Transarterial chemoembolization (TACE) has been widely used for hepatocellular carcinoma. Reducing hypoxia in the tumor microenvironment after TACE remains a challenge as tumor progression is common in post-TACE patients due to the hypoxic tumor microenvironment. In this study, melatonin loaded on p(N-isopropyl-acrylamide-co-butyl methylacrylate) (PIB-M) was used for tumor embolism. Two types of human hepatoma cell lines were used to explore the mechanism by which melatonin prevents the growth and metastasis of cancer cells in vitro. A VX2 rabbit tumor model was used to evaluate the efficacy, mechanism, and safety of PIB-M in vivo. We found that under hypoxic condition, melatonin could inhibit tumor cell proliferation and migration by targeting hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (VEGF-A) in vitro. In vivo, PIB-M inhibited tumor growth and metastasis in rabbit VX2 tumors by promoting apoptosis of tumor cells and targeting related angiogenic proteins and vascular permeability proteins. A high concentration of melatonin in the PIB-M group could be maintained in tumor tissue for 72 h after embolization. The liver and kidney functions were most damaged on the first day but recovered to normal on the seventh day after embolization in the PIB-M group. This novel method may open avenues for reduction of tumor growth and metastasis after TACE and is efficacy and safety, which may be used for treatment for other solid tumors and clinical translation.

中文翻译：

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负载褪黑激素的热敏纳米凝胶用于兔 VX2 肿瘤栓塞的功效、机制和安全性：一种新颖的设计

经动脉化疗栓塞术（TACE）已广泛用于肝细胞癌的治疗。减少 TACE 后肿瘤微环境中的缺氧仍然是一个挑战，因为由于缺氧的肿瘤微环境，肿瘤进展在 TACE 后患者中很常见。在这项研究中，负载褪黑激素的对（N-异丙基丙烯酰胺-甲基丙烯酸丁酯）（PIB-M）被用于肿瘤栓塞。使用两种类型的人肝癌细胞系来探索褪黑素在体外阻止癌细胞生长和转移的机制。使用VX2兔肿瘤模型来评估PIB-M的体内功效、机制和安全性。我们发现，在体外缺氧条件下，褪黑素可以通过靶向缺氧诱导因子1α（HIF-1α）和血管内皮生长因子A（VEGF-A）来抑制肿瘤细胞的增殖和迁移。在体内，PIB-M通过促进肿瘤细胞凋亡并靶向相关血管生成蛋白和血管通透性蛋白来抑制兔VX2肿瘤的肿瘤生长和转移。PIB-M组栓塞后肿瘤组织中褪黑素浓度可维持72 h。PIB-M组栓塞后第1天肝肾功能受损最严重，第7天恢复正常。这种新方法可能为减少TACE后肿瘤生长和转移开辟途径，且有效且安全，可用于其他实体瘤的治疗和临床转化。