Increased expression of Hypoxia-inducible factor-1α (HIF-1α) in the tumor microenvironment, mainly due to tumor growth, plays a major role in the growth of cancer. Tumor cells induce the expression of cyclooxygenase 2 (COX2) and its product, prostaglandin E2 (PGE2), through overexpression of HIF-1α. It has been shown that ligation of PGE2 with its receptor, EP4, robustly promotes cancer progression. HIF-1α/COX2/PGE2/EP4 signaling pathways appear to play an important role in tumor growth. Therefore, we decided to block the expansion of cancer cells by blocking the initiator (HIF-1α) and end (EP4) of this pathway. In this study, we used hyaluronate (HA), and trimethyl chitosan (TMC) recoated superparamagnetic iron oxide nanoparticles (SPIONs) loaded with HIF-1α-silencing siRNA and the EP4 antagonist (E7046) to treat cancer cells and assessed the effect of combination therapy on cancer progression. The results showed that optimum physicochemical characteristics of NPs (size 126.9 nm, zeta potential 27 mV, PDI < 0.2) and linkage of HA with CD44 molecules overexpressed on cancer cells could deliver siRNAs to cancer cells and significantly suppress the HIF-1α in them. Combination therapy of cancer cells by using HIF-1α siRNA-loaded SPION-TMC-HA NPs and E7046 also prevent proliferation, migration, invasion, angiogenesis, and colony formation of the cancer cells, remarkably.

缺氧诱导因子-1α（HIF-1α）在肿瘤微环境中的表达增加，主要是由于肿瘤的生长，在癌症的生长中起主要作用。肿瘤细胞通过HIF-1α的过表达诱导环氧合酶2（COX2）及其产物前列腺素E2（PGE2）的表达。已经显示PGE2与其受体EP4的连接牢固地促进了癌症的发展。HIF-1α/ COX2 / PGE2 / EP4信号通路似乎在肿瘤生长中起重要作用。因此，我们决定通过阻断该途径的启动子（HIF-1α）和末端（EP4）来阻断癌细胞的扩增。在这项研究中，我们使用了透明质酸盐（HA），载有HIF-1α沉默siRNA和EP4拮抗剂（E7046）的三甲基壳聚糖（TMC）涂层超顺磁性氧化铁纳米颗粒（SPIONs）来治疗癌细胞并评估联合治疗对癌症进展的影响。结果表明，NPs（大小为126.9 nm，zeta电位为27 mV，PDI <0.2）的最佳理化特性以及HA与癌细胞上过表达的CD44分子的连接可以将siRNA递送至癌细胞并显着抑制其中的HIF-1α。通过使用加载了HIF-1αsiRNA的SPION-TMC-HA NP和E7046的癌细胞联合治疗还可以显着防止癌细胞的增殖，迁移，侵袭，血管生成和集落形成。结果表明，NPs（大小为126.9 nm，zeta电位为27 mV，PDI <0.2）的最佳理化特性以及HA与癌细胞上过表达的CD44分子的连接可以将siRNA递送至癌细胞并显着抑制其中的HIF-1α。通过使用加载了HIF-1αsiRNA的SPION-TMC-HA NP和E7046的癌细胞联合治疗还可以显着防止癌细胞的增殖，迁移，侵袭，血管生成和集落形成。结果表明，NPs（大小为126.9 nm，zeta电位为27 mV，PDI <0.2）的最佳理化特性以及HA与癌细胞上过表达的CD44分子的连接可以将siRNA递送至癌细胞并显着抑制其中的HIF-1α。通过使用加载了HIF-1αsiRNA的SPION-TMC-HA NP和E7046的癌细胞联合治疗还可以显着防止癌细胞的增殖，迁移，侵袭，血管生成和集落形成。