Tianjin Eye Hospital, Tianjin Key Laboratory of Ophthalmology and Visual Science, Nankai University Affiliated Eye Hospital, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, P. R. China.
Key Laboratory of Cancer Prevention and Therapy, The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, P. R. China.
Nano Lett. 2023 Aug 23;23(16):7665-7674. doi: 10.1021/acs.nanolett.3c02362. Epub 2023 Aug 3.
Precise manipulation of cancer cell death by harnessing reactive oxygen species (ROS) is a promising strategy to defeat malignant tumors. However, it is quite difficult to produce active ROS with spatial precision and regulate their biological outcomes. We succeed here in selectively generating short-lived and lipid-reactive hydroxyl radicals (OH) adjacent to cancer cell membranes, successively eliciting lipid peroxidation and ferroptosis. DiFc-K-pY, a phosphorylated self-assembling precursor that consists of two branched Fc moieties and interacts specifically with epidermal growth factor receptor, can produce membrane-bound nanofibers and enrich ferrocene moieties on cancer cell membranes in response to alkaline phosphatase. Within the acidic tumor microenvironment, DiFc-K-pY nanofibers efficiently convert tumoral HO to active OH around the target cell membranes via Fenton-like reactions, leading to lipid peroxidation and ferroptosis with good cellular selectivity. Our strategy successfully prevents tumor progression with acceptable biocompatibility through intratumoral administration.
利用活性氧（ROS）精确操控癌细胞死亡是一种有前途的治疗恶性肿瘤的策略。然而，要在空间上精确产生活性 ROS 并调节其生物学效应仍然颇具挑战。在这里，我们成功地选择性地在癌细胞膜附近生成短寿命和脂反应性的羟基自由基（OH），从而引发脂质过氧化和铁死亡。DiFc-K-pY 是一种由两个分支 Fc 部分组成的磷酸化自组装前体，它可以特异性地与表皮生长因子受体相互作用，在碱性磷酸酶的作用下，它可以在细胞膜上生成膜结合的纳米纤维，并在癌细胞膜上富集二茂铁部分。在酸性肿瘤微环境中，DiFc-K-pY 纳米纤维通过类 Fenton 反应在靶细胞膜附近有效地将肿瘤 HO 高效转化为活性 OH，导致具有良好细胞选择性的脂质过氧化和铁死亡。我们的策略通过瘤内给药成功地实现了肿瘤进展的抑制，同时具有可接受的生物相容性。
