Bioorthogonal Cascade-Targeting

Still, most drugs used for the conventional treatment of cancer are rather toxins than medicines. In too many cases, this leads to unacceptable poisoning of the patient and intolerable side effects at doses that remain insufficiently curative. Attaching highly potent drugs to so-called ligands, which can act as taxis inside the human body, allows for the development of strategies to shuttle the therapeutic agent to the site of disease. Antibodies that bind to specific targets on the surface of cancer cells have become the ligands of choice in recent years. This enabled the development of several antibody-drug conjugates now used in the clinic for the treatment of various malignant diseases. Nevertheless, due to the limited availability of ideal targets on cancer cells and the stringent requirements on the ligand, there are several complex factors impeding the design of optimized therapeutics. As we still cannot control how chemical compounds move in a cellular environment, a general strategy to achieve exclusive uptake of drugs into cancer cells has yet been out of reach. To engage this challenge, I propose the concept of cascade targeting to direct the delivery and activation of therapeutics in cancer cells with highest precision. To this end, we aim to develop chemical strategies that will enable us to achieve selective delivery and release of the active drug in cancer cells. These cascade processes will be controlled by a single chemical reaction that proceeds safely and efficiently under physiological conditions. We have recently discovered a new mechanism that allows us to choreograph such chemical reactions and control the order of events in a cellular environment. Thereby, cascade-targeting will enable us to selectively navigate compounds into cancer cells and achieve preprogrammed activation of the drug only where and when it is needed. In this project, we thus aim to open new ground by the development of chemical tools and unique strategies, ultimately to lay the foundation for multiple next-generation therapeutic approaches.