Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China; Clinical and Translational Research Center for 3D Printing Technology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai, 200438, China.
Biomaterials. 2021 Jan;268:120537. doi: 10.1016/j.biomaterials.2020.120537. Epub 2020 Nov 17.
Hypoxia has been firmly correlated to the drug resistance of solid tumors. Alleviation of hypoxia by tumor reoxygenation is expected to sensitize the chemotherapy toward solid tumors. Alternatively, ferroptosis provides a therapeutic strategy to overcome apoptotic resistance and multidrug resistance of solid tumors, collaboratively strengthening the chemotherapy toward hypoxic tumors. Herein, an ultrasound (US)-activatable nanomedicine was developed for overcoming hypoxia-induced resistance to chemotherapy and efficiently inhibiting tumor growth by inducing sensitized apoptosis and collaborative ferroptosis of tumor cells. This nanomedicine was constructed by integrating ferrate and doxorubicin into biocompatible hollow mesoporous silica nanoplatforms, followed by assembling a solid-liquid phase-change material of n-heneicosane. The US-induced mild hyperthermia initiates the phase change of n-heneicosane, enabling US-activated co-release of ferrate and doxorubicin. Results reveal that the released ferrate effectively reacts with water as well as the over-expressed hydrogen peroxide and glutathione in tumor cells, achieving tumor-microenvironment-independent reoxygenation and glutathione-depletion in tumors. The reoxygenation down-regulates expressions of hypoxia-inducible factor 1α and multidrug resistance gene/transporter P-glycoprotein in tumor cells, sensitizing the apoptosis-based doxorubicin chemotherapy. More importantly, exogenous iron metabolism from the nanomedicine initiates intracellular Fenton reactions, leading to reactive oxygen species overproduction and iron-dependent ferroptotic death of tumor cells. Furthermore, the glutathione-depletion inactivates the glutathione peroxidase 4 (GPX4, a critical regulatory target in ferroptosis), inhibiting the reduction of lipid peroxides and reinforcing the ferroptotic cell death. The sensitized chemotherapy together with the iron-dependent ferroptosis of tumor cells play a synergistic role in boosting the growth suppression of hypoxic osteosarcoma in vivo. Additionally, the nanomedicine acts as a nanoprobe for in vivo photoacoustic imaging and glutathione tracking, showing great potential as theranostic agents for hypoxic solid tumors treatment.
缺氧与实体瘤的耐药性密切相关。通过肿瘤再氧合缓解缺氧，有望使实体瘤对化疗更加敏感。另一方面，铁死亡为克服实体瘤的凋亡抵抗和多药耐药提供了一种治疗策略，共同增强了缺氧肿瘤的化疗效果。在此，开发了一种超声（US）激活的纳米药物，用于克服化疗诱导的缺氧耐药性，并通过诱导肿瘤细胞敏感的凋亡和协同铁死亡来有效抑制肿瘤生长。该纳米药物通过将高铁酸盐和阿霉素整合到生物相容性的中空介孔硅纳米平台中构建而成，然后组装固体-液相相变材料正二十一烷。US 诱导的温和热疗引发正二十一烷的相变，从而实现 US 激活的高铁酸盐和阿霉素的共释放。结果表明，释放的高铁酸盐有效地与水以及肿瘤细胞中过表达的过氧化氢和谷胱甘肽反应，实现肿瘤微环境独立的再氧合和肿瘤中谷胱甘肽的耗竭。再氧合下调肿瘤细胞中缺氧诱导因子 1α 和多药耐药基因/转运蛋白 P-糖蛋白的表达，使基于凋亡的阿霉素化疗更加敏感。更重要的是，纳米药物中的外源性铁代谢引发细胞内芬顿反应，导致活性氧过度产生和铁依赖性铁死亡细胞死亡。此外，谷胱甘肽耗竭使谷胱甘肽过氧化物酶 4（GPX4，铁死亡的关键调节靶点）失活，抑制脂质过氧化物的还原并加强铁死亡细胞死亡。敏感的化疗与肿瘤细胞的铁依赖性铁死亡协同作用，增强了体内缺氧骨肉瘤的生长抑制作用。此外，该纳米药物可作为体内光声成像和谷胱甘肽跟踪的纳米探针，为缺氧实体瘤治疗的治疗提供了巨大潜力。
