Sanz Del Olmo Natalia, San Jacinto García Jorge, Yin Yikai, Zhao Ying, Hassan Moustapha, Malkoch Michael
Department of Fibre and Polymer Technology, KTH Royal Institute of Technology, Teknikringen 56-68, 100 44 Stockholm, Sweden.
Department of Laboratory Medicine, Experimental Cancer Medicine (ECM), Karolinska Institute, Center of Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden.
J Am Chem Soc. 2025 Jun 4;147(22):18626-18636. doi: 10.1021/jacs.5c00811. Epub 2025 May 23.
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 IC 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.
硒（Se）是一种具有高度生物活性的元素，其有机衍生物因其具有广阔的化疗潜力而越来越受到关注，这主要归功于它们的氧化还原调节活性，这种活性能够选择性地影响具有高水平活性氧（ROS）的癌细胞。然而，它们的高反应性和易自发降解的特性限制了它们在生物医学领域的应用。为了在纳米医学领域发挥它们的潜力，我们展示了新一代具有治疗前景的聚合物，这些聚合物将硒与基于2,2-双（羟甲基）丙酸（双-MPA）的树枝状聚合物相结合，选择双-MPA是因为其具有高化学通用性、低毒性和优异的生物降解性。文献中关于树枝状聚合物的大多数例子都具有休眠的树枝状骨架结构且活性官能团仅在其外围表达出来，这严重限制了它们的功能范围。在这项工作中，我们开发了单分散的树枝状聚合物和第三代以内的线性-树枝状（LD）聚合物，后者能够自组装成树枝状胶束（约20纳米）。这些体系在树枝状核心或外围分支处以单硒化物或二硒化物桥的形式含有硒。硒的引入证明了与两种关键的聚酯合成方法具有出色的兼容性：酸酐化学法和氟化物促进的酯化反应（FPE）。单硒化物和二硒化物键都在树枝状聚合物和树枝状胶束中引入了可降解性和动态行为。然而，它们的生物活性有显著差异。含二硒化物的树枝状聚合物对乳腺癌细胞系表现出巨大的抗癌潜力，其半数抑制浓度（IC）值在微摩尔范围内。其中，第一代含硒树枝状聚合物因其对癌细胞具有良好的选择性而脱颖而出。相比之下，含有单硒化物的树枝状聚合物保留了双-MPA树枝状结构的高生物相容性特征。
