Freeing molecules from chemical cages
Cages may belong to zoos, but this is being challenged by new findings about intelligence other than our own. There is a push for the SeaWorlds of the globe to release the dolphins and orcas they hold in captivity. In the future we may later watch them swim freely in the vastness of the ocean while we, the onlookers, realize our thrill by watching them from a sea cage. Meanwhile, in our bodies, scientists as well have the ability to trap molecules in invisible "cages". A seemingly magical wand – made of light – is required to liberate these molecules at a precise location. But for what reason?
(Neuro)biologists developed the chemical caging technique back in the 70’s in order to study biological processes. The idea behind it is fairly straightforward, and it is just like a Trojan horse: Active compounds – soldiers – are trapped inside a larger framework – the wooden horse– which will get to release its contents at the target site only when light is shed on it. In scientific terms, this is a photochemical cleavage. This way active molecules can reach their destination by stealth, much as the hidden soldiers do before getting into the city of Troy. Once these molecules are freed, they can take part in the chemical reactions of interest.
The whole caging technique is a bit more complex to put in practice, however. The protective groups, i.e. cages, are typically small organic molecules that comply with several criteria, such as being reasonably soluble in aqueous mixtures (since reactions happen in watery biological matrices); being non-toxic to humans; and being efficient in liberating the bioactive products upon light irradiation without damaging the surrounding tissue.
Actually, this is one of the reasons that I work with a two-photon absorption instead of one-photon, along with the advantage of achieving a deeper penetration into tissues. We call these tissue-penetrating caged molecules “probes”. In practice, this means that my group is trying to develop probes that work in the biological window at higher wavelengths of light in combination with specific light sources. We put effort in improving probes in respect to their solubility, absorption, and efficiency. The final goal is to use such probes for novel biomedical applications in the future.
The caging method has been extended to various other biological research areas to date, and it has turned out to be a powerful tool to study pharmacological processes. Photocleavable units may also be built into more complex setups. In the future, such systems might allow targeted, remotely controllable and on demand medical therapies accounting for fewer side effects. The take-home message is that only the necessary amount of medicine would then be active in a given target organ of a patient, thus avoiding a drug overdose. Much like the idea that only well-trained soldiers in sufficient numbers are necessary to overcome a threat with precision. Touché!
I am Petra Dunkel, a pharmacist by training, and currently an Assistant Professor affiliated with the Department of Organic Chemistry at the Semmelweis University in Budapest, Hungary. The research work above was funded by a Marie Curie Intra‐European Fellowship under the guidance of Peter I. Dalko at University of Paris Descartes (grant: FP7‐PEOPLE‐2013‐IEF: 629675). I was recently granted two prestigious national research fellowships in my home country (ÚNKP-19-4 New National Excellence Program of the Ministry for Innovation and Technology; János Bolyai Research Scholarship of the Hungarian Academy of Sciences).
Text by Fernanda Haffner
Illustration by Laurene Gattuso