By Dona Suri
A team of researchers at Ulsan National Institute of Science and Technology (Ulsan, Korea) has created a “nanodrone” that binds and transports Natural Killer (NK)* cells straight into the middle of tumours where the NKs wipe out cancerous cells.
The bio-engineered particle was tested on cancerous mice. (The cancer cells were of the SK-OV-3 type which is a drug-resistant human ovarian cancer cell line.) The tumour was suppressed with no noticeable side effects.
The success of the UNIST researchers’ experiment opens the door to effective treatment of previously intractable types of cancers.
The team, led by Professor Sebyung Kang and Professor Sung Ho Park, call the particle that they created a “nanodrone“.
The word immediately prompts science fiction readers to recall Fantastic Voyage, a 1966 film, transformed into a novel by Isaac Azimov. The UNIST nanodrone bears no resemblance to the cinematic depiction. For one thing, it does not feature curvaceous Raquel Welsh in a diver’s wet suit. (It’s a white wet suit because she plays a doctor!)
The UNIST appellation is descriptive in so far as the particle has the shape of a spherical, hollow cage and in so far as it picks up NK cells and quickly delivers them to specific cancer cells where the NKs get down to their search and destroy mission. But, the simplicity of the term belies the enormous complexity of the particle itself, how it is fabricated and how it operates.
The press release issued by UNIST was written by scientists for scientists. It is full of terms and concepts from the field of molecular biology. So much so that when an ordinary person, even a reasonably educated one, reads through it, he/she is likely to feel a distinct numbness in the prefrontal cortex. Reach all the way to the last sentence … and remain none the wiser.
What the UNIST team did is so astounding and important that it should become widely known and understood. Certainly it is worth the effort to translate the UNIST release from technical language to everyday prose. Here is the result of quite a lot of homework: it is an explanation in plain words, accompanied by a glossary of words and processes.
The transporter is called NKeND (short for NKcell-engaging NanoDrone).
It all starts with a bacterium called Aquifex aeolicus. The characteristics of A. aeolicus are:
It is chemolithoautotrophic – meaning it eats/oxidises inorganic compounds.
It is hyperthermophilic– meaning that it thrives in extremely hot environments—from 140 °F upwards
It is gram-negative – meaning that it has a thin peptidoglycan cell wall guarded by a strong, starchy outer membrane.
And it can move around.
A. aeolicus is processed to get Aquifex aeolicus Lumazine Synthase* (AaLS). This synthase is naturally occurring and it has several advantages when the objective is to load other stuff onto it.
AaLS self-assembles to form symmetrical macromolecules. A macromolecule of AaLS looks like virus.
It forms up in such a way that it leaves a space inside – a nanocompartment.
The symmetry of this macromolecule can be tweaked; it is a malleable scaffold.
It accommodates immunogens (molecules capable of eliciting an immune response). B cell receptors attach to AaLS macromolecules. (B cells make antibodies; antibodies are infection-fighting proteins.)
AaLS was used to make a protein cage whose shape allowed for the incorporation of cancer targeting ligands*.
The UNIST team attached three ligands to the protein cage and these ligands connected to affibodies*. The affibodies hook up the NK cells.
The two affibodies used were HER2Afb or EGFRAfb. Additionally, the protein cage incorporated a ligand that recruited NK cells. The name of this ligand is CD16Nb.
Both HER2 and EGFR are kinases, which means that they are enzymes that catalyze the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation. They bind with residues of a type of amino acid called tyrosine in targeted proteins.
Both HER2 and EGFR belong to the Epidermal Growth Factor Receptor family. HER2 stands for Human Epidermal growth factor Receptor 2 and EGFR stands for Epidermal Growth Factor Receptor.
To attach these ligands and affibodies, the UNIST team used a system called SpyCatcher/SpyTag*. This system enabled them to load everything onto the surface of a single AaLS particle.
In the announcement of their achievement, the team said that they “utilized a ST-fused AaLS (AaLS-ST) as a nanoplatform”.
“ST-fused”? …. Hmmmmm.
The light bulb finally clicks on. ST stands for Spy Tag !
Voila ! Behold, the fully loaded particle.
The UNIST team achieved their NKeND “nanodrone”, loaded it up and launched it into the bloodstream of the mice where it recruited patrolling NK cells. The NKeND hooked into the ovarian cancer cells and the NK cells attacked and killed them.
Here’s what the researchers’ announced (in plain words):
What we did
We grafted human ovarian cancer cells onto mice.
Using AaLS macromolecules to create a protein cage, we fabricated a transporter.
We selected the peptides most suitable for attracting and binding Natural Killer cells.
Using the Spy Catcher/Spy Tag mechanism, we attached the peptides to the protein cage transporter.
We injected the transporter into the bodies of the cancerous mice.
How it worked
To find out whether and how fast the NKeNDs found the tumour, we used two methods: The rosette forming assay and flow cytometry. This evaluation was done in a petrie dish (in vitro).
Rosette assay revealed the presence of the NKeNDs near the tumour site and flow cytometry showed that tumour cells had been destroyed by the NK cells.
We also observed that this operation had no side effects.
We conclude
The NKeND loaded with Natural Killer cells can effectively target tumour sites and suppress tumour growth.
