Johannes Karges and his team have developed a new mechanism of activity against cancer cells.
Photo Credit: © RUB, Marquard
Scientific Frontline: Extended "At a Glance" Summary: Hypoxic Photodynamic Therapy
The Core Concept: A novel photodynamic therapy (PDT) approach utilizing a ruthenium-based active agent to effectively destroy cancer cells even within severe, oxygen-depleted (hypoxic) tumor environments.
Key Distinction/Mechanism: Traditional photodynamic cancer treatments rely on the presence of ambient oxygen to create cell-killing reactive oxygen species, making them largely ineffective in the oxygen-starved centers of fast-growing tumors. This newly developed therapy circumvents the need for molecular oxygen entirely. When oxygen is absent, intracellular iron coordinates with the active agent, triggering an ultra-fast metal-to-metal electron transfer from the excited ruthenium center to the iron center. This process converts naturally occurring hydrogen peroxide within the cell into highly lethal hydroxyl radicals, which cause fatal oxidative damage to the cancer cells.
Major Frameworks/Components:
- Photodynamic Therapy (PDT): An established cancer treatment method where an administered, inactive substance is activated via targeted light irradiation.
- Ruthenium-Based Active Agent (Ru(II) Polypyridine–Deferasirox Conjugate): The light-activated compound capable of entering an excited electronic state to drive the reaction.
- Metal-to-Metal Electron Transfer: The alternate, oxygen-independent chemical pathway where electrons transfer from the ruthenium center to an iron center.
- Hydroxyl Radicals: Highly reactive, cell-destroying molecules generated by the conversion of cellular hydrogen peroxide during the electron transfer process.
Branch of Science: Oncology, Photochemistry, Medicinal Inorganic Chemistry, and Pharmacology
Future Application: This mechanism provides a crucial foundation for treating aggressive, fast-growing solid tumors—such as breast cancer, where it has already been demonstrated in vitro. While not yet tested in human subjects, future clinical applications aim to utilize this agent to eradicate treatment-resistant tumor cores.
Why It Matters: Rapidly growing tumors frequently outpace their vascular supply, creating "dead zones" of low oxygen that render conventional, oxygen-dependent drugs and standard PDT ineffective. By exploiting a cell's own natural metabolic byproducts (hydrogen peroxide) rather than relying on external oxygen, this pharmacological advancement offers a highly viable pathway to destroy previously incurable or therapy-resistant tumor tissue.
Most tumors grow so rapidly that vascular growth cannot keep up, and oxygen-depleted areas form within them. A new active agent could make it possible to treat them with photodynamic therapy.
Photodynamic treatment of cancer is based on administering an initially inactive substance that is only activated in the tumor via targeted light irradiation. It then generates reactive oxygen species that kill the cancer cells. However, this method reaches its limits when no oxygen is present, as is the case with many fast-growing tumors. Professor Johannes Karges’ research group at Ruhr University Bochum has achieved a breakthrough that makes the treatment of such tumors possible: When oxygen is absent, an alternative action mechanism comes into effect. This uses hydrogen peroxide, a natural metabolic product of the cells.
An entirely new action mechanism
Photodynamic therapy, or PDT, is an established method for treating cancer and is widely used in clinical practice. Karges and his team have developed an entirely new action mechanism that functions independently of the oxygen concentration within the tissue: Light converts the ruthenium-based active agent into an excited electronic state. When oxygen is present, energy is transferred to molecular oxygen, creating singlet oxygen, which has a harmful effect on cells. “This process corresponds to the conventional, oxygen-dependent mechanism of photodynamic therapy,” says Karges.
When oxygen is absent, another mechanism comes into effect. The cause is the coordination of intracellular iron to the active agent. This interaction alters the electronic characteristics of the system such that instead of a transfer of energy, an ultra-fast, metal-to-metal transfer of electrons occurs from the excited ruthenium center to the iron center. The hydrogen peroxide is thereby converted into highly reactive hydroxyl radicals. “Because hydrogen peroxide is a natural metabolic product of the cell, this process can occur independently of the molecular oxygen,” explains Karges. The hydroxyl radicals that have formed cause oxidative damage to central cellular structures and thus kill the cancer cells.
This means that the substance remains active even under severe conditions where past therapies have failed. In the current study, the researchers demonstrated this with breast cancer cells. “This method can be used for many different types of tumors, in principle,” says Karges. “However, we have not yet begun trying this out with human subjects and are working to develop this.”
Funding: The work was funded by the Liebig Grant from the Chemical Industry Fund of Verband der Chemischen Industrie, the Life Sciences Bridge Award of the Aventis Foundation, and the Paul Ehrlich & Ludwig Darmstaedter Early Career Award 2024 (issued by the Paul Ehrlich Foundation).
Published in journal: Journal of the American Chemical Society
Authors: Nicolás Montesdeoca, Zisis Papadopoulos, Hung Manh Tran, Steffi Krause Hinojosa, Henrik Sielhorst, Jacqueline Heinen-Weiler, and Johannes Karges\
Source/Credit: Ruhr-Universität Bochum | Meike Drießen
Reference Number: ongy040726_01