22nd September 2023

Johannes Karges: Metal complexes as precision drugs

It’s a very new approach to treating metastases.
German version/Deutsche Version
Metal complexes have been among the most widely used anti-cancer drugs for almost 50 years. Cisplatin and its derivatives are still administered in more than half of all first-line chemotherapies worldwide. However, because they poison cancer cells as well as healthy cells, they produce severe side effects. Compared with modern targeted cancer therapies that intervene in specific signaling pathways of tumor development or unleash the powers of the patient’s own immune system, traditional metal complexes therefore seem to have long since lost their permanent place in oncology in the eyes of many physicians. Johannes Karges’ research could prove them wrong. The young chemist is in the process of turning metal complexes back into beacons of hope by developing them into precision weapons against tumors under the control of light or ultrasound.

Initial spark at Imperial College
Metal complexes are compounds centered on a metal surrounded by organic ligands. In inorganic chemistry, they are preferably used as catalysts. Johannes Karges knew them in this role after completing his bachelor’s degree in Marburg. Bio-inorganics was not on the curriculum there. The medical significance of metal complexes was therefore unknown to him. This changed after he was awarded an Erasmus scholarship at the beginning of his master’s studies, which he used for a six-month research stay at Imperial College in London. He joined Ramon Vilar’s group, which is dedicated to chemical biology. Among other things, it is studying how metal complexes interact with four-stranded DNA and whether this will lead to approaches to cancer therapy. Metal complexes have the advantage that they are usually three-dimensional structures and thus fit better into the binding pockets of nucleic acids or proteins than planar organic carbon compounds. Karges was given the task of synthesizing metal complexes and testing their biological effects. “The possibility of applying metal complexes medicinally fascinated me,” he recalls. “So I decided to go further in the biomedical direction.” The free structure of the Marburg master’s program in chemistry offered him the best opportunity to do so. In lectures and practical courses, he immersed himself in biological and pharmaceutical topics. His master’s thesis, in which he dealt with the design and synthesis of a potential targeted active ingredient from the class of methyltransferase inhibitors, was not completed in a laboratory of the chemistry faculty, but at the Center for Tumor and Immunobiology Marburg.

Suddenly in Paris
Now his biological knowledge had progressed far enough to combine it with the knowledge he had gained in London about metal complexes and the findings from his bachelor’s thesis. In it, he had experimented with lasers that pulsed at an unimaginably fast rate of 10-15 seconds. At the University of Zurich at the time, Gilles Gasser was conducting research on directing lasers at metal complexes to further develop photodynamic cancer therapies. These were the multidisciplinarity and originality Karges was looking for. If he earned his doctorate with Gasser, he hoped, then the various puzzle pieces of his previous education would fit together into a whole. But no sooner had he applied to Gasser than he was told by him that he was leaving Zurich to start his own group in inorganic chemical biology, without already knowing where. “I’m enthusiastic about your research, I’ll follow you anywhere,” Karges replied. And shortly thereafter found himself as Gasser’s first doctoral student at Chimie ParisTech, in almost empty rooms, so that he was actively involved in building a new laboratory from scratch.

Red light for ruthenium
Photodynamic cancer therapies are based on the action of photosensitizers. These molecules are enriched in the tumor tissue, which is then specifically irradiated with light. Because they can chemically convert the energy of the absorbed light to produce extremely reactive oxygen, they can destroy the cancer cells.  The most common photosensitizers are porphyrins, organic substances that are poorly soluble in water and have low stability. The most frequently applied therapeutic agent of this type is a mixture of more than 80 different porphyrins. To improve their limited applications and make them therapeutically useful in a purer form, Johannes Karges set out in his doctoral thesis to develop novel photosensitizers based on metal complexes. He focused on a class of complexes of the transition metal ruthenium. “These compounds proved to be very biocompatible, showed hardly any side effects and, most importantly, had quite strong photophysics.”  The absorption of light energy enabled them to catalyze the formation of oxygen radicals and thus kill tumor cells. However, ruthenium complexes were limited in their effectiveness before Karges’ doctorate by the fact that they only absorbed short-wave light, but this blue light only penetrates about a millimeter deep under the skin. “So I designed ruthenium complexes on the computer that absorb long-wave red light.” The design was followed by synthesis, photophysical characterization and then the first tests in cultures of cancer cells. A six-month doctoral student exchange between the groups of Gilles Gasser in Paris and Hui Xiao at Sun Yat-Sen University in Guanghzhou gave Karges the opportunity to test his most promising ruthenium complexes in animal experiments in China. “We studied mice there with tumors that were considered incurable. When we treated them with photodynamically activated ruthenium complexes, the tumors regressed significantly.” [1]


Four-dimensional cisplatin control
With smart consistency, Karges took the next step in collaboration with Xiao: He packaged a nontoxic precursor of the cancer drug cisplatin into nanoparticles and injected them into mice suffering from an intestinal tumor. The nanoparticles were too large to penetrate healthy tissue, whose cells are tightly fused together, but small enough to squeeze between cancer cells, whose cohesion is patchy because of their very rapid growth. He then converted the selectively enriched precursor in the tumor into the active drug using the energy of focused ultrasound rather than light. Even long-wave light hardly travels further than one centimeter when passing through an organism, whereas ultrasound waves travel ten times that distance. This means that one day they could also reach most tumors in humans. In this way, Karges and Xiao succeeded in spatially and temporally precisely controlling the administration of the highly effective cell poison cisplatin – with the result that the intestinal tumors of the mice disappeared. Johannes Karges achieved this spectacular success with his first own research group at the Ruhr-Universität Bochum.[2]

Rhenium against SARS-CoV-2
As a postdoctoral researcher, he had previously investigated the suitability of metal complexes as enzyme inhibitors at the University of California in San Diego. The question as to which enzyme he should focus on soon became clear. Karges arrived in California shortly before the outbreak of the pandemic. So he concentrated on developing a rhenium complex to inhibit the protease of the new coronavirus, an approach whose basic feasibility he was able to demonstrate. Endowed with a Liebig Fellowship from the German Chemical Industry Association, Karges returned to Germany in the fall of 2022. In Bochum, he joined the Department of Bioinorganic Chemistry. Its head, Nils Metzer-Nolte, had offered to support him with his resources in setting up a junior research group.

Activation of the immune defense against metastases
One of this group’s main projects is aimed at destroying as many cancer cells as possible from cancer patients, i.e., not only the primary tumor but also any metastases that have spread throughout the body from it. Karges’ plan is to let these cells die an immunogenic cell death (ICD). This type of cell death elicits an immune response that not only affects the dying cancer cell but extends to all similar-looking cells. This is because the dying cell exhibits damage-associated molecular patterns (DAMPs) on its membrane, which remains intact. On the one hand, these DAMPs attract phagocytes that eat the dying cell, and on the other hand, through their interaction with antigen-presenting cells, lead to the recruitment of killer T cells against all other cancer cells in the body that indicate that they have a similar problem to the one that has just perished. The induction of an ICD that acts both locally and systemically has been tested as a means of cancer therapy for several years, including the combination of platinum complexes with immune-stimulating checkpoint inhibitors. Karges and his group are in the process of showing that it may be better without checkpoint inhibitors. To do this, he links metal complexes such as cisplatin with chemical address signals so that they migrate from the cell nucleus, where they normally reside, to the endoplasmic reticulum (ER).

Healing stress through aggressive oxygen?
Stress in the ER is in fact a major cause of immunogenic cell death. In this case, stress means that a large amount of reactive oxygen species is formed, which severely disrupts transport processes and protein folding in the ER. “If we make metal complexes in the ER catalysts of the formation of aggressive oxygen, then we only need very small amounts of it to trigger immunogenic cell death, for example, by light irradiation,” says Karges. “The immune system can then attack throughout the body, not just where we have our chemotherapeutic agent.” He says he and his group had proven that this concept works, and the publication on it had already been accepted: “We’ve given mice several tumors that are considered incurable and seen that they all regress, even if we treat only one of these tumors with our compound.” Which metal is best for this was not yet clear, he says. This type of research was really in its infancy, he says. “It’s a very new approach to treating metastases,” Karges sums up. “It has high potential, but whether it will eventually lead to a goal, I can’t say yet.”[3]

A globetrotter with a clear compass
However, it is certain that he will not lose sight of this goal and will pursue it with perseverance – also because he developed the ability to inspire others for a common goal and to take them along with him there at an early age. In the remote village of 1,000 souls in the Rhön region where he grew up, he built up a church youth group, which he led for years. In Marburg, he later served as an ambassador for the Erasmus program. “Without my own Erasmus scholarship, I wouldn’t be where I am today,” he says. “Everyone should have at least one such experience abroad to better understand other people’s perspectives and come up with new ideas for their research.” In his own career, Johannes Karges has always been inspired by foreign ideas and has taken on the challenge of learning something completely new in every place he has traveled to. For good reason, the Ruhr University’s Department of Chemistry welcomed him last November with the words, “A trip around the world. Next stop: Bochum”. It won’t have been the last stop. His journey to a tenured professorship is supported by the Aventis Foundation with a Life Sciences Bridge Award.

Author:  Joachim Pietzsch, Wissenswort
Photos: © Uwe Dettmar

[1] J. Karges, S. Kuang, F. Maschietto, O. Blacque, I. Ciofini, H. Chao, G. Gasser, Rationally Designed Ruthenium Complexes for 1- and 2-photon Photodynamic Therapy, Nat. Commun. 2020, 11, 3262.

[2] G. Liang, T. Sadhukhan, S. Banerjee, D. Tang, H. Zhang, M. Cui, N. Montesdeoca, J. Karges, H. Xiao, Reduction of Platinum(IV) Prodrug Hemoglobin Nanoparticles with Deeply-Penetrating Ultrasound Radiation for Tumor-Targeted Therapeutically Enhanced Anticancer Therapy, Angew. Chem. Int. Ed. 2023, 63, e202301074.

[3] L. Zhang, N. Montesdeoca, J. Karges, H. Xiao, Immunogenic cell death inducing metal complexes for cancer therapy, Angew. Chem. Int. Ed. 2023, 62, e202300662.