Cell therapy involves the transfer of therapeutic immune cells to a target site in a patient's body so they can begin to treat a condition. Getting the cells to the target site may involve the migration of the cells to the relevant tumour site or lymph node, which requires monitoring using imaging techniques.
Ultrasound is a powerful imaging tool, however the short lifetime and large size of clinical contrast agents, limits its use for tracking of cellular therapies. 19F MRI, a new imaging technique, provides direct quantification of cell numbers within the body by imaging the 19F (stable fluorine) nucleus inside the contrast agent. Imaging with 19F MRI provides a lot of information, but is costly and time-intensive. Ultrasound, on the other hand, is quick and very easy to use, though not quantitative to cells. Combining both of these techniques could streamline the imaging process if the same contrast agent could be used for both techniques.
The team of scientists investigated nanoparticles consisting of a liquid perfluorocarbon and biodegradable polymer, which enabled imaging with both 19F MRI and ultrasound. These nanoparticles remain stable for more than 48 hours in vivo during repeat ultrasound imaging sessions. Since they are only 200 nm in size, they can enter the therapeutic immune cells without damage, while other contrast agents, such as microbubbles or vaporizing particles, can damage the cells and provide limited detection times in blood. Interestingly, particles of such a small size cannot normally be detected with ultrasound and the exact mechanism behind the detection of these nanoparticles is unclear. However, neutron experiments at ISIS Neutron and Muon Source and The Institut Laue-Langevin (ILL) helped uncover an important piece of the puzzle, revealing how these nanoparticles work.
The internal structure of the nanoparticles
The internal structure of these nanoparticles is unique for perfluorocarbons, as it is composed of multiple core-shell building blocks. In this multicore-structure, each shell consists of a polymer, poly(lactic-co-glycolic acid) (PLGA), and surfactant, with the cores containing liquid perfluoro-15-crown-5 ether (PFCE). PFCE, which usually repels water, remarkably appeared to be hydrated in the small angle neutron scattering (SANS) experiments carried out at ISIS. The researchers believe the unusual arrangement of PFCE in the polymeric matrix could explain the impressive visibility of these nanoparticles using ultrasound.
The different parts of these nanoparticles were investigated using neutrons and the contrast variation method. Due to the different neutron scattering densities of light and heavy water (H2O and D2O), mixing the two can highlight individual structures in each section of the nanoparticle. The results revealed 12 nm core-shell building blocks, which combine to form each particle.
A future of flexible imaging
These nanoparticles provide exciting prospects for long-term imaging with ultrasound and 19F MRI, but they can also be loaded with different components making them a suitable contrast agent for different techniques, for example fluorescent dyes can be added for microscopy or photoacoustic imaging. The researchers also suggest the potential to customise the size, degradation rate and other surface modifications of the nanoparticles for use in other therapies.
This research could aid the movement towards personalised medication and the desired flexibility in clinical imaging. The nanoparticles have since been approved for a pilot clinical trial, which is one step closer to making this novel solution a reality. A spin-off company, Cenya Imaging, has also been set up.
Research date: March 2019
Full article published in Advanced Functional Materials
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