living, moving animals with great clarity and detail.” The work is described in the April issue of the journal Nature Biomedical Engineering.1 

Engineering SWIR quantum dots to target tissues of interest

While the inner core of a SWIR quantum dot (SWIR-QDs) generates the unique fluorescent properties of short wave infrared light, the other critical component of the dot is the outer surface, which must be engineered to target a tissue of interest. The researchers call this “functionalization,” which means making them useful for specific studies. Bawendi and colleagues engineered three distinct types of SWIR quantum dots to demonstrate their use in studying different tissues and biological processes.

The first type of SWIR-QDs were engineered with phospholipid micelle surface coatings. Micelles are small particles that have a hydrophilic (water-loving) outer shell and a hydrophobic (water repelling) inner layer. The micelle-embedded SWIR-QDs dissolved and circulated through the bloodstream for an extended period, allowing the researchers to study heart and respiration rates in awake mice. The advantage of these SWIR-QDs is the ability to image physiological processes that occur too rapidly to be detected by common imaging methods such as MRI or PET. This ability would allow unobtrusive monitoring of animals in their normal environment for changes in heartbeat and breathing rates during various exercise tests or in response to drug candidates for conditions such as cardiac arrhythmia. 
Whole body scan with lipid micelle SWIR quantum dots

A. Experimental set-up with lipid micelle SWIR quantum dots injected into the circulation and whole body scan with SWIR camera. B. Resulting fluorescent image shows the accumulation of the lipid micelle SWIR quantum dots in the liver (blue circle) and heart (red circle).1

The second type of SWIR-QDs created were embedded in chylomicrons. Chylomicrons are lipoprotein particles that consist of triglycerides, phospholipids, cholesterol, and proteins and are known to transport dietary lipids from the intestines to other locations. These SWIR-QDs were used to study the movement and metabolism of lipids between brown adipose tissue, blood, and liver in real-time. The researchers explained that lipid-coated SWIR-QDs could be used to assess the immediate effects of medications designed to affect lipid metabolism—for example, to increase the liver’s uptake of lipids from the bloodstream of an individual with high cholesterol. 

SWIR quantum dots circulate in mouse brain region without brain tumor

The third type of SWIR-QDs were composites, containing multiples QDs, and coated with PEG, which allows them to dissolve in blood. This third type was used to measure blood flow in the vasculature of the mouse brain by tracking individual SWIR-QD composite particles as they moved through the blood vessels. The researchers could view the dramatic differences between blood flow in healthy vasculature and in vessels at the margin of a brain tumor. These SWIR-QDs would make it possible to measure blood flow in the brain before and after a stroke, and changes in response to experimental stroke medications. 

Limited SWIR quantum dot circulation in brain tumor in lower left

 

“In addition to the ability to test much-needed new medications to treat stroke, the potential application to difficult-to-treat tumors is one that we are also very excited about,” said Bawendi. “We can potentially use SWIR-QDs to study how the blood flow pattern in a tumor changes over time. We could monitor disease progression or regression in response to drug treatment. This opens a new way to assess experimental treatments for both stroke and brain cancer that have not been possible with other imaging methods.”

This extensive collaboration included researchers from: the departments of Materials Science, Engineering, Chemical Engineering, and Mechanical Engineering at MIT; Harvard Medical School, and School of Public Health; Department of Chemistry, Brown University, Providence, Rhode Island; and Raytheon Vision Systems, Goleta, CA. Collaborators outside the U.S. included researchers from: University Medical Center, Hamburg, Germany; the German Cancer Research Center, Heidelberg, Germany; University of Toronto; Korea Institute of Science and Technology, Seoul, Korea; and the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

What are Quantum Dots?

The work was partially funded by the National Institutes of Health through grant # EB015871 from the National Institute of Biomedical Imaging and Bioengineering; several grants from the National Cancer Institute; and grants from the National Institute of Neurological Diseases and Stroke, the National Eye Institute, the National Heart, Lung and Blood Institute, and the National Institute of Diabetes and Digestive and Kidney Diseases. Additional U.S. funding was provided by the U.S. Army Research Office, the U.S. Department of Defense, and the National Science Foundation. International funders included organizations in the European Union, Germany, and Singapore.

1. Next-generation in vivo optical imaging with short-wave infrared quantum dots. Oliver T. Bruns, Thomas S. Bischof, Daniel K. Harris, Daniel Franke, Yanxiang Shi, Lars Riedemann, Alexander Bartelt, Frank B. Jaworski, Jessica A. Carr, Christopher J. Rowlands, Mark W. B. Wilson, Ou Chen, He Wei, Gyu Weon Hwang, Daniel M. Montana, Igor Coropceanu, Odin B. Achorn, Jonas Kloepper, Joerg Heeren, Peter T.C. So, Dai Fukumura, Klavs F. Jensen, Rakesh K. Jain and Moungi G. Bawendi. Nature Biomed Eng. April 10, 2017.

Health Terms: 
Atherosclerosis,
Brain Disorders,
Cancer,
Cardiovascular,
Diagnostic,
Microscopy,
Nanotechnology,
Stroke