Poly(2-oxazoline) - Ferrostatin-1 drug conjugates inhibit ferroptotic cell death

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 con-jugates. 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 pro-vides access to next generation polymeric nanomaterials for anti-ferroptosis applications.

Automated summary

This study reports the synthesis and characterization of water-soluble Fer-1 poly(2-oxazoline)-drug conjugates (PDCs) for anti-ferroptosis therapy. The conjugates showed improved anti-ferroptosis activity compared to reversible linked Fer-1. This work introduces the first active Fer-1 PDCs and a highly tuneable poly(2-oxazoline)-based PDC platform for anti-ferroptosis applications.