Ferroptosis is a form of non-apoptotic iron induced cell death mechanism implicated in neurodegeneration, yet can be ameliorated with potent radical scavengers such as ferrostatin-1 (Fer-1). Currently, Fer-1 suffers from low water solubility, poor biodistribution profile and is unsuitable for clinical application. Fer-1 polymer-drug conjugates (PDCs) for testing as an anti-ferroptosis therapeutic candidate have yet to be described. Here, we report the synthesis and characterization of a library of water-soluble Fer-1 based poly(2-oxazoline)-drug conjugates. The cationic ring opening polymerization (CROP) of water-soluble 2-oxazoline monomers, and a novel protected aromatic aldehyde 2-oxazoline (DPhOx), produced defined copolymers, which after deprotection were available for modification with Fer-1 via reductive amination and Schiff base chemistry. The conjugates were tested for their activity against RSL3-induced ferroptosis in vitro, and first structure-activity relationships were established. Irreversibly conjugated Fer-1 PDCs possessing an arylamine structural motif showed a greatly increased anti-ferroptosis activity compared to reversibly (Schiff base) linked Fer-1. Overall, this work introduces the first active ferrostatin-PDCs and a new highly tuneable poly(2-oxazoline)-based PDC platform, which provides access to next generation polymeric nanomaterials for anti-ferroptosis applications.

Ferroptosis 是一种与神经变性有关的非凋亡性铁诱导的细胞死亡机制，但可以通过有效的自由基清除剂如 ferrostatin-1 (Fer-1) 得到改善。目前，Fer-1具有水溶性低、生物分布差且不适合临床应用的问题。用于测试作为抗铁死亡治疗候选物的 Fer-1 聚合物-药物偶联物 (PDC) 尚未被描述。在这里，我们报告了基于水溶性 Fer-1 的聚 (2-恶唑啉)-药物偶联物库的合成和表征。水溶性 2-恶唑啉单体的阳离子开环聚合 (CROP) 和新型受保护的芳香醛 2-恶唑啉 (DPhOx) 产生了确定的共聚物，脱保护后可用于通过还原胺化和 Schiff 用 Fer-1 改性基础化学。在体外测试了缀合物对 RSL3 诱导的铁死亡的活性，并建立了第一个结构-活性关系。与可逆（希夫碱）连接的 Fer-1 相比，具有芳胺结构基序的不可逆缀合的 Fer-1 PDC 显示出显着增加的抗铁死亡活性。总的来说，这项工作介绍了第一个活性 ferrostatin-PDCs 和一个新的高度可调的基于聚（2-恶唑啉）的 PDC 平台，它为抗铁死亡应用提供了获得下一代聚合物纳米材料的途径。与可逆（希夫碱）连接的 Fer-1 相比，具有芳胺结构基序的不可逆缀合的 Fer-1 PDC 显示出显着增加的抗铁死亡活性。总的来说，这项工作介绍了第一个活性 ferrostatin-PDCs 和一个新的高度可调的基于聚（2-恶唑啉）的 PDC 平台，它为抗铁死亡应用提供了获得下一代聚合物纳米材料的途径。与可逆（希夫碱）连接的 Fer-1 相比，具有芳胺结构基序的不可逆缀合的 Fer-1 PDC 显示出显着增加的抗铁死亡活性。总的来说，这项工作介绍了第一个活性 ferrostatin-PDCs 和一个新的高度可调的基于聚（2-恶唑啉）的 PDC 平台，它为抗铁死亡应用提供了获得下一代聚合物纳米材料的途径。