Department of Magnetic Resonance Imaging, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450002, P. R. China.
Key Laboratory for Functional Magnetic Resonance Imaging and Molecular Imaging of Henan Province, Zhengzhou 450002, P. R. China.
ACS Biomater Sci Eng. 2024 Oct 14;10(10):6352-6362. doi: 10.1021/acsbiomaterials.4c01233. Epub 2024 Sep 12.
Ferroptosis is an appealing cancer therapy strategy based on the HO-involved Fenton reaction to produce toxic OH for lipid peroxidation. However, intracellular HO is easily consumed and results in a deficient Fenton reaction. This obstacle can be overcome by traditional chemotherapeutic drugs for HO supplements. Moreover, a recent work illustrated that dihydroartemisinin (DHA) could promote ferroptosis against tumoral cells, particularly in the presence of ferrous compounds. To achieve combined chemotherapy and ferroptosis, a nanocarrier (NP-Fc) was constructed by using thioketal (TK)-bridged paclitaxel prodrug (PEG-TK-PTX) and ferrocene (Fc)-conjugated PEG-Fc, where DHA was encapsulated by a hydrophobic-hydrophobic interaction. Upon cellular uptake, NP-Fc could facilitate PTX release through TK breakage under an excess HO microenvironment. Owing to the loss of the hydrophobic PTX component, NP-Fc underwent a rapid dissociation for improving DHA to act as a ferroptotic inducer along with Fe supplied from Fc. Moreover, both the chemotherapy-induced reactive oxygen species and the OH produced from reinforced ferroptosis further stimulated the TK cleavage. The "self-catalytic" loop of NP-Fc remarkably improved the antitumor performance in vivo via combined mechanisms, and its tumor inhibition rate reached 78.3%. This work highlights the contribution of ROS-responsive and self-catalytic nanoplatforms for enhancing the potential of combined chemotherapy and ferroptosis for cancer therapy in the future.
铁死亡是一种有吸引力的癌症治疗策略，基于涉及 HO 的芬顿反应产生有毒的 OH 以引发脂质过氧化。然而，细胞内的 HO 很容易被消耗，导致芬顿反应不足。这一障碍可以通过传统的化疗药物来补充 HO 来克服。此外，最近的一项工作表明，二氢青蒿素（DHA）可以在亚铁化合物存在的情况下促进肿瘤细胞的铁死亡。为了实现联合化疗和铁死亡，通过使用硫代缩酮（TK）桥连紫杉醇前药（PEG-TK-PTX）和二茂铁（Fc）修饰的聚乙二醇（PEG-Fc）构建了纳米载体（NP-Fc），其中 DHA 被疏水-疏水相互作用包封。在细胞摄取后，NP-Fc 可以在过量 HO 微环境下通过 TK 断裂促进 PTX 释放。由于疏水性 PTX 成分的损失，NP-Fc 迅速解离，以提高 DHA 作为铁死亡诱导剂的作用，并提供来自 Fc 的 Fe。此外，化疗诱导的活性氧和增强铁死亡产生的 OH 进一步刺激了 TK 切割。NP-Fc 的“自催化”循环通过联合机制显著提高了体内的抗肿瘤性能，其肿瘤抑制率达到 78.3%。这项工作强调了 ROS 响应和自催化纳米平台在增强联合化疗和铁死亡治疗癌症的潜力方面的贡献。
