Researchers in the US are now the first to have used MPI to passively detect cancer by exploiting the abnormal leakiness of tumour blood vessels – a finding that bodes well for the early detection of cancers like breast cancer in patients at risk for the disease (Nano Letters doi: 10.1021/acs.nanolett.6b04865).

Biomedical imaging is important at every stage of diagnosing and treating cancer, beginning with initial screening, through to diagnosis, treatment planning and monitoring. The biggest challenge here is to be able to reliably distinguish tumour tissue from healthy tissue, something that is not as easy as it sounds.

"Conventional anatomical techniques, such as X-ray, X-ray CT, ultrasound and MRI, are very useful for detecting the tissue architecture changes that generally accompany cancer, but the native contrast of tumours may not differ sufficiently from healthy tissue for a confident diagnosis, especially for metastatic or so-called diffuse tumours," explains lead author Elaine Yu, who is completing her Bioengineering PhD in Steven Conolly's lab at the University of California at Berkeley (UCB). "This is why exogenous contrast agents, such as iodine (for X-ray and CT) and gadolinium (for MRI) are often administered to highlight crucial vascular differences between normal and cancerous tissue for more precise screening."

Exploiting the EPR effect

Contrast agents are all injected intravenously, but the way that they highlight tumours differs considerably. Nanosized agents are better than conventional low molecular weight agents in one respect because they are not immediately excreted by the kidneys if designed to be large enough. They are thus able to circulate in the blood for extended periods of time. The naturally leaky vasculature of some tumours also allows nanosized particles to preferentially end up in tumour tissue, where they can be held. This is known as the enhanced permeability and retention (EPR) effect.

"Our work is the first to exploit the EPR effect with the high sensitivity and contrast afforded by magnetic particle imaging," says Yu. "We have succeeded in imaging tumours in rats with vivid tumour-to-background contrast. "Thanks to its high sensitivity and good signal throughout the entire body, we were able to clearly capture the nanoparticle dynamics in the tumour: so-called rim enhancement, peak particle uptake at six hours after administration and eventual clearance beyond 48 hours."

Synthesizing the SPIOs

The MPI-tailored superparamagnetic iron oxide nanoparticle (SPIO) tracers were synthesized by team members at LodeSpin Labs and by Kannan Krishnan's lab at the University of Washington (UW), and were designed for optimal imaging resolution and long blood circulation time. "The iron oxide nanoparticles were made by thermolysis of iron III oleate in 1-octadecene, with subsequent oxidation to achieve the desired magnetic behaviour and coated with the biocompatible coating MPAO-PEG," explains Yu.

The researchers injected the nanoparticles into the tail veins of rats and then performed a series of MPI scans as the nanoparticles travelled through the circulation. Thanks to the EPR effect, the particles preferentially accumulated in tumours and were retained there for up to six days.

Imaging the SPIO electronic moment

MPI was first developed by Philips Research in 2005 and is a tracer imaging technique that directly measures the location and concentration of SPIO nanoparticles in vivo. It images the SPIO electronic moment, which is 22 million times more intense than nuclear MRI moments. When a time-varying exciting field is applied, it causes the moments of the SPIOs to instantaneously "flip", thereby inducing a signal in a receiver coil.

"The advantages of MPI are its superb contrast and sensitivity, which could very soon rival the dose-limited sensitivity of nuclear medicine techniques," Conolly tells our sister site nanotechweb.org. "This is very exciting, since MPI does not rely on ionizing radiation. The scanner and iron oxide tracer are also thought to be safe for humans. Indeed, some SPIO agents are already FDA or EU safety approved for human use in other clinical applications."

MPI tracers are excreted through the liver

Importantly, the MPI tracers are excreted through the liver, rather than through the kidneys, and there is evidence that SPIOs could be safer than iodine and gadolinium for patients with chronic kidney disease. "Given all these advantages, we are very hopeful that MPI could play an important role in early-stage cancer detection. Indeed, we are particularly focusing on early-stage breast cancer detection in the subpopulation of women with radiologically dense breast tissue and who are at high risk for cancer (because of, for example, BRCA1 or BRCA2 defects, or family history of the disease)."

Conolly says that he and his colleagues are now working hard to improve MPI in terms of resolution and sensitivity. "We are also studying MPI for stem-cell tracking, detecting pulmonary embolism, brain perfusion to detect and monitor strokes or traumatic brain injuries, and T-cell immunotherapy studies in collaboration with researchers at Berkeley, the University of California at San Francisco, UW, Case Western, Harvard and Stanford. We would also like to follow up on several promising demonstrations of MPI-guided magnetic fluid hyperthermia exploiting the unique 'focusing' capabilities of MPI to selectively heat tumours or to release chemotherapeutic agents specifically into a tumour. We are doing this work with University of Florida collaborators."

Related stories

• MPI captures beating mouse heart
• 'Immobilized' calibration improves MPI
• Nanoparticles help identify tumour edges
• Multi-colour MPI expands imaging options