Responsive Organoselenium Dendritic Polymers: From Monodisperse Dendrimers to Self-Assembled Micelles for Advanced Therapeutic Applications

Selenium (Se) is a highly biologically active element, and its organic derivatives have attracted growing interest for their promising chemotherapeutic potential, largely due to their redox-modulating activity, which selectively affects cancer cells with high levels of reactive oxygen species (ROS). However, their high reactivity and susceptibility to spontaneous degradation limit their biomedical application. To harness their potential in the realm of nanomedicine, we present a new generation of therapeutically promising polymers that combine Se with 2,2-bis(methylol)propionic acid (bis-MPA)-based dendritic polymers, chosen for their high chemical versatility, low toxicity, and excellent biodegradability. Most examples in the literature about dendritic polymers feature dormant dendritic skeletons with active functional groups expressed only on their periphery, which severely limits their functional scope. In this work, monodisperse dendrimers and linear-dendritic (LD) polymers up to the third generation were developed, with the latter capable of self-assembling into dendritic micelles (∼20 nm). These systems feature Se at the dendritic core or peripheral branches in the form of monoselenide or diselenide bridges. Selenium incorporation demonstrated excellent compatibility with two key polyester synthetic approaches: anhydride chemistry and fluoride-promoted esterification (FPE). Both monoselenide and diselenide linkages introduced degradability and dynamic behavior in dendrimers and dendritic micelles. However, their biological activities differed significantly. Diselenide-containing dendrimers exhibited great anticancer potential against breast cancer cell lines, with IC₅₀ values in the micromolar range. Among these, first-generation Se dendrimers stood out due to their promising selectivity toward cancer cells. In contrast, dendritic polymers incorporating monoselenides retained the high biocompatibility characteristics of bis-MPA dendritic constructs.