Deep-Tissue Biological Imaging with Fluorescent Nanoparticles
Interview By Will Soutter
In this Thought Leader interview, Gang Han tells us about his work on photoluminescent nanoparticles, which show great promise for super-resolution microscopy and deep-tissue imaging.
WS: Can you give us some background to your research on photoluminescent nanoparticles?
GH: My research interest in photoluminescent nanoparticles began as a postdoctoral fellow in the Molecular Foundry at the Lawrence Berkeley National Lab, when I began to be interested in optical imaging using photoluminescent nanoparticles.
One particularly interesting application with respect to such nanoparticles is their amazing capability for use in optical imaging. Together with Dr. Bruce Cohen, I first developed an entirely innovative type of quantum dots that remain dark until they are turned on by pulses of ultraviolet light. Due to their clear advantages (multiplexing capabilities and photostability) over conventional photoswitchable fluorophores, they are well-suited for super-resolution microscopy applications.
I then discovered a novel single molecule imaging toolset (i.e., lanthanide-doped upconverting nanocrystals) that features nearly ideal optical properties for single molecule imaging, which includes exceptional photostability, continuous emission, and no spectral overlap with cellular autofluorescence.
This significant discovery paved the way for the use of UCNPs to trace single biological molecules and thus to unlock various biological mechanisms that were previously inaccessible. As an assistant professor now at the University of Massachusetts Medical School, I have been focusing on systematically designing photoluminescent nanoparticles including new generations of UCNPs with improved optical performance and biocompatibility.
WS: What attracted you to working in this field?
GH: The major motivation for me has been the opportunity to unravel significant biological problems, both on the fundamental scientific level and for clinical application purposes.
For example, there are numerous unsolved questions that can lead to solutions to disease treatment, such as how to detect cancer at earlier stages more often, and how the HIV virus invades the human immune system.
Such answers, among others, rely on finding a new approach that can solve the problems we currently face with looking within the human body to diagnose the development of a disease.
A transmission electron microscopy image of nanoparticles designed for deep-tissue imaging. Each particle consists of a core encased inside a square, calcium-fluoride shell.
WS: Your recent work was published in ACS Nano in August - tell us about the results you discussed in that paper.
GH: This particular work has led to the discovery of a new class of biocompatible nanoparticles. The newly created nanoparticles consist of a nanocrystalline core containing thulium, sodium, ytterbium and fluorine, all encased inside a square, calcium-fluoride shell.
The particles are special for several reasons. First, they absorb and emit near-infrared light, with the emitted light having a much shorter wavelength than the absorbed light. This is different from how molecules in biological tissues absorb and emit light, which means that we can use the particles to obtain deeper, higher-contrast imaging than traditional fluorescence-based techniques.
Second, the material for the nanoparticles' shell - calcium fluoride - is a substance found in bone and tooth mineral. This makes the particles compatible with human biology, reducing the risk of adverse effects. The shell is also found to significantly increase the photoluminescence efficiency.
To emit light, the particles employ a process called near-infrared-to-near-infrared up-conversion, or "NIR-to-NIR." Through this process, the particles absorb pairs of photons and combine these into single, higher-energy photons that are then emitted.
One reason NIR-to-NIR is ideal for optical imaging is that the particles absorb and emit light in the near-infrared region of the electromagnetic spectrum, which helps reduce background interference. This region of the spectrum is known as the "window of optical transparency" for biological tissue, since the biological tissue absorbs and scatters light the least in this range.
We examined the particles in experiments that included imaging them injected in mice, and imaging a capsule full of the particles through a slice of pork more than 3 cm thick. In each case, we were able to obtain vibrant, high-contrast images of the particles shining through tissue.
WS: This obviously has direct applications in biological imaging applications. How soon do you think the results of this will be seen in the medical world?
GH: I do see great potential with respect to these special probes as to usage in the medical field. In this regard, I can foresee their utilization as analytical sensors for biomarkers or diagnoses in just a few years. There are definitely a few barriers to overcome here in order to use such probes directly in patients.
For example, obtaining a complete profile of their biocompatibility and toxicity is one key milestone that needs to be accomplished. We also need to build up specific and special medical devices to adapt to the unique optical properties of these imaging probes. I do believe that these agents will ultimately find their place in doctors’ offices.
WS: What other application areas do you envisage for this technology?
GH: The future applications could be unlimited, as it would provide a way to unlock the current disconnections between in vitro and in vivo studies. For example, these probes can be used by the doctors to identify tumors or other disease development deep beneath the skin that cannot be checked in with traditional agents.
WS: These discoveries will no doubt lead on to more research in the area. What is the next step for this project?
GH: In the next step, we propose to attach tumor homing peptide and tune particle size, upconversion photoluminescence efficiency, and surface functions, which are all key parameters that determine UCNP in vitro and in vivo behavior.
Meanwhile, we will also develop portable devices that can used to detect these nanoparticles towards their future clinic uses.
WS: Where can we find more information about your work?
GH: For more information about this or other research, please feel free to visit my personal website or email me at gang.han@umassmed.edu.
Corresponding author: Dr Gang Han, gang.han@umassmed.edu.
Assistant Professor, University of Massachusetts Medical School. |
WS: Can you give us some background to your research on photoluminescent nanoparticles?
GH: My research interest in photoluminescent nanoparticles began as a postdoctoral fellow in the Molecular Foundry at the Lawrence Berkeley National Lab, when I began to be interested in optical imaging using photoluminescent nanoparticles.
One particularly interesting application with respect to such nanoparticles is their amazing capability for use in optical imaging. Together with Dr. Bruce Cohen, I first developed an entirely innovative type of quantum dots that remain dark until they are turned on by pulses of ultraviolet light. Due to their clear advantages (multiplexing capabilities and photostability) over conventional photoswitchable fluorophores, they are well-suited for super-resolution microscopy applications.
I then discovered a novel single molecule imaging toolset (i.e., lanthanide-doped upconverting nanocrystals) that features nearly ideal optical properties for single molecule imaging, which includes exceptional photostability, continuous emission, and no spectral overlap with cellular autofluorescence.
This significant discovery paved the way for the use of UCNPs to trace single biological molecules and thus to unlock various biological mechanisms that were previously inaccessible. As an assistant professor now at the University of Massachusetts Medical School, I have been focusing on systematically designing photoluminescent nanoparticles including new generations of UCNPs with improved optical performance and biocompatibility.
WS: What attracted you to working in this field?
GH: The major motivation for me has been the opportunity to unravel significant biological problems, both on the fundamental scientific level and for clinical application purposes.
For example, there are numerous unsolved questions that can lead to solutions to disease treatment, such as how to detect cancer at earlier stages more often, and how the HIV virus invades the human immune system.
Such answers, among others, rely on finding a new approach that can solve the problems we currently face with looking within the human body to diagnose the development of a disease.
A transmission electron microscopy image of nanoparticles designed for deep-tissue imaging. Each particle consists of a core encased inside a square, calcium-fluoride shell.
GH: This particular work has led to the discovery of a new class of biocompatible nanoparticles. The newly created nanoparticles consist of a nanocrystalline core containing thulium, sodium, ytterbium and fluorine, all encased inside a square, calcium-fluoride shell.
The particles are special for several reasons. First, they absorb and emit near-infrared light, with the emitted light having a much shorter wavelength than the absorbed light. This is different from how molecules in biological tissues absorb and emit light, which means that we can use the particles to obtain deeper, higher-contrast imaging than traditional fluorescence-based techniques.
Second, the material for the nanoparticles' shell - calcium fluoride - is a substance found in bone and tooth mineral. This makes the particles compatible with human biology, reducing the risk of adverse effects. The shell is also found to significantly increase the photoluminescence efficiency.
To emit light, the particles employ a process called near-infrared-to-near-infrared up-conversion, or "NIR-to-NIR." Through this process, the particles absorb pairs of photons and combine these into single, higher-energy photons that are then emitted.
One reason NIR-to-NIR is ideal for optical imaging is that the particles absorb and emit light in the near-infrared region of the electromagnetic spectrum, which helps reduce background interference. This region of the spectrum is known as the "window of optical transparency" for biological tissue, since the biological tissue absorbs and scatters light the least in this range.
We examined the particles in experiments that included imaging them injected in mice, and imaging a capsule full of the particles through a slice of pork more than 3 cm thick. In each case, we were able to obtain vibrant, high-contrast images of the particles shining through tissue.
WS: This obviously has direct applications in biological imaging applications. How soon do you think the results of this will be seen in the medical world?
GH: I do see great potential with respect to these special probes as to usage in the medical field. In this regard, I can foresee their utilization as analytical sensors for biomarkers or diagnoses in just a few years. There are definitely a few barriers to overcome here in order to use such probes directly in patients.
For example, obtaining a complete profile of their biocompatibility and toxicity is one key milestone that needs to be accomplished. We also need to build up specific and special medical devices to adapt to the unique optical properties of these imaging probes. I do believe that these agents will ultimately find their place in doctors’ offices.
WS: What other application areas do you envisage for this technology?
GH: The future applications could be unlimited, as it would provide a way to unlock the current disconnections between in vitro and in vivo studies. For example, these probes can be used by the doctors to identify tumors or other disease development deep beneath the skin that cannot be checked in with traditional agents.
WS: These discoveries will no doubt lead on to more research in the area. What is the next step for this project?
GH: In the next step, we propose to attach tumor homing peptide and tune particle size, upconversion photoluminescence efficiency, and surface functions, which are all key parameters that determine UCNP in vitro and in vivo behavior.
Meanwhile, we will also develop portable devices that can used to detect these nanoparticles towards their future clinic uses.
WS: Where can we find more information about your work?
GH: For more information about this or other research, please feel free to visit my personal website or email me at gang.han@umassmed.edu.
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