Light therapy
Photodynamic therapy in oncology
Photodynamic therapy is widely regarded as one of the most precise tools in modern oncology. Yet despite its elegance, its clinical outcomes can be surprisingly difficult to predict. The therapy relies on a photosensitizing compound that, when activated by light, produces singlet oxygen—a highly reactive form of oxygen capable of destroying cancer cells. Even with refined protocols and state-of-the-art dyes, patients with seemingly similar tumors can respond very differently.
Research led by Dr. Maciej Spiegel of Wroclaw Medical University offers a compelling explanation for this inconsistency. The effectiveness of PDT, he argues, cannot be traced to a single variable such as tumor biology or light dosage. Instead, it is governed by ultrafast processes unfolding on femtosecond and picosecond timescales—within individual molecules themselves.
At these extreme timescales, photochemical reactions determine whether absorbed light energy is converted into a therapeutic weapon or dissipated harmlessly as heat. If energy is lost too early, the photosensitizer’s potential is exhausted before it can act, rendering the treatment ineffective.
The Microenvironment as a Molecular Switch
In a study published in Dyes and Pigments, Dr. Spiegel applies quantum chemical methods to investigate rubiadin, a naturally occurring plant pigment found, among other sources, in madder (Rubia tinctorum). His analysis reveals that the photodynamic activity of this compound depends decisively on the microenvironment of the cancer cell. Subtle changes in local conditions determine whether rubiadin becomes a potent antitumor agent—or remains chemically inert.
Dr. Maciej Spiegel, PhD (PharmD), Department of Organic Chemistry and Pharmaceutical TechnologyFaculty of PharmacyWroclaw Medical University
Dr. Maciej Spiegel, PhD (PharmD), Department of Organic Chemistry and Pharmaceutical TechnologyFaculty of PharmacyWroclaw Medical University
Dr. Spiegel uses rubiadin as a model to understand the variability of therapeutic results. This compound absorbs light effectively, yet its efficacy hinges on the presence of just one proton. This seemingly minor structural difference drastically alters the molecule's photophysical properties.
— In a slightly acidic environment, the neutral form of rubiadin generates singlet oxygen very efficiently, — explains Dr. Spiegel. — However, at a pH close to physiological levels, the dissociated form dominates, which dissipates energy through processes that do not lead to phototoxicity.
Only the neutral molecule undergoes ultrafast intramolecular proton transfer in the excited state. This process directs energy to the triplet state, which is requisite for the production of destructive singlet oxygen. However, this molecular “switch” fails in the case of an anion; consequently, the light energy is dispersed, and the therapeutic effect vanishes.
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The Ion Trap and Protection of Healthy Tissues
However, this phenomenon offers a beneficial effect regarding phototoxicity for healthy tissues. Cancer cells are characterized by an inverted pH gradient compared to healthy cells—they are acidic on the outside and alkaline on the inside. Thus, rubiadin molecules in the vicinity of cancer cells are effectively absorbed into the cell.
The subsequent rapid dissociation, in turn, traps them inside the cell, as ion transport across membranes is limited. As a result, the inactive anionic forms constitute a reservoir that gradually replenishes the depleting concentration of the neutral form.
Why Does “More” Not Mean “Better”?
Dr. Spiegel's research sheds new light on the optimization of treatment protocols. It appears that increasing the light dose does not always improve results and may even be counterproductive. Mathematical models indicate, among other findings, that excessive irradiation leads to a rapid depletion of local tissue oxygen reserves before the blood can replenish them. Success, therefore, depends on the precise balancing of all components of photodynamic activity.
— If the dye's mechanism of action depends solely on oxygen, excess light becomes harmful, — emphasizes the scientist. — Energy that is not utilized in the chemical reaction is transferred to nearby tissues, increasing the risk of damage to healthy areas.
In this context, rubiadin exhibits unique properties. In addition to generating singlet oxygen and oxygen radicals, it can directly oxidize biomolecules, including DNA, via its triplet state. Furthermore, this compound intercalates into the DNA double helix. This process not only potentially blocks cancer cell proliferation but may also sensitize the genome to direct light exposure.
A Broader Perspective
By combining molecular modeling with oncology, Dr. Spiegel advocates for a paradigm shift in the search for new drugs. Despite numerous publications reporting newly synthesized dyes, clinical applications remain rare because studies often fail to account for the physicochemical complexity of a living organism.
— The photosensitizer is the key, and the tumor tissue is a complex lock, — notes the researcher. — Success depends not only on the shape of the key but also on the mechanics of the lock.
The future, therefore, lies in designing precise therapeutic protocols tailored to the specific combination of microenvironmental conditions and the drug employed.
Only then will light in oncology become a fully predictable tool, rather than just a promise.
D. Sikora
FAQ: Precision at the level of the cell
What is rubiadin, and what are its potential medical applications
Rubiadin is a natural compound from the anthraquinone group, isolated from the roots of plants in the Rubiaceae family, such as Rubia cordifolia and Rubia tinctorum. Due to its planar, highly conjugated aromatic structure, this molecule can effectively absorb light, making it a promising photosensitizer for photodynamic therapy. Its unique structure allows for selective therapeutic action, reducing the risk of systemic side effects typical of conventional oncology
What physicochemical process determines the high efficiency of the triplet state of rubiadin?
The compound's quantum efficiency is due to ultrafast intramolecular proton transfer in the excited state. In its neutral form, this process occurs on a sub-picosecond timescale and is virtually barrier-free, leading to immediate tautomerization of the molecule. This specific phenomenon opens highly effective intersystem crossing channels to triplet states, which are necessary to initiate the photochemical reactions that destroy the tumor. The anionic form is not subject to this process, which explains its molecular inertness.
How does the pH of the environment affect the phototoxic activity of rubiadin?
The core of the compound's action lies in its acid-base balance. In the extracellular, slightly acidic environment of the tumor, rubiadin exists in its neutral form, allowing it to diffuse freely across lipid membranes into cells. However, due to the higher (physiological or slightly alkaline) pH of the cytosol, the threshold (pH 7.3–7.5) is exceeded, and the compound is deprotonated to its anionic form. This generates a so-called "ion trap": the phototoxically inactive, negatively charged anion loses its ability to diffuse back out and becomes trapped inside the cell. As a result, rubiadin accumulates selectively in the tumor, creating a permanent reservoir that gradually replenishes the concentration of the active neutral form as it is consumed during irradiation
What molecular mechanisms and targets determine the phototoxicity of rubiadin?
The results indicate the coexistence of three pathways of cell structure destruction, establishing rubiadin as a multitarget photosensitizer. The key pathway (Type II) involves the direct transfer of energy from the dye's triplet state to molecular oxygen. This process occurs with near-unity efficiency for the neutral form, leading to the formation of singlet oxygen—the primary agent in destroying cancer cells. An important auxiliary role is played by the Type III mechanism, in which excited rubiadin directly oxidizes biomolecules, allowing for effective phototoxicity even under hypoxic (oxygen-deficient) conditions. Conversely, the mechanisms that generate reactive oxygen species via radical processes (Type I) are characterized by a high activation barrier, despite the rapid kinetics of the initial reactions. This limits the efficiency of superoxide radical generation, which is why this pathway plays only a secondary role for rubiadin.
What do mathematical models say about the stability of rubiadin therapy?
A model based on ordinary differential equations has demonstrated that this system exhibits high self-organization and stability. This implies that the effectiveness of rubiadin therapy should be less sensitive to microscopic environmental variability.
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This material is based on the article:
Author: Maciej Spiegel
DOI: https://doi.org/10.1016/j.dyepig.2025.113387
Web. A. Maj
Photos: freepik.com
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