An injectable and active hydrogel induces mutually enhanced mild magnetic hyperthermia and ferroptosis

Xiaobin Chen; Hancheng Wang; Jiayue Shi; Zhiyong Chen; Yaoben Wang; Siyi Gu; Ye Fu; Jiale Huang; Jiandong Ding; Lin Yu

doi:10.1016/j.biomaterials.2023.122139

An injectable and active hydrogel induces mutually enhanced mild magnetic hyperthermia and ferroptosis

Biomaterials. 2023 Jul:298:122139. doi: 10.1016/j.biomaterials.2023.122139. Epub 2023 Apr 27.

Authors

Xiaobin Chen¹, Hancheng Wang¹, Jiayue Shi¹, Zhiyong Chen¹, Yaoben Wang¹, Siyi Gu¹, Ye Fu¹, Jiale Huang¹, Jiandong Ding¹, Lin Yu²

Affiliations

¹ State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, 200438, China.
² State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, 200438, China. Electronic address: yu_lin@fudan.edu.cn.

PMID: 37148756
DOI: 10.1016/j.biomaterials.2023.122139

Abstract

Magnetic hyperthermia therapy (MHT) is a promising new modality to deal with solid tumors, yet the low magnetic-heat conversion efficacy, magnetic resonance imaging (MRI) artifacts, easy leakage of magnetic nanoparticles, and thermal resistance are the main obstacles to expand its clinical applications. Herein, a synergistic strategy based on a novel injectable magnetic and ferroptotic hydrogel is proposed to overcome these bottlenecks and boost the antitumor efficacy of MHT. The injectable hydrogel (AAGel) exhibiting a sol-gel transition upon heating is made of arachidonic acid (AA)-modified amphiphilic copolymers. Ferrimagnetic Zn_0.4Fe_2.6O₄ nanocubes with high-efficiency hysteresis loss mechanism are synthesized and co-loaded into AAGel with RSL3, a potent ferroptotic inducer. This system maintains the temperature-responsive sol-gel transition, and provides the capacity of multiple MHT and achieves accurate heating after a single injection owing to the firm anchoring and uniform dispersion of nanocubes in the gel matrix. The high magnetic-heat conversion efficacy of nanocubes coupled with the application of echo limiting effect avoids the MRI artifacts during MHT. Besides the function of magnetic heating, Zn_0.4Fe_2.6O₄ nanocubes combined with multiple MHT can sustain supply of redox-active iron to generate reactive oxygen species and lipid peroxides and accelerate the release of RLS3 from AAGel, thus enhancing the antitumor efficacy of ferroptosis. In turn, the reinforced ferroptosis can alleviate the MHT-triggered thermal resistance of tumors by impairment of the protective heat shock protein 70. The synergy strategy achieves the complete elimination of CT-26 tumors in mice without causing local tumor recurrence and other severe side effects.

Keywords: Ferroptosis; Hysteresis loss; Magnetic hyperthermia therapy (MHT); Multiple hyperthermia; Theranostics; Thermosensitive hydrogel.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Ferroptosis*
Hydrogels
Hyperthermia, Induced* / methods
Mice
Nanoparticles*
Neoplasms* / therapy

Substances

Hydrogels