Key Laboratory of Tumor Immunological Prevention and Treatment, Department of Oncology, Yan'An Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650118, China.
Department of Chemistry, University of Zabol, Zabol, Iran.
Anticancer Agents Med Chem. 2024;24(13):1016-1028. doi: 10.2174/0118715206289666240423091244.
Although tamoxifen (TMX) belongs to selective estrogen receptor modulators (SERMs) and selectively binds to estrogen receptors, it affects other estrogen-producing tissues due to passive diffusion and non-differentiation of normal and cancerous cells and leads to side effects.
The problems expressed about tamoxifen (TMX) encouraged us to design a new drug delivery system based on magnetic nanoparticles (MNPs) to simultaneously target two receptors on cancer cells through folic acid (FA) and hyaluronic acid (HA) groups. The mediator of binding of two targeting agents to MNPs is a polymer linker, including dopamine, polyethylene glycol, and terminal amine (DPN).
Zeta potential, dynamic light scattering (DLS), and Field emission scanning electron microscopy (FESEM) methods confirmed that MNPs-DPN-HA-FA has a suitable size of ~105 nm and a surface charge of -41 mV, and therefore, it can be a suitable option for carrying TMX and increasing its solubility. The cytotoxic test showed that the highest concentration of MNPs-DPN-HA-FA-TMX decreased cell viability to about 11% after 72 h of exposure compared to the control. While the protective effect of modified MNPs on normal cells was evident, unlike tamoxifen, the survival rate of liver cells, even after 180 min of treatment, was not significantly different from the control group. The protective effect of MNPs was also confirmed by examining the amount of malondialdehyde, and no significant difference was observed in the amount of lipid peroxidation caused by modified MNPs compared to the control. Flow cytometry proved that TMX loaded onto modified MNPs can induce apoptosis by targeting the overexpressed receptors on cancer cells. Real-time PCR showed that the modified MNPs activated the intrinsic and extrinsic mitochondrial pathways of apoptosis, so the Bak1/Bclx ratio for MNPs-DPN-HAFA- TMX and free TMX was 70.82 and 0.38, respectively. Also, the expression of the caspase-3 gene increased 430 times compared to the control. On the other hand, only TNF gene expression, which is responsible for metastasis in some tumors, was decreased by both free TMX and MNPs-DPN-HA-FA-TMX. Finally, molecular docking proved that MNPs-DPN-HA-FA-TMX could provide a very stable interaction with both CD44 and folate receptors, induce apoptosis in cancer cells, and reduce hepatotoxicity.
All the results showed that MNPs-DPN-HA-FA-TMX can show good affinity to cancer cells using targeting agents and induce apoptosis in metastatic breast ductal carcinoma T-47D cell lines. Also, the protective effects of MNPs on hepatocytes are quite evident, and they can reduce the side effects of TMX.
虽然他莫昔芬（TMX）属于选择性雌激素受体调节剂（SERMs），并选择性地与雌激素受体结合，但由于正常和癌细胞的被动扩散和非分化，它会影响其他产生雌激素的组织，从而导致副作用。
关于他莫昔芬（TMX）的问题促使我们设计了一种基于磁性纳米粒子（MNPs）的新药物输送系统，通过叶酸（FA）和透明质酸（HA）基团同时靶向癌细胞上的两个受体。两种靶向剂与 MNPs 结合的介质是聚合物连接子，包括多巴胺、聚乙二醇和末端胺（DPN）。
Zeta 电位、动态光散射（DLS）和场发射扫描电子显微镜（FESEM）方法证实，MNPs-DPN-HA-FA 具有约 105nm 的合适尺寸和-41mV 的表面电荷，因此可以作为携带 TMX 并增加其溶解度的合适选择。细胞毒性试验表明，与对照组相比，暴露 72 小时后，MNPs-DPN-HA-FA-TMX 的最高浓度将细胞活力降低至约 11%。虽然修饰后的 MNPs 对正常细胞的保护作用明显，但与他莫昔芬不同，即使经过 180 分钟的治疗，肝细胞的存活率与对照组相比没有显著差异。还通过检查丙二醛的量来证实 MNPs 的保护作用，与对照组相比，修饰后的 MNPs 引起的脂质过氧化量没有明显差异。流式细胞术证明，载有 TMX 的修饰 MNPs 可以通过靶向癌细胞上过表达的受体诱导细胞凋亡。实时 PCR 显示，修饰的 MNPs 激活了细胞凋亡的内在和外在线粒体途径，因此 MNPs-DPN-HA-FA-TMX 和游离 TMX 的 Bak1/Bclx 比值分别为 70.82 和 0.38。此外，与对照组相比，caspase-3 基因的表达增加了 430 倍。另一方面，只有 TNF 基因的表达，它负责一些肿瘤的转移，被游离的 TMX 和 MNPs-DPN-HA-FA-TMX 降低。最后，分子对接证明 MNPs-DPN-HA-FA-TMX 可以与 CD44 和叶酸受体提供非常稳定的相互作用，诱导癌细胞凋亡，并降低肝毒性。
所有结果表明，MNPs-DPN-HA-FA-TMX 可以使用靶向剂与癌细胞表现出良好的亲和力，并诱导转移性乳腺导管癌 T-47D 细胞系细胞凋亡。此外，MNPs 对肝细胞的保护作用非常明显，它们可以降低 TMX 的副作用。
