Hyperpolarized Metabolic Imaging Visualizes ‘Real-Time’ Disease Progress

Most major diseases are somehow linked to metabolic alterations. But being able to see the changes as they occur and to see if a treatment is working in ‘real time’ is now nearer at hand thanks to Hyperpolarized Metabolic Imaging. This technology has created new possibilities to non-invasively study biochemical changes in disease processes by improving the sensitivity of Magnetic Resonance by more than 20,000-fold as reported in the Proceedings of the National Academy of Sciences.

SPINlab™, a powerful new imaging technology, harnesses hyperpolarized Carbon ¹³C (carbon-13) to view metabolic processes in real time. This approach will help researchers to study the realtime metabolism of disease, moving beyond morphology and functionality to reveal visual information about the flow, perfusion, metabolism, and organ and cell viability in living creatures.

First Real-Time Results

Researchers from the University of California at San Francisco (UCSF), in collaboration with GE Healthcare, have produced the first results in humans of a new technology that promises to rapidly assess the presence and aggressiveness of prostate tumors in real time, by imaging the tumor’s metabolism to assess the precise outlines of a tumor, its response to treatment, and how quickly it is growing.

This year, UCSF researchers using an early prototype of the technology, presented their results of “A first-in-human phase I imaging study using hyperpolarized ¹c-13 pyruvate (h-Py) in patients with localized prostate cancer” at the American Society for Clinical Oncology and published in the Journal of Clinical Oncology. Pyruvate is a naturally occurring byproduct of glucose. Their results showed that h-Py converted to hyperpolarized ¹³C lactate is detectable through MRI spectroscopy and can be used to study differentiation in prostate cancer. The h-Py MRI showed a 10,000-fold enhancement in signal-to-noise ratio and allowed the researchers to view metabolic alterations in vivo, or within living human subjects for the first time.

Studies say that one in six American men will develop prostate cancer and it is estimated that more than two million American men are living with the disease, making it one of the most common cancer in men nationwide and one of the leading causes of cancer death in men. But the disease ranges widely in rate of growth and aggressiveness. Most tumors are the slow growing variety. The National Cancer Institute of the National Institutes of Health advises that “active surveillance,” in other words deferring treatment until certain clinical changes are evident, may allow men with slower growing tumors to avoid radical treatment while ensuring that men with aggressive disease are treated earlier. But determining which tumors will be the faster-growing, more aggressive type has been difficult to determine until now.

University of California San Francisco researchers spoke about their earlier studies using this technology in preparation for the first-in-human phase I imaging studies and the benefits of this new molecular imaging technology in a video posted on the UCSF website. See:http://www.techbriefs.com/tv/cancerimaging.

How It Works

Jan Henrik Ardenkjaer-Larsen, principal scientist at GE and head of the Danish Research Center for Magnetic Resonance (DRCMR) hyperpolarization group, is one of the research team members who has been actively involved with this program for many years. Describing the SPINlab™ platform, (Fig. 1) he said: “The user simply loads the agent into the SPINlab™, allows the automated process of hyperpolarization to take place without consideration of the intricate physics, and finally obtains the hyperpolarized agent ready for use. The improvement in sensitivity can be exploited in multiple ways. Some of the applications include reduced detection limits, accelerated measurement speed and enhanced spatial resolution to investigate low levels of metabolites in cellular and disease models as well as biochemical assays.”

In April of this year, Ardenkjaer-Larsen was awarded the Günther Laukien Prize for Hyperpolarization for his seminal work on the hyperpolarization technique embodied in the SPINlab™ platform.

To achieve this improvement in sensitivity, SPINlabTM generates an ultra-low temperature (-272 °C or 1 °K) environment in a high magnetic field (5 Tesla) with microwave irradiation (140 GHz) in a fully automated system with an ergonomic user interface. Traditionally, such low temperature is achieved by the evaporation and consumption of large quantities of liquid cryogens, which is costly and inconvenient to the user. SPINlabTM reaches this extremely low temperature without any consumption of cryogens in the cryostat. The cryostat is located inside a welded stainless steel can with a superconducting magnet, charcoal filters, heaters, sensors, and other devices.

The cryostat (Fig. 2) is filled with liquid Helium to cool the magnet to 1°K. When a supply of liquid Helium has cooled the magnet coil to 1°K, the coil is charged with an electrical current. The current is then able to circulate freely in the coil without the dissipative effects of electrical resistance in the coil.

The agents are lowered into the liquid Helium in the cryostat, and soak there near the superconducting magnet. The magnet field induces the spin axis of the ¹³C electrons to re-align with the magnet pole axis. The longer the soak near the magnet, and the stronger the magnet, result in a greater percentage of electrons that become hyperpolarized as shown in Figure 3. The SPINlabTM uses a 3.5 Tesla magnet, and can work with magnets up to 5.0 Tesla. The greater the percentage of hyperpolarization, the greater the ¹³C sensitivity in an MRI, and the longer the hyperpolarization effect is available for enhanced imaging results.

Metabolically relevant agents are processed with the SPINlabTM in a custom- designed disposable fluid path. (Fig. 4) The device facilitates the movement of the agent through its mechanical and fluidics processing steps. The fluid path is a highly engineered plastic component that contains the agent of interest and solvents. It tolerates extreme temperature (-272 °C to 150 °C), pressure (to 15 bar) and is chemically resistant. The fluid path ensures a robust process and integrity of the agent and provides the customer with a convenient and automated work flow for characterization or biological studies.

A Look Ahead

The innovations in SPINlab™ have now automated the concept and complex physics of hyperpolarization to enable researchers to explore in vitro and in vivo biochemistry in real-time. Pre-clinical researchers have produced more than 500 publications studying potential applications for this powerful technology.

This technology was also entered in this year’s Create the Future Design Contest to help stimulate and reward engineering innovation. The entry can be seen at: http://contest.techbriefs.com/component/content/article/2748 .

In the fall of 2011, GE Healthcare announced that it is dedicating $1 billion of its total R&D budget over the next five years to expand its advanced cancer diagnostic and molecular imaging capabilities. It launched a new entity, Research Circle Technology Inc. (RCT) to create an alliance between GE’s scientists and leading universities, provide access to GE’s technology and healthcare expertise, and accelerate and enhance the development of metabolic imaging and other innovative technology.

“The focused goal of RCT is open collaboration to bring hyperpolarization technology to the world’s leading researchers and enable their studies to better understand the biochemistry of life,” said Jonathan A. Murray, Managing Director of RCT. “The early results are very exciting and we are delighted to collaborate with this community to help bring this innovative technology to its full potential.”

The progress of this technology platform has been a result of collaborative efforts between RCT and its developers. KMC Systems, Inc., a contract design and manufacturer of medical instruments (Merrimack, NH) developed, built, integrated, and tested the SPINlab™ automation platform. The disposable fluid path was developed by Wi, Inc. (Englewood, CO), and the cryostat was provided by Oxford Instruments (Tubney Woods, Abingdon, Oxford shire, UK).

Materials for this article supplied by GE Healthcare, KMC Systems Inc., the University of California, San Francisco, and the Danish Research Center for Magnetic Resonance. For more information, Click Here 

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