Delivering medicines with microscopic flowers

By Fabio Bergamin, Science Editor at ETH Zurich

Summary:
- Using microparticles consisting of extremely thin petals, medicines can be delivered via the bloodstream in a precisely targeted manner, for example to a tumour or blood clot.
- Ultrasound and other acoustic procedures guide the particles through the body and reveal their locations.
- This makes the particles easy to deploy, as ultrasound procedures are common practice in medicine.

How can medicines be directed to the precise location within the body where they need to act? Scientists have been researching this question for a long time. An example would be delivering cancer drugs directly to a tumour so that they only take effect at this specific location, without causing side effects in the rest of the body. Research is under way to identify carrier particles to which active ingredients can be bound. Particles of this kind must meet an array of requirements, including the following three: firstly, they must be able to absorb as many molecules of the active substance as possible; secondly, it must be possible to guide them through the bloodstream using a simple technique such as ultrasound; and thirdly, it must be possible to track their journey through the body with a non-invasive imaging procedure. This final point is the only way of verifying whether the medicines have successfully been delivered.

Finding a single solution that meets all of these requirements has been challenging. Research lead by ETH Zurich has now unveiled a special class of particles meeting all these criteria. Not only are these particles effective; they appear visually striking under a microscope too, resembling tiny paper flowers or desert roses. They are made of extremely thin petals that arrange themselves into flowers. These flower particles are one to five micrometres in diameter, which is slightly smaller than a red blood cell.

The particles resemble tiny paper flowers or sand roses and assemble in a self-organised manner. (Visualisations: Kim et al. Advanced Materials 2024, modified)

Their shape has two main advantages. Firstly, the flower particles have an enormous surface area in relation to their size. The spaces between the many densely packed flower petals are only a few nanometres wide and act like pores. This means they can absorb very large amounts of therapeutically active substances. Secondly, the flower petals scatter sound waves or they can be coated with molecules that absorb light, thus can easily be made visible using ultrasound or optoacoustic imaging.

These findings have just been reported by the groups led by Daniel Razansky and Metin Sitti in a study published in the journal Advanced Materials. Razansky is Professor of Biomedical Imaging with double appointment at ETH Zurich and the University of Zurich. Sitti is an expert in microrobotics and, until recently, was a professor at ETH Zurich and Director at the Max Planck Institute for Intelligent Systems in Stuttgart prior to moving to Koç University in Istanbul.

Better than gas bubbles

“Previously, researchers primarily investigated tiny gas bubbles as a method of transport through the bloodstream using ultrasound or other acoustic methods,” said Paul Wrede, co-author of the study and doctoral student in Razansky’s group. “We have now demonstrated that solid microparticles can also be acoustically guided.” The advantage of the flower particles over the bubbles is that they can be loaded with larger quantities of active ingredient molecules. “We don’t just inject the particles and hope for the best. We actually control them.”
Paul Wrede

The researchers demonstrated that the flower particles could be loaded with a cancer drug in Petri dish experiments. They also injected the particles into the bloodstreams of mice. Using focused ultrasound, they were able to keep the particles in a pre-determined position within the circulatory system. This was successful despite the rapid blood circulation surrounding the particles. Focused ultrasound is a technique whereby sound waves are concentrated at a localized spot. “In other words, we don’t just inject the particles and hope for the best. We actually control them,” said Wrede. The researchers are hoping that this technology will one day be used to deliver medicines to tumours or clots that block blood vessels.

This particle, which is composed of nanosheets, is three micrometres in size (electron microscope image). (Image: Dong Wook Kim / Max Planck Institute for Intelligent Systems)

The particles may be made from a variety of materials and have different coatings depending on what they are being used for and the researchers’ preferred imaging procedure for controlling the position of the particles. “The underlying working principle is based on their shape, not the material they are made from,” said Wrede. In their study, the researchers investigated flower particles made of zinc oxide in detail. They also tested particles made of polyimide and a composite material consisting of nickel and organic compounds.
Now the researchers would like to refine their concept. They are planning to conduct more animal tests first, after which the technology may become beneficial for patients with cardiovascular disease or cancer.

Reference
Kim DW, Wrede P, Estrada H, Yildiz E, Lazovic J, Bhargava A, Razansky D, Sitti M: Hierarchical Nanostructures as Acoustically Manipulatable Multifunctional Agents in Dynamic Fluid Flow. Advanced Materials, 14 October 2024, doi: 10.1002/adma.202404514