Anyone afflicted with cancer will often face a long and difficult journey. The early stages of any medical intervention will necessarily include a biopsy, tissue sample collection, such as a liquid biopsy which uses a blood sample. These aren’t perfect, but medical researchers are trying to improve them, with one such method being how to amplify the signals indicating cancer cells. This should be possible as all cells release tiny telltale particles known as extracellular vesicles. Professor Keisuke Goda from the Department of Chemistry at the University of Tokyo and his team members found a way to engineer extracellular vesicles in a way never seen before which could improve liquid biopsies and aid in some other medical and research applications..

“Each extracellular vesicle is only about a thousandth the width of a human hair and carries a tiny sample of material from the cell that made it like a little molecular ‘message in a bottle.’ Cancer cells release these packages too but finding them in blood is like searching for a few specific grains of sand on a beach,” said Assistant Professor Tianben Ding from the Department of Chemistry. “So, we developed a simple way to make both the packages and the cancer cells much easier to find. By coating the packages with tiny amounts of lanthanide metals, we made matching packages and cells stick together over 25 times more strongly. This provides a versatile platform that can improve how engineered extracellular vesicles interact with their target cells, enabling applications ranging from cancer detection to targeted drug delivery and rejuvenation.”

The researchers named the enhanced effect super homotypic targeting because it dramatically amplifies cells’ natural tendency to recognize others of the same type. Rather than creating a single new diagnostic test, the researchers see the technique as a platform for engineering extracellular vesicles to perform different tasks. For the purpose of this study, they focused on sialic acid, a sugar abundantly present on the surface of many cancer cells. Lanthanide ions such as europium and terbium bind strongly to this sugar, allowing engineered extracellular vesicles to form much stronger interactions with cells of the same type.

“By decorating extracellular vesicle surfaces with these ions, we effectively added many extra ‘grips,’ so extracellular vesicles and cells of the same lineage bound to one another more strongly, and a capture process that used to take more than two days finished in about three hours,” said Ding. “Using a cell’s own vesicles, upgraded with metal ions, as a way to boost recognition between same-type cells is a new concept. We’re thrilled that we could turn it into two working diagnostic tools with record-breaking sensitivity, rather than just making a single small improvement.”

The team demonstrated these techniques and their results first in cell cultures, then in mice test subjects, and finally in human triple-negative breast cancer samples. The tools referred to above serve as a detector that captures a cancer’s extracellular vesicles and as a probe made of an extracellular vesicle that finds cancer cells to amplify their signals. The latter effectively boosts the signal indicating presence of a cancer cell by a factor of 10,000. This makes even a single cell in a relatively large sample possible to find with a set of typical lab equipment, achieving extreme sensitivity and extreme selectivity at the same time.

“The biggest challenge was achieving both extreme sensitivity and extreme selectivity at the same time. Cancer signals in blood are hard to detect with just a few dozen extracellular vesicles in a milliliter of serum, or a single cancer cell among billions of healthy blood cells,” said Ding. “Making a test more sensitive means detecting more false signals too, so we carefully optimized the chemistry to strengthen the binding between matching cells and extracellular vesicles while minimizing unwanted interactions. We also developed a way to amplify the signal around 10,000 times, making even a single cancer cell detectable. Seeing this work consistently in cultured cells, mice and patient samples made all the effort worthwhile.”