Department of Nanobiotechnology, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran.
ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
BMC Complement Med Ther. 2024 Sep 20;24(1):337. doi: 10.1186/s12906-024-04631-x.
BACKGROUND: Drug combination therapy is preferred over monotherapy in clinical research to improve therapeutic effects. Developing a new nanodelivery system for cancer drugs can reduce side effects and provide several advantages, including matched pharmacokinetics and potential synergistic activity. This study aimed to examine and determine the efficiency of the gemini surfactants (GSs) as a pH-sensitive polymeric carrier and cell-penetrating agent in cancer cells to achieve dual drug delivery and synergistic effects of curcumin (Cur) combined with tamoxifen citrate (TMX) in the treatment of MCF-7 and MDA-MB-231 human BC cell lines. METHODS: The synthesized NPs were self-assembled using a modified nanoprecipitation method. The functional groups and crystalline form of the nanoformulation were examined by Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), differential scanning calorimetry (DSC), and dynamic light scattering (DLS) used to assess zeta potential and particle size, and the morphological analysis determined by transmission electron microscopy (TEM). The anticancer effect was evaluated through an in vitro cytotoxicity MTT assay, flow cytometry analysis, and apoptosis analysis performed for mechanism investigation. RESULTS: The tailored NPs were developed with a size of 252.3 ± 24.6 nm and zeta potential of 18.2 ± 4.4 mV capable of crossing the membrane of cancer cells. The drug loading and release efficacy assessment showed that the loading of TMX and Cur were 93.84% ± 1.95% and 90.18% ± 0.56%, respectively. In addition, the drug release was more controlled and slower than the free state. Polymeric nanocarriers improved controlled drug release 72.19 ± 2.72% of Tmx and 55.50 ± 2.86% of Cur were released from the Tmx-Cur-Gs NPs after 72 h at pH = 5.5. This confirms the positive effect of polymeric nanocarriers on the controlled drug release mechanism. moreover, the toxicity test showed that combination-drug delivery was much more greater than single-drug delivery in MCF-7 and MDA-MB-231 cell lines. Cellular imaging showed excellent internalization of TMX-Cur-GS NPs in both MCF-7 and MDA-MB-231 cells and synergistic anticancer effects, with combination indices of 0.561 and 0.353, respectively. CONCLUSION: The combined drug delivery system had a greater toxic effect on cell lines than single-drug delivery. The synergistic effect of TMX and Cur with decreasing inhibitory concentrations could be a more promising system for BC-targeted therapy using GS NPs.
背景：在临床研究中，药物联合治疗优于单药治疗，以提高治疗效果。开发新的癌症药物纳米递药系统可以降低副作用，并提供多种优势，包括匹配的药代动力学和潜在的协同活性。本研究旨在研究和确定双子表面活性剂（GSs）作为一种 pH 敏感的聚合物载体和细胞穿透剂在癌症细胞中的效率，以实现姜黄素（Cur）与他莫昔芬柠檬酸盐（TMX）联合治疗 MCF-7 和 MDA-MB-231 人乳腺癌细胞系的双重药物传递和协同作用。
方法：采用改良的纳米沉淀法自组装合成纳米粒子。傅里叶变换红外光谱（FTIR）、X 射线衍射（XRD）、差示扫描量热法（DSC）和动态光散射（DLS）用于评估纳米制剂的功能基团和晶体形态，用于评估 Zeta 电位和粒径的纳米制剂，通过透射电子显微镜（TEM）进行形态分析。通过体外细胞毒性 MTT 测定、流式细胞术分析和凋亡分析评估抗癌作用，以进行机制研究。
结果：定制的 NPs 具有 252.3±24.6nm 的尺寸和 18.2±4.4mV 的 zeta 电位，能够穿过癌细胞的膜。药物负载和释放效果评估表明，TMX 和 Cur 的负载分别为 93.84%±1.95%和 90.18%±0.56%。此外，药物释放比游离状态更受控和更慢。聚合物纳米载体提高了控释效果 72.19%±2.72%的 Tmx 和 55.50%±2.86%的 Cur 在 pH=5.5 时 72 小时后从 Tmx-Cur-Gs NPs 中释放出来。这证实了聚合物纳米载体对控释机制的积极影响。此外，毒性试验表明，在 MCF-7 和 MDA-MB-231 细胞系中，联合药物递送比单一药物递送的毒性更大。细胞成像显示 TMX-Cur-GS NPs 在 MCF-7 和 MDA-MB-231 细胞中均具有优异的内化作用，并具有协同抗癌作用，其组合指数分别为 0.561 和 0.353。
结论：联合药物递送系统对细胞系的毒性作用大于单一药物递送。TMX 和 Cur 联合使用，抑制浓度降低，可能是一种更有前途的 GS NPs 靶向乳腺癌治疗系统。
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