Shandong Provincial Key Laboratory of Detection Technology for Tumor Markers, College of Chemistry and Chemical Engineering, Linyi University, Shandong 276005, China.
Shandong Provincial Key Laboratory of Detection Technology for Tumor Markers, College of Life Science, Linyi University, Shandong 276005, China.
Acta Biomater. 2024 Aug;184:419-430. doi: 10.1016/j.actbio.2024.06.029. Epub 2024 Jun 25.
Traditional cancer chemotherapy suffers from low efficacy and severe side effects, limiting its use as a first-line treatment. To address this issue, we investigated a novel way to induce lipid peroxidation (LPO), which plays an essential role in ferroptosis and may be useful against cancer cells and tumors. In this study, a pH-responsive synergistic cancer therapy nanoplatform was prepared using CaCO co-loaded with oleanolic acid (OA) and lipoxygenase (LOX), resulting in the formation OLCaP NP. This nanoplatform exhibited good drug release properties in an acidic tumor environment owing to the presence of CaCO. As a result of acidic stimulation at tumor sites, the OLCaP NP released OA and LOX. OA, a chemotherapeutic drug with anticancer activity, is already known to promote the apoptosis of cancer cells, and LOX is a natural enzyme that catalyzes the oxidation of polyunsaturated fatty acids, leading to the accumulation of lipid peroxides and promoting the apoptosis of cancer cells. More importantly, OA upregulated the expression of acyl-coenzyme A synthetase long-chain family member 4 (ACSL4), which promoted enzyme-mediated LPO. Based on our combined chemotherapy and nanocatalytic therapy, the OLCaP NP not only had remarkable antitumor ability but also upregulated ACSL4 expression, allowing further amplification of LPO to inhibit tumor growth. These findings demonstrate the potential of this nanoplatform to enhance the therapeutic efficacy against tumors by inducing oxidative stress and disrupting lipid metabolism, highlighting its clinical potential for improved cancer treatment. STATEMENT OF SIGNIFICANCE: This study presents a novel nanoplatform that combines oleanolic acid (OA), a chemotherapeutic drug, and lipoxygenase (LOX), which oxidizes polyunsaturated fatty acids to trigger apoptosis, for targeted cancer therapy. Unlike traditional treatments, our nanoplatform exhibits pH-responsive drug release, specifically in acidic tumor environments. This innovation enhances the therapeutic effects of OA and LOX, upregulating acyl-CoA synthetase long-chain family member 4 expression and amplifying lipid peroxidation to promote tumor cell apoptosis. Our findings significantly advance the existing literature by demonstrating a synergistic approach that combines chemotherapy and nanocatalytic therapy. The scientific impact of this work lies in its potential to improve cancer treatment efficacy and specificity, offering a promising strategy for clinical applications and future research in cancer therapy.
传统癌症化疗存在疗效低和副作用严重的问题，限制了其作为一线治疗的应用。为了解决这个问题，我们研究了一种诱导脂质过氧化（LPO）的新方法，LPO 在铁死亡中起关键作用，可能对癌细胞和肿瘤有效。在这项研究中，使用碳酸钙负载熊果酸（OA）和脂氧合酶（LOX）制备了一种 pH 响应协同癌症治疗纳米平台，形成了 OLCaP NP。由于存在碳酸钙，该纳米平台在酸性肿瘤环境中具有良好的药物释放性能。由于肿瘤部位的酸性刺激，OLCaP NP 释放 OA 和 LOX。OA 是一种具有抗癌活性的化疗药物，已知可促进癌细胞凋亡，LOX 是一种天然酶，可催化多不饱和脂肪酸的氧化，导致脂质过氧化物的积累，促进癌细胞凋亡。更重要的是，OA 上调了长链酰基辅酶 A 合成酶家族成员 4（ACSL4）的表达，促进了酶介导的 LPO。基于我们的联合化疗和纳米催化治疗，OLCaP NP 不仅具有显著的抗肿瘤能力，还上调了 ACSL4 的表达，进一步放大 LPO 以抑制肿瘤生长。这些发现表明，这种纳米平台通过诱导氧化应激和破坏脂质代谢来增强抗肿瘤能力，具有提高癌症治疗效果的临床潜力。意义声明：本研究提出了一种新型纳米平台，将化疗药物熊果酸（OA）和脂氧合酶（LOX）结合在一起，氧化多不饱和脂肪酸触发细胞凋亡，用于靶向癌症治疗。与传统治疗方法不同，我们的纳米平台在酸性肿瘤环境中具有 pH 响应性药物释放。这种创新增强了 OA 和 LOX 的治疗效果，上调了长链酰基辅酶 A 合成酶家族成员 4 的表达，并放大了脂质过氧化作用，促进肿瘤细胞凋亡。我们的研究结果通过展示一种结合化疗和纳米催化治疗的协同方法，显著推进了现有文献。这项工作的科学影响在于它有可能提高癌症治疗的疗效和特异性，为癌症治疗的临床应用和未来研究提供了有前途的策略。
