Yu Wenqi, Lin Ruyi, He Xueqin, Yang Xiaotong, Zhang Huilin, Hu Chuan, Liu Rui, Huang Yuan, Qin Yi, Gao Huile
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
Department of Orthopedics, Zhuhai Hospital, Jinan University, Zhuhai People's Hospital, Guangdong 519000, China.
Acta Pharm Sin B. 2021 Sep;11(9):2924-2936. doi: 10.1016/j.apsb.2021.04.006. Epub 2021 Apr 13.
Solid tumors always exhibit local hypoxia, resulting in the high metastasis and inertness to chemotherapy. Reconstruction of hypoxic tumor microenvironment (TME) is considered a potential therapy compared to directly killing tumor cells. However, the insufficient oxygen delivery to deep tumor and the confronting "Warburg effect" compromise the efficacy of hypoxia alleviation. Herein, we construct a cascade enzyme-powered nanomotor (NM-si), which can simultaneously provide sufficient oxygen in deep tumor and inhibit the aerobic glycolysis to potentiate anti-metastasis in chemotherapy. Catalase (Cat) and glucose oxidase (GOx) are co-adsorbed on our previously reported CAuNCs@HA to form self-propelled nanomotor (NM), with hexokinase-2 (HK-2) siRNA further condensed (NM-si). The persistent production of oxygen bubbles from the cascade enzymatic reaction propels NM-si to move forward autonomously and in a controllable direction along HO gradient towards deep tumor, with hypoxia successfully alleviated in the meantime. The autonomous movement also facilitates NM-si with lysosome escaping for efficient HK-2 knockdown to inhibit glycolysis. results demonstrated a promising anti-metastasis effect of commercially available albumin-bound paclitaxel (PTX@HSA) after pre-treated with NM-si for TME reconstruction. This cascade enzyme-powered nanomotor provides a potential prospect in reversing the hypoxic TME and metabolic pathway for reinforced anti-metastasis of chemotherapy.
实体瘤总是表现出局部缺氧，导致高转移率和对化疗的惰性。与直接杀死肿瘤细胞相比，重建缺氧肿瘤微环境（TME）被认为是一种潜在的治疗方法。然而，向深部肿瘤输送氧气不足以及与之对抗的“瓦伯格效应”削弱了缺氧缓解的效果。在此，我们构建了一种级联酶驱动的纳米马达（NM-si），它可以同时在深部肿瘤中提供足够的氧气并抑制有氧糖酵解，以增强化疗中的抗转移作用。过氧化氢酶（Cat）和葡萄糖氧化酶（GOx）共吸附在我们先前报道的CAuNCs@HA上形成自驱动纳米马达（NM），并进一步浓缩六磷酸果糖激酶-2（HK-2）小干扰RNA（NM-si）。级联酶促反应持续产生的氧气泡推动NM-si自主且可控地沿HO梯度向深部肿瘤移动，同时成功缓解缺氧。自主运动还促进NM-si逃逸出溶酶体，以有效敲低HK-2从而抑制糖酵解。结果表明，用NM-si预处理以重建TME后，市售的白蛋白结合紫杉醇（PTX@HSA）具有良好的抗转移效果。这种级联酶驱动的纳米马达在逆转缺氧TME和代谢途径以增强化疗的抗转移作用方面提供了潜在的前景。
