Periodic Reporting for period 1 - RUPTURE (Selenium Containing Rupturing Dendritic Prodrugs for Therapeutic Applications)
Reporting period: 2023-02-01 to 2025-01-31
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.
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.
The RUPTURE project successfully facilitated the integration of Se into the skeleton of dendritic polymers. Various strategies were explored to incorporate Se in both diselenide and monoselenide forms into the dendritic structure. The results demonstrated excellent compatibility between Se incorporation and dendritic growth, highlighting the critical role of Se linkage selection in influencing the stability and biological performance of the dendrimers.
The family of Se-containing dendrimers developed in this project demonstrated remarkable dynamicity due to their redox responsiveness. Specifically, in tumor microenvironments, the concentration of glutathione (GSH) is several-fold higher than in normal cells. Additionally, intracellular GSH levels are approximately three orders of magnitude higher than those in the extracellular environment. Consequently, these systems act as targeting pro-drugs, with Se serving as the primary driver of selectivity. This specificity was validated through in vitro assessments, which demonstrated a marked preference for cancer cells over non-cancerous counterparts. Furthermore, these dendrimers exhibited a propensity for hydrolysis, a desirable feature from a biological perspective.
To further explore the potential of incorporating Se into dendritic structures, amphiphilic dendritic polymers containing Se were successfully developed. These constructs exhibited the ability to self-assemble in water into spherical micellar structures and selectively degrade under oxidative stress. This breakthrough opens a new avenue for designing smart, Se-based dendrimer carriers capable of selectively releasing therapeutic cargo in response to specific stimuli.
The family of Se-containing dendrimers developed in this project demonstrated remarkable dynamicity due to their redox responsiveness. Specifically, in tumor microenvironments, the concentration of glutathione (GSH) is several-fold higher than in normal cells. Additionally, intracellular GSH levels are approximately three orders of magnitude higher than those in the extracellular environment. Consequently, these systems act as targeting pro-drugs, with Se serving as the primary driver of selectivity. This specificity was validated through in vitro assessments, which demonstrated a marked preference for cancer cells over non-cancerous counterparts. Furthermore, these dendrimers exhibited a propensity for hydrolysis, a desirable feature from a biological perspective.
To further explore the potential of incorporating Se into dendritic structures, amphiphilic dendritic polymers containing Se were successfully developed. These constructs exhibited the ability to self-assemble in water into spherical micellar structures and selectively degrade under oxidative stress. This breakthrough opens a new avenue for designing smart, Se-based dendrimer carriers capable of selectively releasing therapeutic cargo in response to specific stimuli.
This project not only demonstrates the successful incorporation of Se into dendritic polymers but also its integration into supramolecular constructs such as micelles. Achieving these milestones required overcoming the significant challenges posed by selenium's inherently high reactivity and lack of stability, which have long limited its use in advanced materials. These breakthroughs open new possibilities in nanomedicine, where Se, historically regarded as a highly toxic element, could offer a solution to the lack of selectivity in current treatments. Furthermore, this work underscores the importance of advancing dendrimer research toward greater sophistication, enabling these platforms to evolve beyond simple carriers into versatile systems for delivering effective, targeted therapies.