State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, 200438, China.
State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, 200438, China.
Biomaterials. 2023 Jul;298:122139. doi: 10.1016/j.biomaterials.2023.122139. Epub 2023 Apr 27.
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 ZnFeO 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, ZnFeO 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.
磁热疗（MHT）是一种有前途的治疗实体瘤的新方法，但低的磁热转换效率、磁共振成像（MRI）伪影、磁性纳米粒子易泄漏和热阻是限制其临床应用的主要障碍。在此，提出了一种基于新型可注射磁性和铁死亡水凝胶的协同策略，以克服这些瓶颈并提高 MHT 的抗肿瘤疗效。可注射水凝胶（AAGel）在加热时表现出溶胶-凝胶转变，由花生四烯酸（AA）修饰的两亲嵌段共聚物组成。合成了具有高效磁滞损耗机制的亚铁磁性 ZnFeO 纳米立方，并与强效铁死亡诱导剂 RSL3 共负载到 AAGel 中。该系统保持了温度响应的溶胶-凝胶转变，并提供了多次 MHT 的能力，并由于纳米立方在凝胶基质中的牢固锚定和均匀分散，在单次注射后即可实现精确加热。纳米立方的高磁热转换效率与回声限制效应的应用相结合，避免了 MHT 期间的 MRI 伪影。除了磁加热功能外，ZnFeO 纳米立方与多次 MHT 结合使用可以持续供应氧化还原活性铁以产生活性氧和脂质过氧化物，并加速 RLS3 从 AAGel 的释放，从而增强铁死亡的抗肿瘤疗效。反过来，增强的铁死亡通过损害保护性热休克蛋白 70 来减轻 MHT 引发的肿瘤热阻。协同策略使 CT-26 肿瘤在小鼠中完全消除，而不会导致局部肿瘤复发和其他严重的副作用。
