Schiff-Base Cross-Linked Poly(2-oxazoline) Micelle Drug Conjugates Possess Antiferroptosis Activity in Numerous In Vitro Cell Models

Abstract

A great deal of nanocarriers have been applied to induce ferroptosis in cancer research, yet there are limited examples of nanocarrier formulations to rescue ferroptosis, which can be applied to neurodegeneration, inflammation, liver damage, kidney disease, and more. Here, we present the synthesis, characterization, and in vitro evaluation of pH-responsive, core-cross-linked micelle (CCM) ferrostatin-1 (Fer-1) conjugates with amine, valproic acid, and biotin surface chemistries. Fer-1 release from stable and defined CCM Fer-1 conjugates was quantified, highlighting the sustained release for 24 h. CCM Fer-1 conjugates demonstrated excellent ferroptosis rescue by their antilipid peroxidation activity in a diverse set of cell lines in vitro. Additionally, CCMs showed tunable cell association in SH-SY5Y and translocation across an in vitro blood–brain barrier (BBB) model, highlighting potential brain disease applications. Overall, here, we present a polymeric Fer-1 delivery system to enhance Fer-1 action, which could help in improving Fer-1 action in the treatment of ferroptosis-related diseases.

Biotin-Initiated Poly(oxazoline)s

“…Single biotin molecules have been previously added onto P(Ox) scaffolds through postpolymerization click chemistry at the initiator or side chain positions, or through postpolymerization carbodiimide chemistry at the terminal ends (Figure B). − These approaches are disadvantageous because they introduce biotin at subquantitative yields (66%), are slow (48 h), require an additional step, and/or lack stoichiometric control. Installing biotin in a controlled and efficient manner would increase the utility and accessibility of biotinylated P(Ox)s. A more reliable and efficient approach would be to introduce biotin as either an electrophilic initiator or a nucleophilic terminator.…”