Description of the mechanism could enhance the efficiency of photodynamic therapy, a medical treatment for cancer and bacterial infection, and permit the development of more efficient sunscreens (image: Journal of the American Chemical Society)
Published on 05/13/2021
By André Julião | Agência FAPESP – The incidence of light plays a key role in the changes undergone by human cells. A well-known example is sunlight, which can cause skin aging and cancer. How this happens, however, is poorly understood.
For the first time, researchers have succeeded in describing the mechanism by which light destroys lipid membranes, which can lead to cell death. Potential future applications of the discovery include more efficient versions of photodynamic therapy, a medical treatment for some kinds of cancer and bacterial infection. In addition, knowledge of the mechanism paves the way to the development of more efficient sunscreens and skin protection products.
To date, researchers have defined parameters for the creation of molecules that are more efficient at damaging membranes to make cells more susceptible to photodynamic therapy. Their results, published in Journal of the American Chemical Society, derive from the PhD research of Isabel Bacellar at the University of São Paulo’s Chemistry Institute (IQ-USP) in Brazil, under the aegis of the Center for Research on Redox Processes in Biomedicine (Redoxome), one of the Research, Innovation and Dissemination Centers (RIDCs) funded by FAPESP.
Part of the study was performed with a scholarship for a research internship abroad.
“We show that when it comes to choosing a photosensitizer [a substance that can be activated by light in order to damage cell membranes], it’s not enough to look only at how much singlet oxygen [a powerful reactive oxygen species] it generates, as has been done hitherto,” said Bacellar, currently a postdoctoral fellow at the University of Montreal in Canada. “Singlet oxygen is important, but we discovered that the key to the membrane damage process is the amount of lipid aldehydes produced by the photosensitizer.” Lipid aldehydes open pores in cell membranes and lead to extrusion of the contents of cells or their organelles.
“Once you understand the membrane damage mechanism, you can develop a molecule that’s more efficient both in destroying the membranes of organelles in the case of cancer and bacterial infection, and in preventing the damage caused by exposure to sunlight,” said Mauricio da Silva Baptista, Full Professor at IQ-USP and principal investigator for the study.
From butter to skin
Every cell is surrounded by a membrane composed of a double layer of lipids that separates it from the external environment. Phospholipids form the structural framework for this bilayer and tend to undergo oxidation, which can make the membrane permeable and lead to cell death. Using light to induce oxidation can significantly increase the extent of lipid damage.
“Lipid oxidation occurs even in the dark, but light intensifies it. A similar process occurs in butter, which contains lipids and becomes rancid if left outside the refrigerator for too long. That’s also lipid oxidation,” Baptista said.
To arrive at the results, the researchers used an experimental model involving two photosensitizers applied to artificial membranes made of substances present in cell membranes. The photosensitizers were methylene blue and DO15.
DO15 performed better, making the membranes more permeable significantly faster than methylene blue. The researchers then identified and quantified the substances produced by chemical reactions between the membranes and the photosensitizers, such as hydroperoxides, alcohols, ketones and phospholipid aldehydes, to understand the mechanisms and why DO15 was more efficient in permeabilizing the membranes. The most important finding was a significant increase in aldehyde production in the presence of DO15.
“Singlet oxygen, hitherto considered the most important agent in this process, and hydroperoxide are indeed important, but our study shows that the production of aldehyde is the main factor in the destruction of the lipid membrane,” Bacellar said.
Baptista’s group and collaborators are now working on the development of even more efficient molecules than DO15 to make cell membranes more light-sensitive. If they succeed, it may be possible to produce new photosensitizers for photodynamic therapy.
The article “Photosensitized membrane permeabilization requires contact-dependent reactions between photosensitizer and lipids” (doi: 10.1021/jacs.8b05014) by Isabel O. L. Bacellar, Maria Cecilia Oliveira, Lucas S. Dantas, Elierge B. Costa, Helena C. Junqueira, Waleska K. Martins, Andrés M. Durantini, Gonzalo Cosa, Paolo Di Mascio, Mark Wainwright, Ronei Miotto, Rodrigo M. Cordeiro, Sayuri Miyamoto and Mauricio S. Baptista can be read at pubs.acs.org/doi/10.1021/jacs.8b05014.