Final Report Summary - RUPROLIGHT (Light-activatable ruthenium-based anticancer prodrugs)
This ERC project aimed at studying the preparation and biological activity of a new family of photoactivated chemotherapy (PACT) compounds based on ruthenium, a metal with finely tunable photochemical properties. Ru-based PACT compounds lie at the crossing point between photodynamic therapy (PDT) sensitizers, which kill cancer cells by absorbing light and transferring its energy to the dioxygen molecules present in the tumor, and metal-based anticancer drugs such as cisplatin, which kill cells by binding to nuclear DNA. Like in PDT the aim of PACT compounds is also to kill cancer cells only at the place of light irradiation, and thus to avoid the side effects of conventional chemotherapy, but the phototoxicity is in principle independent on the presence of dioxygen in the tumor tissues, because the activation mechanism is independent on dioxygen.
During this project the researchers found out that PACT should be developed for treating dioxygen-poor tumors, a subset of tumors that are particularly difficult to treat with most existing treatments. They experimentally demonstrated for the first time that indeed ruthenium-based PACT were equally activated by light irradiation in cancer cells grown under low dioxygen concentration, than in cancer cells grown under air. To do these studies, the researchers built a special setup capable of shining blue, green, or red light in highly reproducible conditions onto cancer cells grown under low dioxygen concentrations. The researchers obtained this results by using nitrogen- or sulfur-based protecting ligands, that bind strongly to the metal in the dark and prevent the metal to interact with DNA, but that upon light irradiation are cleaved off the molecule, thereby recovering its DNA-binding properties.
Another question looked at by the researchers was that of the color of the light necessary to activate the ruthenium compound. Red or near-infrared light penetrates much better into biological tissues and is more suited for phototherapy. However, the energy of each photon in red or NIR light beams is usually too low for triggering the photochemistry of ruthenium compounds. Blue light, on the other hand, has more energy, but it penetrates less far into biological tissues. To solve this problem, the researchers found two different solutions. First, they looked at upconverting drug delivery systems that can “upgrade” red or NIR photons into green or blue photons. These high-energy photons can then be transferred to the ruthenium prodrug attached to the nanoparticle, and activation of the compound is accompanied by its release from the nanoparticle surface. Upconverting drug delivery systems were studied in detailed in this ERC project. The researchers found that indeed PACT ruthenium compounds can be activated using 800 or 980 nm light that lies in the NIR region of the spectrum. However, they also realized that the amount of light necessary to trigger drug activation and release is too high for clinical applications, where reasonable light irradiation times (<60 min) and intensities (<1 W.cm-2) are required.
A second solution to the problem of the activation wavelength is more straightforward: For a long time chemists thought that light should be irradiated at wavelength where the compound absorbs best. However, the ERC researchers found out that it is perfectly acceptable to have a slight misfit between the wavelength of activation, and the wavelength where the compound absorbs best. For example, green light can activate pretty well ruthenium compounds that absorb better in the blue region of the spectrum, and red light can activate compounds that absorb better in the green region of the spectrum. Overall, one of the important outcomes of this project is that it is possible to make ruthenium compounds that can be directly activated with red light, and that such compounds represent excellent potential for phototherapeutic applications in oxygen-poor tumors.
During this project the researchers found out that PACT should be developed for treating dioxygen-poor tumors, a subset of tumors that are particularly difficult to treat with most existing treatments. They experimentally demonstrated for the first time that indeed ruthenium-based PACT were equally activated by light irradiation in cancer cells grown under low dioxygen concentration, than in cancer cells grown under air. To do these studies, the researchers built a special setup capable of shining blue, green, or red light in highly reproducible conditions onto cancer cells grown under low dioxygen concentrations. The researchers obtained this results by using nitrogen- or sulfur-based protecting ligands, that bind strongly to the metal in the dark and prevent the metal to interact with DNA, but that upon light irradiation are cleaved off the molecule, thereby recovering its DNA-binding properties.
Another question looked at by the researchers was that of the color of the light necessary to activate the ruthenium compound. Red or near-infrared light penetrates much better into biological tissues and is more suited for phototherapy. However, the energy of each photon in red or NIR light beams is usually too low for triggering the photochemistry of ruthenium compounds. Blue light, on the other hand, has more energy, but it penetrates less far into biological tissues. To solve this problem, the researchers found two different solutions. First, they looked at upconverting drug delivery systems that can “upgrade” red or NIR photons into green or blue photons. These high-energy photons can then be transferred to the ruthenium prodrug attached to the nanoparticle, and activation of the compound is accompanied by its release from the nanoparticle surface. Upconverting drug delivery systems were studied in detailed in this ERC project. The researchers found that indeed PACT ruthenium compounds can be activated using 800 or 980 nm light that lies in the NIR region of the spectrum. However, they also realized that the amount of light necessary to trigger drug activation and release is too high for clinical applications, where reasonable light irradiation times (<60 min) and intensities (<1 W.cm-2) are required.
A second solution to the problem of the activation wavelength is more straightforward: For a long time chemists thought that light should be irradiated at wavelength where the compound absorbs best. However, the ERC researchers found out that it is perfectly acceptable to have a slight misfit between the wavelength of activation, and the wavelength where the compound absorbs best. For example, green light can activate pretty well ruthenium compounds that absorb better in the blue region of the spectrum, and red light can activate compounds that absorb better in the green region of the spectrum. Overall, one of the important outcomes of this project is that it is possible to make ruthenium compounds that can be directly activated with red light, and that such compounds represent excellent potential for phototherapeutic applications in oxygen-poor tumors.