School of Chemistry and Chemical Engineering, Southeast University, Nanjing 214122, PR China.
School of Chemistry and Chemical Engineering, Southeast University, Nanjing 214122, PR China.
Int J Pharm. 2023 Apr 5;636:122822. doi: 10.1016/j.ijpharm.2023.122822. Epub 2023 Mar 12.
Chemodynamic therapy (CDT) has emerged as a powerful tumor treatment option by inducing the imbalance of redox homeostasis in cancer cells. Nevertheless, the therapeutic outcomes were greatly limited because of insufficient endogenous HO and upregulated cellular antioxidant defense in the tumor microenvironment (TME). Herein, a liposome-incorporated in-situ alginate hydrogel locoregional treatment strategy was developed, which involves using hemin-loaded artesunate dimer liposomes (HAD-LP) as redox-triggered self-amplified C-center free radical nanogenerator to enhance CDT. First, HAD-LP based on artesunate dimer glycerophosphocholine (ART-GPC) was prepared by a thin film method. Their spherical structure was manifested by dynamic light scattering (DLS) and transmission electron microscope (TEM). The generation of C-center free radicals from HAD-LP was carefully evaluated by using methylene blue (MB) degradation method. The results suggested that the hemin was reduced to heme under the action of glutathione (GSH), which could catalyze the breakage of endoperoxide of ART-GPC derived dihydroartemisinin (DHA) to generate toxic C-centered free radicals in a HO and pH-independent manner. Moreover, the change of intracellular GSH and free radical level was monitored through ultraviolet spectroscopy and confocal laser scanning microscope (CLSM). It was revealed that the hemin reduction induced GSH depletion and elevated free radical level, disrupting cellular redox homeostasis. After co-incubation with MDA-MB-231 or 4 T1 cells, HAD-LP was found to be highly cytotoxic. In order to prolong retention and improve antitumor efficacy, HAD-LP was mixed with alginate and injected intratumorally into 4 T1 tumor bearing mice. The injected HAD-LP and alginate mixture formed in-situ hydrogel and achieved best antitumor effect with the growth inhibition rate of 72.6%. Together, the hemin-loaded artesunate dimer liposome-incorporated alginate hydrogel possessed effective antitumor activity through redox-triggered C-center free radical generation induced apoptosis in a HO and pH-independent manner, which might be a promising candidate in the application of chemodynamic anti-tumor therapy.
化学动力学疗法（CDT）通过诱导癌细胞氧化还原平衡失调，已成为一种强大的肿瘤治疗选择。然而，由于肿瘤微环境（TME）中内源性 HO 不足和细胞抗氧化防御上调，治疗效果受到了极大限制。在此，开发了一种基于脂质体包载的海藻酸钠水凝胶局部治疗策略，该策略涉及使用载血红素青蒿琥酯二聚体脂质体（HAD-LP）作为氧化还原触发的自扩增 C 中心自由基纳米发生器来增强 CDT。首先，通过薄膜法制备了基于青蒿琥酯二聚体甘油磷酸胆碱（ART-GPC）的 HAD-LP。其球形结构通过动态光散射（DLS）和透射电子显微镜（TEM）得到体现。通过亚甲蓝（MB）降解法仔细评估了 HAD-LP 中 C 中心自由基的生成。结果表明，血红素在谷胱甘肽（GSH）的作用下还原为血红素，血红素可以在 HO 和 pH 独立的情况下，催化来源于 ART-GPC 的二氢青蒿素（DHA）的过氧化物环断裂，生成有毒的 C 中心自由基。此外，通过紫外光谱和共聚焦激光扫描显微镜（CLSM）监测细胞内 GSH 和自由基水平的变化。结果表明，血红素还原诱导 GSH 耗竭和自由基水平升高，破坏细胞氧化还原平衡。HAD-LP 与 MDA-MB-231 或 4T1 细胞共孵育后发现具有高细胞毒性。为了延长保留时间并提高抗肿瘤疗效，将 HAD-LP 与海藻酸钠混合并注射到荷 4T1 肿瘤的小鼠肿瘤内。注入的 HAD-LP 和海藻酸钠混合物形成原位水凝胶，并以 72.6%的肿瘤生长抑制率达到最佳抗肿瘤效果。总之，载血红素青蒿琥酯二聚体脂质体包载的海藻酸钠水凝胶通过氧化还原触发的 C 中心自由基生成诱导细胞凋亡，在 HO 和 pH 独立的情况下发挥有效的抗肿瘤活性，有望成为化学动力学抗肿瘤治疗的一种有前途的候选药物。
