An and Logic Gate for Magnetic Resonance Imaging-Guided Ferroptosis Therapy of Tumors.

Abstract

To improve the magnetic resonance imaging (MRI) efficiency and ferroptosis therapy efficacy of exceedingly small magnetic iron oxide nanoparticles (IO, < 5nm) for tumors via enhancing the sensitivity of tumor microenvironment (TME) responsiveness, inspired by molecular logic gates, we designed and constructed a self-assembled IO with a AND logic gate function. Typically, cystamine (CA) was conjugated onto the end of poly(2-methylthio-ethanol methacrylate) (PMEMA) to generate PMEMA-CA. The PMEMA-CA was grafted onto the surface of brequinar (BQR)-loaded IO to form IO-BQR@PMEMA. The self-assembled IO-BQR@PMEMA (SA-IO-BQR@PMEMA) was obtained due to the hydrophobicity of PMEMA. The carbon-sulfur single bond of PMEMA-CA can be oxidized by the reactive oxygen species (ROS) in TME to thio-oxygen double bond, resulting in the conversion from being hydrophobic to hydrophilic. The disulfide bond of PMEMA-CA can be broken by the glutathione (GSH) in TME, leading to the shedding of PMEMA from the IO surface. Under the dual actions of ROS and GSH in TME (i.e., AND logic gate), SA-IO-BQR@PMEMA can be disassembled to release IO, Fe2+/3+ , and BQR. In vitro and in vivo results demonstrate the AND logic gate function and mechanism, the high T1 MRI performance and exceptional ferroptosis therapy efficacy for tumors, and the excellent biosafety of SA-IO-BQR@PMEMA. This article is protected by copyright. All rights reserved.