Platinum complexes are one of the most commonly used drugs against cancer. They are successful, but have serious side effects. An international research team led by Dr. Johannes Karges from the Department of Chemistry and Biochemistry at the Ruhr University Bochum in Germany has developed a complex that accumulates in tumor tissue and is activated there by ultrasound.
Therefore, its cell-damaging effects are exerted only where it is actually needed. We developed a treatment with ultrasonic activation that penetrates to a few centimeters,” says Karges. This may enable treatments with fewer side effects, even for large, deep-rooted tumors.
The researchers published their results in the journal Angewandte Chemie International Edition on March 24, 2023.
Harmless in healthy tissue
The platinum (II) complexes cisplatin, oxaliplatin, and carboplatin are among the most commonly used anticancer agents. Their clinical success is offset by severe side effects such as nausea, vomiting, renal damage and myelosuppression. To overcome these limitations, major research efforts have been invested in the development of so-called platinum(IV) complex prodrugs over the past decades. “These prodrugs are stable, inactive and therefore completely harmless,” explains Johannes Karges. “In healthy tissue, they should be intact. In cancer tissue, however, they should be rapidly transformed into therapeutically active platinum(II) complexes.”
Energy is required for the reduction of metal complexes. Previous studies have reported activation by ultraviolet, blue or red light. “The problem is that light can only penetrate less than 1 cm deep in the body, so it doesn’t reach many tumors,” explains Johannes Karges. To overcome this limitation, his team for the first time combined a platinum (IV) complex prodrug with an acoustic sensitizer that can be selectively activated by ultrasound irradiation.
Nanoparticles accumulate in tumors
To develop therapeutically active conjugates, researchers encapsulated platinum(IV) conjugate prodrugs and acoustic sensitizers together in hemoglobin to form nanoparticles. “We were able to observe that nanoparticles selectively accumulated in intestinal tumors in mice after injection into the bloodstream, supporting targeted therapy,” reports Johannes Karges. “After ultrasound, the platinum(IV) prodrug was activated at the tumor site, causing the release of cisplatin, which is toxic to cells, and almost completely eradicated the tumor.”
Advantages of ultrasound
These results may pave the way for the development of new techniques and drugs to treat very large or deep-rooted tumors. Ultrasound can penetrate tissue more than an order of magnitude deeper than near-infrared light. In addition, ultrasound therapy is generally considered minimally invasive and easy to use. Another advantage is that hospitals usually already have the necessary equipment. “Our work is still basic research,” he emphasizes Johannes Karges. “It is not yet foreseeable if and when treatments based on this will be available in clinical settings.”
Original: Activate anticancer drugs with ultrasound
Than: Ruhr University Bochum
