Cancer remains one of the leading causes of death globally, with 20 million new cases diagnosed in 2022. Currently, standard cancer treatments typically involve a combination of surgery, radiation therapy, and the use of anti-cancer drugs in chemotherapy. One of the major limitations of traditional small-molecule chemotherapeutics is their lack of selectivity for cancer cells, which often leads to severe side effects. These issues have driven increased efforts to develop more selective and innovative alternatives to address these challenges. In this context, nanomedicine, with a particular focus on polymer therapeutics, has emerged as a groundbreaking and rapidly advancing field of research. Among all polymeric nanocarriers, dendrimers stand out as the most precise polymer constructs for delivering exact payloads of active drugs with the capability of accumulating effectively in tumor environments due to the enhanced permeability and retention (EPR) effect. Despite their versatility, dendritic macromolecules are predominantly employed as carriers for therapeutic cargoes in most studies, with limited attention given to harnessing their unique structural features for more sophisticated applications. This highlights a growing need for innovative designs that fully exploit the intrinsic structural potential of these systems.
In order to provide dendrimers with inherent anticancer potential as well as dynamicity, selenium (Se) has been the focus of the RUPTURE project. As a trace element, Se is crucial for maintaining various bodily functions, playing a key role in the activity of Se-dependent enzymes that help maintain redox balance in cells and prevent severe diseases. Driven by the remarkable biological activity of Se, organic Se chemistry has progressed rapidly, leading to the development of numerous organoselenium compounds with promising anti-cancer properties. One such compound, ethaselen, has advanced to phase 1c of clinical trials (NCT02166242) for the treatment of non-small cell lung cancer. However, the incorporation of Se into polymers has been a significant challenge due to the inherent instability and high reactivity of Se-derived compounds. This difficulty is even more pronounced in dendrimers, where structural perfection is paramount.
The main objective of RUPTURE is to overcome this challenge and reduce the current toxicity associated with cancer treatments, by developing a new generation of biodegradable dendritic prodrugs in which Se functionalities are embedded as dormant species which intracellularly collapse and influence the cellular redox state leading to cell death.
