Doxorubicin Intracellular Remote Release from Biocompatible Oligo(ethylene glycol) Methyl Ether Methacrylate-Based Magnetic Nanogels Triggered by Magnetic Hyperthermia

Abstract

Hybrid nanogels, composed of thermoresponsive polymers and superparamagnetic nanoparticles, are attractive nanocarriers for biomedical applications, being able-as a polymer matrix-to uptake and release high quantities of chemotherapeutic agents and-as magnetic nanoparticles-to be heated when exposed to an alternative magnetic field (AMF), better known as magnetic hyperthermia. Herein, biocompatible, pH-responsive, magnetoresponsive, and thermoresponsive nanogels, based on oligo(ethylene glycol) methyl ether methacrylate monomers and a methacrylic acid comonomer were prepared by conventional precipitation radical copolymerization in water, post-assembled by complexation with iron oxide magnetic nanoparticles (MNPs) of maghemite (γ-Fe₂O₃), and loaded with an anticancer drug (doxorubicin, DOX), for remotely controlled drug release by a "hot spot", as an athermal magnetic hyperthermia strategy against cancer. These nanogels, denoted MagNanoGels, with a hydrodynamic diameter from 328 to 460 nm, as a function of the MNP content, have a swelling-deswelling behavior at their volume phase temperature transition around 47 °C in a physiological medium (pH 7.5), which is above the human body temperature (37 °C). Applying an alternative magnetic field increases the release of DOX by 2-fold, while no macroscopic heating was recorded. This enhanced drug release is due to a shrinking of the polymer network by local heating, as illustrated by the MagNanoGel size decrease under an AMF. In cancer cells, not only do the DOX-MagNanoGels internalize DOX more efficiently than free DOX, but also DOX intracellular release can be remotely triggered under an AMF, in athermal conditions, thus enhancing DOX cytotoxicity.

Keywords: cancer therapy; magnetic hyperthermia; magnetic nanoparticles; oligo(ethylene glycol) methyl ether methacrylate nanogels; remote drug release.