Researchers from the Institute of Advanced Chemistry of Catalonia (IQAC) of the CSIC have developed a series of drugs, photosensitive molecules, which can be reversibly activated by external light, thus achieving a much more localized and controlled effect.
This research, published in the journal Journal of Medicinal Chemistrypoints out that photopharmacology (drugs controlled by light) paves the way for highly specific therapies that may open new avenues for the treatment of diseases such as cancer.
Drugs were developed, photosensitive molecules that are reversibly activated by light, achieving a much more localized and controlled effect.
A limitation of cancer drugs is that they often cannot fully differentiate between cancer cells and healthy cells. This lack of selectivity in current chemotherapy limits its therapeutic window, which decreases the effectiveness of the treatment and causes unwanted side effects.
“Photosensitive drugs, whose activity can be reversibly controlled precisely with external light, can solve this problem, as they provide great control of the site of action and for the desired time, thus reducing side effects and increasing their effectiveness.”, explains Laia Josa Culleré, researcher in the Medicinal Chemistry and Synthesis group at IQAC and main author of this study.
New advances in light-regulated drugs
The use of light is especially attractive in the investigation of new addressable antitumor drugs, as it allows the control of antitumor activity by adjusting parameters such as wavelength, intensity and exposure time.
Photosensitive drugs provide great control over the site of action and for a desired time, thus reducing side effects and increasing their effectiveness.
Laia Josa Culleré, lead author of the study
Thus, photosensitive molecules change their structure when illuminated under particular light conditions, so that an effect on specific target receptors can be induced under light control. This may allow external control of the drug’s therapeutic effect with greater precision.
“So far, this type of medicine is in the experimental phase for applications in the retina or pain, but for now there are not many studies with good results in oncology”, clarifies the researcher.
This study focused on a common target in oncology: histone deacetylase (HDAC) enzymes.
This study focused on a common target in oncology, histone deacetylase (HDAC) enzymes. When these enzymes are regulated incorrectly, they prevent the expression of certain genes, such as tumor suppressors, and therefore, under these circumstances, cells are more likely to become cancer cells. For this reason, several drugs are being developed with the aim of inhibiting poorly regulated HDACs in order to slow the progression of this disease.
Currently, there are conventional drugs that act on these enzymes, but they have low selectivity and toxic effects. Therefore, this research focused on designing molecules based on these conventional drugs, but which could be reversibly regulated by light, allowing their activity to be controlled by changes in lighting conditions.
These types of drugs are in the experimental phase for applications in the retina or pain, but so far there are not many studies with good results in oncology.
Early results showed that when these molecules were activated by light, they inhibited HDACs, as opposed to when they were inactive in the dark. The limitation of these first molecules is that they required ultraviolet light to be activated, which can be harmful to cells and have low penetration into biological tissues. Therefore, the molecules were optimized to activate in green light (visible light), also obtaining better results under illumination than in the dark.
The results showed an increase in cancer cell death after green light illumination.
Finally, the activity of these molecules was verified in four cancer cell lines: cervical, breast, leukemia and colon. Results showed increased cancer cell death after green light illumination, but had no effect when kept in the dark. “One of the strengths of the study is that these molecules were able to activate with visible light (green), while almost all molecules described against cancer are activated with ultraviolet light, which is less effective and limits the approach for in vivo tests and in patients”, explains Amadeu Llebaria, head of the Chemistry and Medicinal Synthesis group at IQAC.
Objective: more specific and controlled therapies
As a result of the study, the researchers developed a small library of drugs, photosensitive molecules, which make it possible to control the viability of the cells just by illuminating them with visible light, which is more permeable and less harmful to the cells. It is believed that these results will open the way, in the future, to be able to study the effect of these molecules in vivo, in zebrafish or in mice, selectively illuminating the tumor area to activate the drug, while it is kept in the rest of the body in its inactive form, avoiding unwanted side effects on healthy tissues.
“We believe that the study of these photosensitive molecules is important to establish an in vivo proof of concept on the use of photopharmacology to treat cancer more effectively and safely”, concludes Josa Culleré.
Josa, L. et al. Visible Light Controlled Histone Deacetylase Inhibitors for Targeted Cancer Therapy. JMedicinal Chemistry Seminar (2023).